Assessment: Use of epidural steroid injections to treat radicular lumbosacral pain
Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology
Abstract
Based on the available evidence, the Therapeutics and Technology Assessment subcommittee concluded that 1) epidural steroid injections may result in some improvement in radicular lumbosacral pain when assessed between 2 and 6 weeks following the injection, compared to control treatments (Level C, Class I-III evidence). The average magnitude of effect is small and generalizability of the observation is limited by the small number of studies, highly selected patient populations, few techniques and doses, and variable comparison treatments; 2) in general, epidural steroid injection for radicular lumbosacral pain does not impact average impairment of function, need for surgery, or provide long-term pain relief beyond 3 months. Their routine use for these indications is not recommended (Level B, Class I-III evidence); 3) there is insufficient evidence to make any recommendation for the use of epidural steroid injections to treat radicular cervical pain (Level U).
Chronic back pain and its associated disabilities represent an important health problem.1 The rising prevalence of obesity may increase the impact of chronic back pain. The competitive nature of the modern workplace places individuals with less than perfect health and, in particular, those with painful conditions at a disadvantage. Workplace accommodation may not be an option for many occupations and, even where possible, is frequently linked with economic losses for employee and employer alike.
In 1998, individuals with back pain in the United States were estimated to have incurred total health care expenditures of $90.7 billion.2 Inpatient care accounted for 31% of the expenditure, followed by expenditure for office-based visits (26%), prescription drugs (15.6%), and outpatient services (13.1%). Emergency department visits and home health visits each accounted for 3%. Of the $90.7 billion total expenditures incurred by these individuals, the expenditures attributable directly to the back pain totaled approximately $26.3 billion,2 of which 42% were for office-based visits, 18% for outpatient services, 17% for inpatient care, 15% for prescription drugs, and 4% for emergency room visits. The estimated cost of treatments for spinal pain (medical therapy, epidural steroid injections, spinal cord stimulation, and intrathecal narcotics) for 1990 was at least $13 billion, growing by 7% per year.3 Medicare part B claims in 1999 for 40.4 million covered individuals were $49.9 million for lumbar epidural steroid injections, $8.5 million for lumbar facet or peri-facet joint injections, and $5.6 million for cervical or thoracic epidural steroid injections.4
Low back pain may occur without or with radicular features (the latter often referred to as sciatica). In the strictest sense, sciatica refers to pain running down the posterior aspect of the lower extremity. A less restrictive usage to refer to lower back pain with radiation is found in the literature reviewed for this report. A structural cause for sciatica, such as a herniated disc or foraminal stenosis, may or may not be found with investigations. Abnormalities on imaging may be seen in asymptomatic subjects, thus it may not be correct to infer a causal role for radiologic structural changes even if they are concordant with the distribution of sciatica.
Reports of epidural corticosteroid injections to treat sciatica date back to the 1950s.5,6 Their use has increased over time despite limited quality data, as reflected by conflicting reviews of their efficacy and safety.7–9 These reviews varied in terms of criteria for inclusion of patients, study design, types of interventions, outcome measures, and use of additional treatments. A recent review (2004) by the Technology Assessment Committee of the Institute of Clinical Systems Improvement (ICSI)10 focused on fluoroscopically guided, transforaminal epidural steroid injections in radicular lumbar pain. Although it used an evidence-based approach, the rating system is different from that of the American Academy of Neurology (AAN). It concluded that, even though results based on limited data appeared to be promising, there was insufficient evidence to comment on the efficacy of transforaminal epidural steroid injections in radicular lumbar pain.10
A recent editorial11 discussing the role of placebo-controlled trials emphasizes that pain treatments considered effective based on uncontrolled clinical observations or case studies may be found to be ineffective when tested within well-designed placebo-controlled studies. To avoid this error, higher quality evidence requires performance of studies incorporating rigorous case definition, use of controls (placebo or active), use of a standardized efficacy scale, masking of patient and evaluator regarding treatment, and gathering of safety data in different treatment arms. The data should permit calculation of the number of patients needed to treat in order to make one more patient better than what would be obtained with a control treatment (placebo or alternative active treatment).
A listing of important questions regarding epidural steroids appears in table 1. However, the number of high quality of studies was limited. Therefore, the question “What is the evidence to support use of epidural steroid injections in radicular lumbosacral pain to produce pain relief?” was dealt with first. Other endpoints considered within the higher quality studies so identified were considered, as were endpoints identified by reviewers for which there were high quality data.
Methods.
Efficacy.
Medline searches were conducted in April 2003 and February 2005 using combinations of the terms “epidural injections” or “epidural steroids,” “double-blind,” “placebo-controlled,” and “radiculopathy.” A search of the Cochrane database of systematic reviews found no review on the use of epidural steroid injections to treat radicular pain. The following inclusion criteria were used:
1) clear case definition;
2) clear measure of outcome (pain relief) using a standardized measure;
3) use of a control group (placebo or active);
4) randomization;
5) at least double-blind study design, so that neither patient nor assessor of measure of outcome would know the treatment arm; or triple-blind, if the physician injecting the treatment also did not know what treatment was administered;
6) prospective study design;
7) adequate statistical analysis.
The references of articles identified primarily and within select review articles were scanned for additional articles meeting the inclusion criteria: none were found. Articles identified by reviewers of earlier versions of the manuscript were considered also. The highest level of evidence was used to make the conclusions and recommendations for this parameter. Since articles on epidural steroid treatment of radicular cervical pain did not meet these criteria, epidural steroids to treat radicular lumbosacral pain alone will be considered.
Safety.
A separate Medline search using the key words “epidural steroid” and “complications” was performed to identify reported complications with the procedure. Results from selected articles and from the efficacy studies selected for inclusion are summarized briefly.
Results.
Efficacy.
The search yielded 37 articles, 4 of which met the predetermined inclusion criteria.12–15 These are summarized in an evidence table (table 2). Full review of a fifth article16 resulted in its exclusion since outcome measures were unclear, times for the reported outcomes were uncertain, and results of statistical analysis for the outcomes of interest were unavailable. The two articles identified as of the highest quality in the ICSI review17,18 were summarized also in table 2. Some of the studies combined steroids with a local anesthetic, using the local anesthetic as a control or normal saline as the control, while others compared steroids to normal saline.
Safety.
The most common complication is a transient headache whether or not associated with identifiable dural puncture.14 More serious complications, summarized in a 1996 review,19 were several cases of aseptic meningitis, arachnoiditis, and conus medullaris syndrome, typically after multiple subarachnoid injections. Two cases of epidural abscess, one case of bacterial meningitis, and one case of aseptic meningitis were also listed (subarachnoid drug placement could not be ruled out in the meningitis cases).19 A retroperitoneal hematoma was reported in one patient on anticoagulant therapy who received a fluoroscopically guided transforaminal injection of steroids.18 Transient complications have been encountered also during fluoroscopically guided caudal epidural injections, including insomnia, transient non-positional headaches, increased back pain, facial flushing, vasovagal reactions, nausea, and increased leg pain.20 No major neurologic complications (spinal hematomas) were encountered in a series of 1,035 individuals who received epidural steroid injections while on antiplatelet therapy.21 Minor complications (blood during needle placement) were encountered in 5.2%, and transient worsening of symptoms or emergence of new neurologic symptoms for more than 24 hours after the injection occurred in 4% of patients with median duration of 3 days and range 1 to 20 days. Additional qualitative safety data reporting serious complications were rare.21 An additional potential risk of radiographically guided transforaminal injections is radiation exposure; however, the radiation exposure of the spinal interventionalist was well within safety limits if proper techniques were followed.22
The role of practitioner experience and radiologic confirmation of needle placement cannot be determined based on these reports. The results of the one high quality study with radiologic confirmed needle placement did not provide direct comparison of techniques. Therefore, the utility of, or need for, fluoroscopic confirmation of needle placement is unclear.
Discussion.
Comparison to the results of the ICSI review.
This evidence-based review focusing specifically on fluoroscopically guided transforaminal epidural injections10 identified two studies it considered of high quality, which had not been identified by the Medline searches. One article studied pain relief,18 and we concurred that it was of high quality (Class I evidence). Its results were consistent with studies performed without radiologic guidance. The second article used avoidance of surgery as its primary outcome measure.17 However, methodologic limitations resulted in a lower rating under our system (Class III evidence). The limitations included small sample size, the highly selected sample due to self-selection of participants, imprecise case definition, lack of control for possible confounding factors, and insufficient information about why subjects proceeded to surgery. Its findings favoring efficacy, while concordant with those of a previously identified article,13 were discordant from those of articles that were rated higher, that showed no impact on utilization of surgery.14,18 The lack of overlap between high quality articles found using the two search strategies resulted from use of different search terms. The ICSI review did not retrieve articles that did not use fluoroscopy, and the high quality article reporting results with transforaminal, peri-radicular injections using fluoroscopy did not incorporate the terms we had used in our original search. However, the results with the two search strategies were similar, strengthening the validity of our conclusions and recommendations.
Principal findings, in clinical perspective.
With regards to the primary question of this review, amelioration of pain, the findings of the four high quality studies12–14,18 are internally consistent, showing the following efficacy pattern compared to a control group: no efficacy at 24 hours12; some efficacy at 2 to 6 weeks13,14,18; no difference14 or rebound worsening at 3 months18 and 6 months18; and no difference at 1 year.13,18 The immediate postinjection amelioration of leg, but not back pain, may have been due to the local anesthetic with which the steroid was mixed in one study.18
These results support the individual perception of benefit of epidural steroids, expressed in terms of short-term symptomatic relief, a positive result in and of itself. However, the average effect difference (advantage of steroids over control treatment) was small, usually falling short of the value proposed as a clinically meaningful average difference18—15 mm on the 100 mm visual analogue pain scale. Other investigators have shown that, at the individual level, an optimal value for a clinically meaningful change on a 0 to 10 pain intensity scale is a 2-point absolute change (or a 33% relative change).23–25 However, the available studies did not express the magnitude of relief in terms of the percent of patients attaining a clinically meaningful response, and thus do not permit calculations of number of patients needed to treat in order to benefit one patient.
These results are consistent with the results of a study comparing 43 patients treated with epidural methylprednisolone applied during unilateral lumbar discectomy with matched historical controls that showed reduced need for narcotic and non-narcotic pain medications and muscle relaxants during the postoperative period, and shorter hospital stay in treated patients (an average of 2.72 days in treated patients vs 4.35 days in the untreated patients).26 Reported complications of epidural steroid injections are usually minor and transient: the most frequent is a transient headache. Reported major complications are rare (aseptic meningitis, arachnoiditis, bacterial meningitis, epidural abscess, and conus medullaris syndrome), and may result from subarachnoid, rather than epidural injection. There may be underreporting of complications, and the reported safety track record of experienced practitioners with large volumes may not reflect the track record of smaller volume or less experienced practitioners. These results do not answer most of the other questions listed in table 1. With regards to the specific question of avoidance of surgery, the data on face value are conflicting, with the better designed studies showing no benefit to epidural steroids. The data from the less well-designed studies are harder to interpret and generalize, as are data from uncontrolled clinical settings. The data do not permit inferring if surgery is avoided due to the treatment effect of injected steroids, due to placebo effect, or because the treatment “buys time” for a natural history of improvement.10 The data do not address how epidural steroid injections might compare to other treatment modalities and the role of patient and provider characteristics, including temperament and pain tolerance, in selecting among various treatment options. The recommendations gave greater weight to the data from the better designed studies, showing that epidural steroid injections did not result in less surgery.
However, an uncontrolled study27 with partial follow-up of treated patients has identified factors that predict poor outcome: 1) greater number of previous treatments for pain; 2) more medications taken; 3) pain not necessarily increased by activity; 4) pain increased by coughing. Factors that predict no benefit 1 year after treatment include 1) pain does not interfere with activities; 2) unemployment due to pain; 3) normal straight leg raising tests before treatment; 4) pain not decreased by medication. Better designed studies are needed to confirm these observations, and express them in contemporary terms of numbers needed to treat, relative to presence or absence of predictive factors for poor outcome.
Limitations.
This review is limited by its inability to compare all techniques and all treatment approaches. However, the findings in terms of pain relief and some of the secondary measures are similar for the earlier studies and for those that used fluoroscopy and transforaminal injections. This review did not assess issues of frequency of injection or dosage, and did not evaluate operator experience, which was implied to be high in all the published reports. The generalizability of the findings is limited. The focus on pain relief, guided by the chief indication for which epidural steroid injections are used, is a limitation, compared to using improvement of function as the primary outcome variable. However, it frames the subjective impressions of patients and providers in evidence-based terminology that may guide the future evaluation of this treatment modality.
Recommendations and conclusions.
1.
Epidural steroid injections may result in some improvement in radicular lumbosacral pain when determined between 2 and 6 weeks following the injection, compared to control treatment (Level C, Class I-III evidence). The average magnitude of effect is small, and the generalizability of the observation is limited by the small number of studies, limited to highly selected patient populations, the few techniques and doses studied, and variable comparison treatments.
2.
In general, epidural steroid injections for radicular lumbosacral pain have shown no impact on average impairment of function, on need for surgery, or on long-term pain relief beyond 3 months. Their routine use for these indications is not recommended (Level B, Class I-III evidence).
3.
Data on use of epidural steroid injections to treat cervical radicular pain are inadequate to make any recommendation (Level U).
Recommendations for future research.
1.
Further studies of the efficacy of epidural steroids for radicular lumbosacral pain should be well-designed, meeting the following criteria: a) clear case definition; b) clear measures of outcome using standardized tools, with function as the primary measure and clinically meaningful improvement in pain23–25 as a secondary measure; c) use of a control group (placebo or active); d) prospective design; e) randomization; f) double-blind study design, so that neither patient nor assessor of measure of outcome knows the treatment arm; or triple-blind, if physician administering the epidural steroids also does not know what treatment is administered; g) adequate power; and h) adequate statistical analysis.
2.
Studies of use of epidural steroids to treat radicular cervical pain or non-radicular low back or cervical pain should also be designed rigorously, meeting similar criteria.
3.
The principal questions to be answered are as follows:
(a)What is the degree of efficacy, expressed in terms of magnitude of effect, duration of effect, and percent of patients who achieve clinically meaningful improvement, in comparison to alternative treatments?
(b)Using a controlled design: are there predictors of lack of efficacy or poor efficacy? Consider studying first patients without putative predictors of poor efficacy.
(c)How many treatments are appropriate, and at what intervals?
(d)How frequent are complications, and what are they?
4.
Initially, it will be necessary to standardize some of the variables reflected in the questions in table 1, such as a specific technical approach, the minimal competency of the treating physician, and utilization of additional therapies.
5.
Subsequently, research can be directed to evaluate the role of these variables. In particular, different techniques will need to be assessed using standardized methodology.
Mission statement of TTA.
The Therapeutics and Technology Assessment Subcommittee (TTA) produces evidence-based statements that assess the safety, utility, and effectiveness of new, emerging, or established therapeutic agents or technologies in the field of neurology. These are developed through a rigorous process of defining the topic, evaluating and rating the quality of the evidence, and translating the conclusions of the evidence into practical recommendations that can help to guide the practice of Neurology.
Disclaimer.
This statement is provided as an educational service of the American Academy of Neurology. It is based on an assessment of current scientific and clinical information. It is not intended to include all possible proper methods of care for a particular neurologic problem or all legitimate criteria for choosing to use a specific procedure. Neither is it intended to exclude any reasonable alternative methodologies. The AAN recognizes that specific patient care decisions are the prerogative of the patient and the physician caring for the patient, based on all of the circumstances involved.
Conflict of interest statement.
The American Academy of Neurology is committed to producing independent, critical and truthful clinical practice guidelines (CPGs). Significant efforts are made to minimize the potential for conflicts of interest to influence the recommendations of this CPG. To the extent possible, the AAN keeps separate those who have a financial stake in the success or failure of the products appraised in the CPGs and the developers of the guidelines. Conflict of interest forms were obtained from all authors and reviewed by an oversight committee prior to project initiation. AAN limits the participation of authors with substantial conflicts of interest. The AAN forbids commercial participation in, or funding of, guideline projects. Drafts of the guideline have been reviewed by at least three AAN committees, a network of neurologists, Neurology peer reviewers, and representatives from related fields. The AAN Guideline Author Conflict of Interest Policy can be viewed at www.aan.com. With regards to this specific report, all authors have stated that they have nothing to disclose. One of the authors performs epidural steroid injections.
Appendix 1
Therapeutics and Technology Assessment subcommittee members: Yuen T. So, MD, PhD (Co-Chair); Janis Miyasaki, MD, FAAN (Co-Chair); Douglas S. Goodin, MD (ex-officio); Carmel Armon, MD, MHS, FAAN (ex-officio); Richard M. Dubinsky, MD, MPH, FAAN; Mark Hallett, MD, FAAN; Cynthia L. Harden, MD; Michael A. Sloan, MD, MS, FAAN; James C. Stevens, MD, FAAN; Fenwick T. Nichols, III, MD; Kenneth J. Mack, MD, PhD; Paul W. O'Connor, MD; Vinay Chaudhry, MD, FAAN.
Appendix 2
AAN classification of evidence for therapeutic intervention
Class I. Prospective, randomized, controlled clinical trial with masked outcome assessment, in a representative population. The following are required: a) primary outcome(s) clearly defined; b) exclusion/inclusion criteria clearly defined; c) adequate accounting for dropouts and cross-overs with numbers sufficiently low to have minimal potential for bias; and d) relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.
Class II. Prospective matched group cohort study in a representative population with masked outcome assessment that meets a-d above OR a RCT in a representative population that lacks one criteria a-d.
Class III. All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.*
Class IV. Evidence from uncontrolled studies, case series, case reports, or expert opinion.
*Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g. blood tests, administrative outcome data).
Appendix 3
Classification of recommendations
A= Established as effective, ineffective, or harmful for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)
B= Probably effective, ineffective, or harmful for the given condition in the specified population. (Level B rating requires at least one Class I study or at least two consistent Class II studies.)
C= Possibly effective, ineffective, or harmful for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)
U= Data inadequate or conflicting; given current knowledge, treatment is unproven.
Spanish Translation
Files in this Data Supplement:
Spanish Translation - (PDF file)
Footnote
See the conflict of interest statement at the end of the text.
Received July 6, 2006. Accepted in final form December 1, 2006.
Approved by the Therapeutics and Technology Assessment Subcommittee on July 28, 2006; by the Practice Committee on November 11, 2006; and by the AAN Board of Directors on December 7, 2006.
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Riew KD, Yin YY, Gilula L, et al. The effect of nerve-root injections on the need for operative treatment of lumbar radicular pain. J Bone Joint Surg 2000;82:1589–1593.
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Abrahm SE, O'Connor TC. Complications associated with epidural steroid injections. Reg Anesth 1996;21:149–162.
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We read the Report of the TTA subcommittee with interest. [1] We feel that the report by Armon et al could confuse physicians and patients. The abstract reports that there is insufficient evidence to recommend the use of epidural steroid injections to treat radicular cervical pain (Level U), even though the focus of the review is the use of epidural steroid injections to treat radicular lumbosacral pain and the studies included in the synthesis related solely to this focus.
Principles of evidence-synthesis, and specifically evidence- synthesis and evidence-based interventional pain management have been described. [2] Recently, Abdi et al performed a systematic review that separated lumbar epidural steroid injections into caudal (8 randomized trials), interlaminar (11 randomized trials), and transforaminal (6 randomized trials), as these approaches are distinct techniques with variable effectiveness and separate applications. [3]
In addition, Abdi et al included other observational studies and an examination of the methodologies and criteria of both AHRQ and Cochrane reviews. They concluded that there was moderate evidence to support the long-term (i.e.- > 6 weeks) effectiveness of caudal and transforaminal epidural steroid injections and limited evidence to support the effectiveness of lumbar interlaminar epidural steroid injections.
Armon et al only included four studies considered to have met the predetermined inclusion criteria, although previous studies have included larger numbers of randomized trials in systematic evaluations including the Cochrane review [4] and European guidelines. [5] For these reasons, the report by Armon et al may negatively affect the successful conduct of interventional pain management.
References
1. Armon C, Argoff CE, Samuels J, Backonja MM. Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: use of epidural steroid injections to treat radicular lumbosacral pain: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2007;68:723-729.
2. Manchikanti L, Boswell MV, Giordano J. Evidence-based interventional pain management: principles, problems, potential and applications. Pain Physician 2007; 10:329-356.
3. Abdi S, Datta S, Trescot AM et al. Epidural steroids in the management of chronic spinal pain: A systematic review. Pain Physician 2007; 10:185- 212.
4. Nelemans PJ, Debie RA, DeVet HC, Sturmans F. Injection therapy for subacute and chronic benign low back pain. Spine 2001; 26:501-515.
5. Airaksinen O, Brox JI, Cedraschi C, Hildebrandt J, Klaber-Moffett J, Kovacs F., et al. Chapter 4: European guidelines for the management of chronic nonspecific low back pain. Eur Spine J 2006; 15:S192-S300.
Disclosure: The authors report no conflicts of interest.
Manchikanti et al refer Neurology readers to four papers to dispel confusion that they attribute to our report. Review of the data in these papers affirms our original conclusions.
Regarding cervical transforaminal injections, Abdi et al [3] considered two randomized trials, each comparing two active treatments without placebo controls and four non-randomized trials without controls. These studies do not meet the inclusion criteria of our original assessment, which required placebo controls [1], leaving unchanged our conclusion that there is insufficient evidence to recommend the use of epidural steroids to treat cervical radicular pain.
Differences in inclusion criteria, including a broader case definition and consideration of uncontrolled studies and studies without placebo controls, led to listing of a larger number of studies within the reviews cited by Manchikanti et al of epidural steroid injections for low back pain [3-5], compared to our listing [1]. However, the conclusions of those reviews are not too dissimilar from ours.
Abdi et al [3] concur with our conclusions as applied to interlaminar epidural injections. While they use the language "moderate evidence" in support of efficacy of transforaminal and caudal routes of injection of injection, this appears to be done at variance with the classification system provided in the methods section of their review. According to this system, the presence of conflicting data that showed in some studies lack of efficacy for injections via these routes should have resulted in the wording "limited evidence," similar to that used for the interlaminar route.
Furthermore, the paper does not reflect awareness of methodological limitations in some studies alleging efficacy. The two other reviews -- the European Guidelines [4] and Nelemans et al [5] -- come to conclusions similar to, or more proscriptive, than ours. In particular, Nelemans et al [4] (not a Cochrane review), considering radicular and non-radicular low back pain, concludes that "convincing evidence is lacking regarding the effects of injection therapy on low back pain."
We are encouraged that even individuals who appear to dispute the content or clarity of our findings provide data that, when examined, are supportive of our conclusions. The precise wording of our assessment reflects the terminology and classification system used by the AAN.
Disclosure: The authors report no conflicts of interest.
Armon et al present a medical legal dilemma for the AAN. [1] In published guidelines for qualifications of physician expert witnesses, it is stated that experts should have evidence of competence in an area of relevance to the opinion including publications. [2] Whereas the subject article presents guidelines, the authors are indirectly providing expert opinions in such cases whether the forum is a court, licensing board, peer review body or other lawful agency.
Randomized controlled trials (RCTs) have been lauded in the subject article. Alternative opinions suggest that this may be taken too far. [3] In the present matter, performing a placebo controlled randomized study may not be especially venerable because of patient expectations that arise out of the consenting process. To be ethical, a recruiter must share beliefs that epidural steroids have not been proven to be better than placebos. The consenting process may ultimately induce pharmacological unblinding due to systemic steroid effects. In this process, the recruiter is likely to induce, in the subject, expectations for no benefit or complication. These negative expectations may be an underestimated factor affecting outcomes in placebo controlled randomized studies. Furthermore, many patients may decline during the recruitment process when confronted with unsavory choices. How recruitment induced biases affect the outcomes of research was not discussed in the subject article.
If RCTs are performed for the subject issue, two separate interventional study arms could be compared. In this case, the study recruiter can ethically discuss two options that are thought to be beneficial. The latter approach would not scare off study participants because it would induce expectations of improvement. Assuming that placebo effects are not dramatically higher than treatment effects, an observed difference between study groups may be determined.
Pharmacologically induced unblinding would not occur in the latter circumstance. A study, not mentioned by the subject review article, exemplified the above proposal. The former study demonstrated the superiority of selective transformaminal injections compared to interspinous epidural injections. [4] Experts should be aware of this and similar studies.
References
1. Armon C, Argoff CE, Samuels J, Backonja MM. Assessment: Use of epidural steroid injections to treat radicular lumbosacral pain. Neurology 2007; 68: 723-729.
2. Williams, MA. Mackin GA, Beresford, HR, et al. American Academy of Neurology qualifications and guidelines for the physician expert witness. Neurology 2006;66:13-14.
3. Smith G, Pell J. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomized controlled trials. BMJ 2003; 327: 1459-1461.
4. Thomas E, Cyteval C, Abiad L, Picot MC, Taourel P, Blotman F. Efficacy of transformaminal versus interspinous corticosteroid injection in discal radiculalgia. A prospective randomized, double blind study. Clinical Rheumatology 2003; 22: 299-304.
Disclosure: The author reports no conflicts of interest.
The AAN practice parameters are evidence-based reviews of topics relevant to the practice of neurology. The process is described in detail on the website (http://www.aan.com/go/practice/guidelines) and does not include expert opinion or consensus. The Disclaimer, appended to each assessment, states clearly that the AAN views the assessments as an educational service to its members.
The AAN's Guidelines for Qualification of Physician Expert Witnesses are not factored explicitly in selecting the individuals involved in the preparation, review, and approval of guidelines. [2] The AAN Conflict of Interest Policy for Practice Guidelines is more germane to author panel composition. The readers may be reassured, that (a) the authors of the present assessment have not published previously on the topic of epidural steroids; and (b) that three of four do not derive any income from epidural steroid injections. Multiple stages of review, including independent review by Neurology, before an assessment is approved by the AAN Board of Directors, assure the integrity of the process.
The obvious truth, that when death is a certain outcome [3] an intervention that prevents that outcome does not require a placebo control is not germane to the topic. An editorial cited in our original review [5] clarifies the roles of placebo controls in pain therapy clinical trials.
Dr. Jordan proposes that studies comparing two active treatment arms for pain are more ethical than placebo-controlled studies. [4] The prerequisites for a valid comparison of two active treatment modalities are: (a) both need to have been shown effective against placebo; and (b) the comparison of the two needs to have been preceded by studies to determine the optimal dose or method of administration for each. Lacking (a) – treatment A may appear better, yet be no better than placebo, because treatment B makes patients worse. Lacking (b) – treatment A may appear superior to treatment B because treatment A is applied in an optimal manner, whereas treatment B is applied in a suboptimal manner.
In the study cited by Dr. Jordan [4], the investigators utilized, in the interspinous arm an apparent subtherapeutic dose, equivalent to 27-33% of the dose used currently for this route of administration [6-9], to support a conclusion of superiority for the transforaminal arm. They did not make this explicit. In our opinion, the study's methods do not support its conclusions and we do not perceive it to be a model for ethical superiority.
ACKNOWLEDEMENT: The authors acknowledge Yuen T. So, M.D., Ph.D., and Janis Miyasaki, M.D., MEd, FRCPC, TTA co-chairs, and Gary Gronseth, M.D. and Jacqueline French, M.D., QSS co-chairs, for their critique of earlier versions and affirmation of the final version of this response. This response has been reviewed also by Murray G. Sagsveen, JD, CAE, General Counsel, AAN.
References:
5. Fillingim RB, Price DD. What is controlled for in placebo-controlled trials? Mayo Clinic Proc 2005;80:1119–1121.
6. White AH. Injection Techniques for diagnosis and Treatment of Low Back Pain. Ortho Clin North Am 1983;14:553-567.
7. Buchner M, Zeifang F, Brocai DR, Schiltenwolf M. Epidural corticosteroid injection in the conservative management of sciatica. Clin Orthop 2000;375:149–156.
8. Arden NK, Price C, Reading I, et al. A multicentre randomized controlled trial of epidural corticosteroid injections for sciatica: the WEST study. Rheumatology 2005;44:1399-1406.
9. McAuley D. Corticosteroid converter. GlobalRPH.com 2006. http://www.globalrph.com/corticocalc.htm converter.
Disclosure: The authors report no conflicts of interest.
The AAN committee's rigorously ascertained assessment of epidural steroid injection efficacy provides an overdue authoritative guideline. [1] Our own earlier review also affirmed that reports of serious complications are inadequate to establish statistical prevalence. [2]
Evidence-based clinical studies have significant data of collateral value. In the 2007 Physicians Desk Reference, the manufacturer of methylprednisolone acetate (Pharmacia and Upjohn), states that the drug is "an anti-inflammatory glucocorticoid." However, we were unable to discover any valid pathological or clinical evidence that inflammation is a pathological component of clinical radiculopathy/back pain. [2] A likely hypothesis for short-term symptomatic improvement is the toxic effect of the usual hypertonic injectate mixture at the bedside of steroid, anesthetic, and often radiological contrast agent. Indeed, Pharmacia and Upjohn warn that "This product contains benzyl alcohol [also other preservatives], which is potentially toxic when administered locally to neural tissue…Because of possible physical incompatibilities, DEPO-MEDROL Sterile Aqueous Suspension should not be diluted or mixed with other solutions."
Concerning complications they warn of "Adverse reactions reported with intrathecal/epidural routes of administration: arachnoiditis, meningitis, paraparesis/paraplegia, sensory disturbances, bowel/bladder dysfunction, headache, seizures…DEPO-MEDROL Sterile Aqueous Suspension is contraindicated for intrathecal administration. Reports of severe medical events have been associated with this route of administration." Our references indicated that inadvertent intrathecal injection during lumbar epidural infusion occurs in at least 5 to 6% of cases. [2]
Concerning the professional popularity of this practice, a recent editorial in Pain concluded, "Those who have a firm conviction that they must use injections come in three groups. One is the misguided who cannot separate placebo effect, natural history of disease and regression to the mean from therapeutic effect. The second group is those who feel that they must do something…They stick and inject in the hope rather than the belief that what they do is helpful. The third group is in it for the money." [3]
References
1. Armon C, Argoff CE, Samuels J, Backonja MM. Assessment: Use of epidural steroid injections to treat radicular lumbosacral pain. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2007;68:723-729.
2. Nelson DA, Landau WM. Intraspinal steroids: history, efficacy, accidentality, and controversy with review of United States Food and Drug Administration reports. J Neurol Neurosurg Psychiatry 2001;70:433-443.
3. Butler SH. Editorial: Primum non nocere—first do no harm. Pain 2005;116:175-176. Disclosure: The authors report no conflicts of interest.
We thank Drs. Nelson and Landau for their gracious appraisal of our work [1], and for referring the readers of Neurology to their own assessment of epidural steroid injections [2]. They raise the intriguing hypothesis that the possible short term benefit of epidural steroid injections may be due to toxicity of the injectate rather than to a therapeutic effect of the steroids. Their hypothesis might be testable by utilizing epidural steroid injections and two control arms. One control arm would receive a control solution that is matched to the active solution in all aspects (volume, osmolality, preservatives) but without any steroids, and the other would receive normal saline. Until that is done, this remains a hypothesis.
Drs. Nelson and Landau proceed to cite the manufacturer's cautions regarding uses of SoluMedrol as listed in the 2007 Physician Desk Reference (PDR). They state in their letter: "Our references indicated that inadvertent intrathecal injection during lumbar epidural infusion occurs in at least 5% to 6% of cases [2]." We asked Dr. Landau to indicate which references they were relying on, and he directed us to two. [4,5] It may be seen, that the citations do not support the wording used by Drs. Nelson and Landau. Moreover, White reported specifically that in 300 patients treated using fluoroscopy, "complications occurred in 0.4%. These were local sacral pain, transient hypotension, and two cases of dural penetration through the lumbar route."
We note further, that, while 2 out of 300 cases are 0.7%, dural penetration it is not the same as intrathecal injection. [4, 5] We recognize that published series may underestimate the frequency of complications, and agree with Drs. Nelson and Landau that case reports of serious complications are inadequate to establish the frequency of their occurrence, due to the absence of a denominator. We stand by our original presentation of the safety profile of epidural steroids [1], which is not intended to supplant the PDR, and appreciate Drs. Nelson and Landau's comments referring the readers also to the PDR.
Finally, our work is an evidence-based assessment of epidural steroid injections. Since the available reviewed studies do not address the motivation of the treatment provider, it was beyond the scope of our work to explore such issues. We hope that additional studies to establish verifiable indications, expected outcomes and likely complications of epidural steroid injections will optimize the use of this treatment.
References
4. Dilke TFW, Burrry HC, Grahame R. Extradural Corticosteroid Injection in management of Lumbar Nerve Root Compression BMJ 1973;2:635-637.
CITATION: "There were no complications … A minority of patients experience transient pain of sciatic distribution during extradural injection. Cerebrospinal fluid was inadvertently tapped on six occasions in the course of this trial [100 patients], and when this happened the needle was withdrawn and an extradural injection was carried out immediately through an adjacent interspinous space." (page 637, column 1)
5. White AH. Injection Techniques for diagnosis and Treatment of Low Back Pain. Ortho Clin North Am 1983;14:553-567.
CITATION: "We did find, however, in our double-blind study, that even by these techniques we are not accurately in the epidural space as much as 25 per cent of the time and do occasionally enter the thecal space, which can complicate the clinical picture." (page 556 column 1) Disclosure: The authors report no conflicts of interest.