Steven P. Cohen, MD; Ronald L. White, MD; Connie Kurihara, RN; Thomas M. Larkin, MD; Audrey Chang, PhD; Scott R. Griffith, MD; Christopher Gilligan, MD; Ralph Larkin, PhD; Benny Morlando, RN; Paul F. Pasquina, MD; Tony L. Yaksh, PhD; Conner Nguyen, MD
Disclaimer: The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.
Acknowledgment: The authors thank Drs. Robin Howard, Hui Zheng, Shruti Kapoor for their statistical assistance and Ms. Shari Brownlee for constructing the figure.
Grant Support: Funded in part by a Congressional Grant from the John P. Murtha Neuroscience and Pain Institute, the International Spinal Intervention Society, and the Center for Rehabilitation Sciences Research.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-1654.
Reproducible Research Statement:Study protocol: Available from Dr. Cohen (e-mail, mailto:firstname.lastname@example.org). Statistical code: Available from Dr. Chang (e-mail, mailto:email@example.com). Data set: Available from Dr. Cohen (e-mail, mailto:firstname.lastname@example.org) per approval from the U.S. Army and Walter Reed National Military Medical Center.
Requests for Single Reprints: Steven P. Cohen, MD, 550 North Broadway, Suite 301, Baltimore, MD 21029; e-mail, mailto:email@example.com.
Current Author Addresses: Dr. Cohen: 550 North Broadway, Suite 301, Baltimore, MD 21029.
Dr. White: Landstuhl Regional Medical Center, CMR 401, Box 1251, APO AE 09180.
Ms. Kurihara, Dr. Griffith, and Mr. Morlando: Walter Reed National Military Medical Center, Pain Treatment Center, 8901 Wisconsin Avenue, Bethesda, MD 20889.
Dr. T.M. Larkin: Parkway Neuroscience and Spine Institute, 17 Western Maryland Parkway, Hagerstown, MD 21740.
Dr. Chang: Walter Reed National Military Medical Center, Department of Clinical Investigation, Building 17, Bethesda, MD 20889.
Dr. Gilligan: Massachusetts General Hospital, Massachusetts General Hospital Pain Center, Wang Room 330, 15 Parkman Street, Boston, MA 02114.
Dr. R. Larkin: 400 2nd Avenue, 12-D, New York, NY 10010.
Dr. Pasquina: 4325 Rosedale Avenue, Bethesda, MD 20814.
Dr. Yaksh: Department of Anesthesiology, University of California, San Diego, Anesthesia Research Laboratory 0818, 9500 Gilman Drive (CTF-C 312), La Jolla, CA 92093.
Dr. Nguyen: Landstuhl Regional Medical Center, CMR 402, APO AE 09180.
Author Contributions: Conception and design: S.P. Cohen.
Analysis and interpretation of the data: S.P. Cohen, A. Chang, R. Larkin.
Drafting of the article: S.P. Cohen, A. Chang.
Critical revision of the article for important intellectual content: R.L. White, T.M. Larkin, C. Gilligan, T.L. Yaksh.
Final approval of the article: S.P. Cohen, R.L. White, C. Kurihara, T.M. Larkin, A. Chang, S.R. Griffith, C. Gilligan, R. Larkin, B. Morlando, P.F. Pasquina, T.L. Yaksh, C. Nguyen.
Provision of study materials or patients: S.P. Cohen, R.L. White, C. Kurihara, T.M. Larkin, S.R. Griffith, C. Nguyen.
Statistical expertise: A. Chang, R. Larkin.
Obtaining of funding: P.F. Pasquina, T.L. Yaksh.
Administrative, technical, or logistic support: C. Kurihara, T.M. Larkin, C. Gilligan, B. Morlando, C. Nguyen.
Collection and assembly of data: S.P. Cohen, R.L. White, C. Kurihara.
Cohen S., White R., Kurihara C., Larkin T., Chang A., Griffith S., Gilligan C., Larkin R., Morlando B., Pasquina P., Yaksh T., Nguyen C.; Epidural Steroids, Etanercept, or Saline in Subacute Sciatica: A Multicenter, Randomized Trial. Ann Intern Med. 2012;156:551-559. doi: 10.7326/0003-4819-156-8-201204170-00397
Download citation file:
Published: Ann Intern Med. 2012;156(8):551-559.
Perineural inhibitors of tumor necrosis factor have recently generated intense interest as an alternative to epidural steroid injections for lumbosacral radiculopathy.
To evaluate whether epidural steroids, etanercept, or saline better improves pain and function in adults with lumbosacral radiculopathy.
A multicenter, 3-group, randomized, placebo-controlled trial conducted from 2008 to 2011. Randomization was computer-generated and stratified by site. Pharmacists prepared the syringes. Patients, treating physicians, and nurses assessing outcomes were blinded to treatment assignment. (ClinicalTrials.gov registration number: NCT00733096)
Military and civilian treatment centers.
84 adults with lumbosacral radiculopathy of less than 6 months' duration.
2 epidural injections of steroids, etanercept, or saline, mixed with bupivacaine and separated by 2 weeks.
The primary outcome measure was leg pain 1 month after the second injection. All patients had 1-month follow-up visits; patients whose condition improved remained blinded for the 6-month study period.
The group that received epidural steroids had greater reductions in the primary outcome measure than those who received saline (mean difference, −1.26 [95% CI, −2.79 to 0.27]; P = 0.11) or etanercept (mean difference, −1.01 [CI, −2.60 to 0.58]; P = 0.21). For back pain, smaller differences favoring steroids compared with saline (mean difference, −0.52 [CI, −1.85 to 0.81]; P = 0.44) and etanercept (mean difference, −0.92 [CI,−2.28 to 0.44]; P = 0.18) were observed. The largest differences were noted for functional capacity, in which etanercept fared worse than the other treatments: steroids vs. etanercept (mean difference, −16.16 [CI, −26.05 to −6.27]; P = 0.002), steroids vs. saline (mean difference, −5.87 [CI, −15.59 to 3.85]; P = 0.23), and etanercept vs. saline (mean difference, 10.29 [CI, 0.55 to 20.04]; P = 0.04). More patients treated with epidural steroids (75%) reported 50% or greater leg pain relief and a positive global perceived effect at 1 month than those who received saline (50%) or etanercept (42%) (P = 0.09).
Short-term follow-up, small sample size, and a possibly subtherapeutic dose of etanercept.
Epidural steroid injections may provide modest short-term pain relief for some adults with lumbosacral radiculopathy, but larger studies with longer follow-up are needed to confirm their benefits.
The John P. Murtha Neuroscience and Pain Institute, International Spinal Intervention Society, and Center for Rehabilitation Sciences Research.
Gregory A.Plotnikoff, Senior Consultant
Allina Center for Healthcare Research and Innovation
April 27, 2012
Non-inferiority of Placebo?
Lumbar epidural steroid injections are one of the most common procedures in the world. The financial costs are significant for payers and steroid injections are not without risks for patients.
The authors are to be congratulated for their excellent contribution to the ongoing discussion of "best practices" for low back pain. Unexpectedly, they demonstrated non-inferiority of the epidural saline (placebo) injection compared to the steroid injection. Clinicians now must wrestle with this contrarian finding when counseling patients from an evidence-based perspective.
The study has limited generalizability because of the military population and small sample size studied. The authors should follow up with a larger three-arm study of injected saline, injected corticosteroid or the other needling therapy for low back pain, acupuncture.
NicholasCohen, Emeritus Professor
University of Rochester Medical Center
May 1, 2012
Re:Non-inferiority of Placebo?
I would have liked to have seen a comparison of the placebo group with results from a group that received nothing. In other words, was there any "medicinal" benefit of the placebo injection itself? If so, then in this, as well as in many other studies, the placebo should not be considered inert.
Harry W.Daniell, M.D.
University of California at Davis Medical School
Opioid Consumers may Respond Poorly to Epidural Corticosteroiods
Please consider the attached "Letter to the Editor" in response to the article by Drs. Cohen et al. It should be of interest to pain therapists who utilize intervention techniques or prescribe opioids, and may expand recognition of the importance of opioid endocrinopathy in clinical practice. Much evidence supports the presence of clinically relevant cortisol deficiency following either opioid (Arch Surg 2008;143:1147-1148) or benzodiazepine (J Steroid Biochem Mol Biol 1995;53:75-79) administration, with this deficiency most frequent when these medications are used concurrently. The statement suggesting that a short course of post-epidural oral corticosteroids can be deleted if it is not appropriate.
Opioid Consumers May Respond Poorly to Epidural Corticosteriods
By recording the chronic opioid use of their subjects, Cohen et al. (1) have created an additional opportunity for better definition of patients who may benefit from epidural corticosteroid injection therapy for chronic low-back pain. Useful information may result from comparison of the effectiveness of epidural therapy in opioid consumers and non- consumers in each of the 3 arms of their study, with additional useful information also potentially available by including information on benzodiazepine use in the analysis.
Chronic opioid consumers often have different personality and hormonal characteristics than non-consumers, with a majority of them being hypogonadal, many demonstrating depression which responds to testosterone replacement (2) and many chronically consuming benzodiazepines in addition to their opioids. Both opioids and benzodiazepines quickly inhibit cortisol formation (3) with this inhibition usually not recognized clinically, but with opioids occasionally inducing severe adrenal insufficiency when prescribed as sole agents (4) and more frequently when utilized in combination with other medications which also inhibit the HPA axis (3). The therapeutic benefit from epidural corticosteroids apparently results from their local anti-inflammatory action, but each injection also abruptly stops the formation of ACTH and cortisol for several post- injection weeks (5), inducing cortisol deficiency, one manifestation of which might be a transient pro-inflammatory interval capable of negating some of the steroid-induced anti-inflammatory influence. The possibility of greater intensity and longer duration of this post-epidural interval during concurrent opioid or benzodiazepine administration has apparently not been investigated, except for the study be Kay et al. (5) who demonstrated more severe and prolonged post-epidural inhibition of both ACTH and cortisol following the use of midazolam administered intravenously in a dose of 0.07mg/kg as pre-medication before each of three weekly epidural triamcinolone injections. The chronic use of opioids or other medications by their subjects was not reported by Kay et al., but these medications might potentially have intensified the HPA observations which they reported. These observations also suggest the possibility that a short post-injection period of oral corticosteroid replacement might enhance the therapeutic effectiveness of many epidural corticosteroid injections. Our interest in these phenomena was enhanced by our recent identification of new-onset symptomatic but transient adrenal insufficiency which had resulted in hospitalization of 3 chronic opioid consumers during the month following epidural corticosteroid therapy, a pattern which was accompanied by only short-term improvement in their back pain. Signed,
Harry W. Daniell, M.D.
Harry W. Daniell, M.D.
By: Harry W. Daniell, M.D.
Department of Family Practice
University of California Davis Medical School
Davis California, USA
1. Cohen SP, White RL, Kurihara C, Larkin TM, Chang A, Griffith SR, et al. Epidural steroids, Etanercept, or saline in subacute sciatica. Ann Intern Med. 2012;156:551-559.
2. Daniell HW, Lentz R, Mazer NA. Open-Label pilot study of testosterone patch therapy in men with opioid-induced androgen deficiency. J Pain. 2006;7(3):200-210.
3. Daniell HW. Opioid and benzodiazepine contributions to etomidate- associated adrenal insufficiency. Intensive Care Med. 2008;34:2117-2118.
4. Kay J, Findling JW, Raff H. Epidural triamcinolone suppresses the pituitary-adrenal axis in human subjects. Anesth Analg. 1994;79:501-505.
5. Ottmanns KM, Fehm HL, Peters A, Chronic fentanyl applications induces adrenocortical insufficiency. J Intern Med. 2005;257:478-480.
TedDreisinger, Outcomes Research
May 3, 2012
Efficacy in a broader context?
The article by Cohen is both interesting, reflecting findings by other researchers and suggests alignment with the updated Cochrane review by Staal, et al.(1) Epidural steroids may have efficacy in the short term, but the literature equivocates enough that the European (2) and UK (3) Guidelines do not recommend their use in patients with either acute or chronic non-specific back pain.
The bigger problem is not efficacy under proper indication, but rather the explosion in use of injection therapy far exceeding evidence for their use. Manchikanti (4) et al found a 543% increase of facet joint injections among Medicare patients from 1997 to 2006, with an over all increase in interventional pain services of 197%! In addition, there is a 7.7 fold variance in uses between different states. (5) All of this muddies the waters both for the clinician and patient. In addition, the real indicator of success of interventional medicine should be a reduction in healthcare costs - for example, acting as a serious demonstrated barrier to potential surgeries.
It is understandable Cohen et al were focused on the effects of Corticosteroid, Etanercept and saline, in this well designed study. A study like this could be expanded to one more arm - exercise. The one consistent recommendation in all international guidelines for the successful management of back and neck pain is aggressive exercise therapy. (6) It would be interesting to see some interventional papers using aggressive exercise as an arm to the design.
The broader dialogue, however in this time of evidence based medicine and increased government oversight, should be efficacy in the context of cost containment.
1. Staal JB, de Bie R, de Vet HC, Hildebrandt J, Nelemans P. Injection therapy for subacute and chronic low-back pain. Cochrane Database Syst Rev. 2008(3):CD001824.
2. Airaksinen O, Brox JI, Cedraschi C, et al. Chapter 4. European guidelines for the management of chronic nonspecific low back pain. Eur Spine J. Mar 2006;15 Suppl 2:S192-300.
3. Savigny P, Watson P, Underwood M. Early management of persistent non- specific low back pain: summary of NICE guidance. Bmj. 2009;338:b1805.
4. Manchikanti L, Singh V, Pampati V, Smith HS, Hirsch JA. Analysis of growth of interventional techniques in managing chronic pain in the Medicare population: a 10-year evaluation from 1997 to 2006. Pain Physician. Jan-Feb 2009;12(1):9-34.
5. Friedly J, Chan L, Deyo R. Geographic variation in epidural steroid injection use in medicare patients. J Bone Joint Surg Am. Aug 2008;90(8):1730-1737.
6. Hayden JA, van Tulder MW, Malmivaara A, Koes BW. Exercise therapy for treatment of non-specific low back pain. Cochrane Database Syst Rev. 2005(3):CD000335.
Edward L.Tobinick, MD
May 14, 2012
Epidural etanercept for sciatica: trial design considerations
Double-blind, placebo-controlled studies are meant to provide the highest evidence standard upon which to base clinical recommendations. In order to meet this goal the clinical trial must be properly designed, a task that can be exceedingly difficult. A recent large-scale analysis of the clinical trials registered in the ClinicalTrials.gov database found that a majority of trials fall short of producing high quality evidence needed to guide medical decision making. The authors specifically said "....small trials are unlikely to be informative in many other settings, such as.....comparing effective treatments to enable better decisions in practice." The concept of the Cohen et al. etanercept vs. epidural steroid trial was theoretically sound: a comparative effectiveness trial that addresses a major unmet medical need, i.e. a safe and effective non- surgical treatment for intractable disc-related pain. However the methodological limitations of the Cohen study, which space limitations prevent discussing fully, may cast some doubt on the generalizability of the study's findings with respect to the potential utility of etanercept in this setting. Some of these limitations, such as the fact that the etanercept dose utilized may have been inadequate, have already been touched on by the study's authors. Others may be gleaned by a comparison of the Cohen results with those of previously published successful trials of etanercept for disc-related pain[2-5]. For example, perhaps the inclusion criteria in the Cohen 2012 study, pain duration from 1 to 6 months was a factor; in our 2004 observational study, the mean duration of pain was 9.8 years. Favorable clinical experience during more than a decade of utilization of perispinal etanercept in more than 3,000 patients with disc-related pain has been reported. An additional favorable placebo-controlled study of epidural etanercept has also been completed: Cephalon required its successful completion as a prerequisite to the commercial development of their domain TNF antibody, CEP-37247, for sciatica, and that development has now begun. Ohtori et al. have recently published a randomized comparative effectiveness trial comparing epidural etanercept to epidural dexamethasone. Not only was epidural etanercept superior during the study, Ohtori reported that the proportion of patients who underwent surgery within 12 months was significantly higher in the dexamethasone group compared with the etanercept group (The Spine Blog, March 16, 2012). Further study of epidural etanercept in larger studies with higher doses may help explain the divergence of the Cohen 2012 results from their own 2009 trial results.
1. Califf RM, Zarin DA, Kramer JM, Sherman RE, Aberle LH, Tasneem A. Characteristics of clinical trials registered in ClinicalTrials.gov, 2007- 2010. JAMA, 307(17), 1838-1847 (2012).
2. Tobinick E, Davoodifar S. Efficacy of etanercept delivered by perispinal administration for chronic back and/or neck disc-related pain: a study of clinical observations in 143 patients. Curr Med Res Opin, 20(7), 1075-1085 (2004).
3. Cohen SP, Bogduk N, Dragovich A et al. Randomized, double-blind, placebo-controlled, dose-response, and preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica. Anesthesiology, 110(5), 1116-1126 (2009).
4. Tobinick E. Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Rev Neurother, 10(6), 985-1002 (2010).
5. Ohtori S, Miyagi M, Eguchi Y et al. Epidural administration of spinal nerves with the tumor necrosis factor-alpha inhibitor, etanercept, compared with dexamethasone for treatment of sciatica in patients with lumbar spinal stenosis: a prospective randomized study. Spine (Phila Pa 1976), 37(6), 439-444 (2012).
The author has issued and pending U.S. and foreign patents, including, but not limited to U.S. patents 6419944, 6537549, 6982089, and 8119127, that describe methods of use of etanercept for sciatica and additional neurological disorders.
to gain full access to the content and tools.
Learn more about subscription options.
Register Now for a free account.
Results provided by:
Copyright © 2016 American College of Physicians. All Rights Reserved.
Print ISSN: 0003-4819 | Online ISSN: 1539-3704
Conditions of Use
This PDF is available to Subscribers Only