Corticosteroid Choice for Epidural Injections

Point/Counterpoint

Corticosteroid Choice for Epidural Injections

Guest Discussants: Michael J. DePalma, MD

CASE SCENARIO S.S. is a 66-year-old otherwise healthy woman who, 4 years ago, had a left L5 lumbosacral radiculitis due to spinal stenosis, which was treated with a transforaminal epidural injection at L5-S1 with 80 mg triamcinolone. She has been completely pain free, with no functional limitations or pain medication usage until 4 months ago when her exact pain returned. She then noticed a gradual worsening of left low back pain with radiation to the posterior thigh, calf, and top of the foot, without any underlying trauma. Her pain is better with sitting, and worsens with standing and walking. She is only able to walk 100 feet before having to sit down due to pain, but she can walk further if bent over a shopping cart. Results of a physical examination are unchanged from her last examination 4 years ago, with no focal sensory abnormalities, but manual muscle testing revealed left extensor hallucis longus weakness graded at 4/5. She had a negative straight leg raise and no pain with sacroiliac joint or hip provocative maneuvers bilaterally. No hip flexion contractors were noted on the Thomas test. She had decreased lumbar spine extension due to pain, but full flexion. In the past 4 months, she has tried nonsteroidal anti-inflammatory drugs and extensive physical therapy with minimal relief. She currently requires 4-6 Vicodin (Abbott Laboratories, Abbott Park, IL) daily for pain; she still is significantly limited in her ability to walk. A repeated magnetic resonance imaging is unchanged from 4 years ago and demonstrates left-sided subarticular stenosis at L4-L5 that affects the left L5 traversing nerve root. Given her previous positive response to an epidural injection, she is requesting a repeated epidural corticosteroid injection. She asks if you will use the same medication that she previously received. Michael DePalma, MD, will argue that the procedure should be done with a particulate corticosteroid similar to her first injection. Alison Stout, DO, will argue that a nonparticulate corticosteroid should be used to prevent the possibility of paralysis.

Virginia iSpine Physicians, PC, and Virginia Spine Research Institute, Inc, Richmond, VA Disclosure: nothing to disclose

Alison Stout, DO Evergreen Spine and Sport Center, Kirkland, WA Disclosure: nothing to disclose

Feature Editor: David J. Kennedy, MD Department of Orthopaedic Surgery, Stanford University, 450 Broadway Street, Pavilion C, MC 6342, Redwood City, CA 94063 Disclosure: nothing to disclose

Michael J. DePalma, MD, Responds This illustrative case exemplifies a spine condition that is becoming more prevalent as the life expectancy in the United States expands. Health care concerns specific to the aging spine include acquired spinal stenosis. Degenerative changes within the lumbosacral spine occur concomitantly with advanced age. Such degenerative changes contribute to lumbar spinal stenosis (LSS) and can involve the central and/or lateral canals and the intervertebral foramen. The prevalence of acquired LSS is 4% in patients younger than 40 years old but increases to 19.4% in the 60-69 year old group [1]. Within this older age group, approximately 10% of this population will experience symptoms related to the LSS [2]. As is the case in our clinical vignette, neurogenic claudication and/or radicular pain can be clinical features of LSS. The character of this pain can range from deep, crampy, and achy PM&R 1934-1482/13/$36.00 Printed in U.S.A.

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to sharp and lancinating. Dural tension signs are not always positive but, when present, would suggest nerve root inflammation [3]. Our patient’s symptoms and physical examination findings certainly fall within this spectrum. From an anatomic perspective, the lumbosacral nerve root is susceptible to biomechanical and biochemical insults. The nerve root lacks a perineurium and, therefore, tensile strength and a diffusion barrier. Consequently, the nerve root is less resilient to tension forces and chemical irritants. In addition, the nerve root epineurium, which provides a mechanical cushion resistant to compression, is less abundant and underdeveloped. The fasciculi internal to the nerve root do not branch to form a plexiform pattern but instead run in parallels, loosely held together by connective tissue. Furthermore, the nerve root lymphatic system is poorly equipped to © 2013 by the American Academy of Physical Medicine and Rehabilitation Vol. 5, 524-532, June 2013 http://dx.doi.org/10.1016/j.pmrj.2013.05.017

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adequately clear inflammatory mediators once the inflammatory cascade is initiated. An inflamed nerve root, therefore, is predisposed to a chronic inflammatory reaction marked by invasion of fibroblasts with eventual development of intraneural fibrosis [4]. Spinal stenosis can result in neurogenic and/or vascular compression of the contents of the spinal canal at one or more levels [5-7]. It is a condition in which there usually is an intermittent compression of the nerve roots, and this could lead to hyperemia, venous congestion [8], leakage of neurotoxic substances, and inflammatory cell infiltration [8,9]. In vitro studies that simulated LSS have documented the presence of venous congestion, intraneural edema, and impaired axonal transport due to chronic compression [10-12]. Corticosteroids instilled into the epidural space function to impair prostaglandin synthesis, block nociceptive C-fiber conduction, stabilize cellular membranes, and, possibly, alter the flow of nerve root blood and chemotoxic mediators [13-16]. It, therefore, is attractive to expose the patient who is experiencing LSS-related radicular pain to corticosteroid in the attempt to curtail the symptoms. The route of delivery of the therapeutic agent then becomes the focus of attention. Intramuscular steroid injections [17,18], interlaminar epidural steroid injections (ESI) [19-21], and caudal ESIs [22,23] are not significantly more effective than sham controls for pain relief. Instillation of steroid via the transforaminal approach has emerged as an intriguing technique that allows the steroid to directly access the putatively painful nerve root. In this instance, a symptomatic nerve root can be reached by the injectate regardless of whether the stenosis is located within the central or lateral canals or the foramina. Outcomes for radicular pain reduction after transforaminal ESIs (TFESI), however, may vary according to the location of compression. Nonetheless, a repeated TFESI is a sensible option for our patient. TFESIs are conclusively effective at reducing herniated nucleus pulposus (HNP)-induced radicular pain in the absence of concomitant spinal stenosis [24]. The proportion of such patients treated with TFESIs who experience a predefined category of successful outcomes is significantly greater than the proportion of similar patients treated by other injections [24]. However, the comparison of the mean outcome scores of each of these treated groups of patients does not reveal the advantage of TFESI in achieving successful outcomes because responses for each individual subject are masked by the outlying responses of singular subjects within the group [24]. If the focus remains on the number of overall subjects treated by TFESIs who achieve a predefined success, then the nonresponders’ scores can then be reviewed appropriately, whereas the number of treated patients who experience relief can be measured directly. When using published data as a guiding light for direction in deciding how to manage patients, one must think in terms of the proportion of patients we would expect to achieve an acceptable out-

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come. Similarly, one must decide whether the acceptable outcome as defined in publications is in agreement with one’s own such definition for his or her patients. In preparation for responding to our patient’s request, we can consult the current literature. By using group data, investigators have reported improvement in mean pain scores at 1 month [25] and 12 months [26] after TFESI in patients with LSS. The long-term improvements were observed in patients documented to have central canal stenosis that may or may not have been concurrently associated with foraminal stenosis [26]. These were uncontrolled prospective cohort studies, and the mean data may not represent what we should expect for our patient. Other investigators have reported that 54% (95% confidence interval {CI}, 40%-68%) of patients with LSS experienced ⱖ50% reduction [27] in radicular pain, and 60% (95% CI, 30%-90%) of patients reported ⱖ60% reduction [28] in radicular pain at 6 months after TFESI. At 12 months, 47% (95% CI, 32%-62%) of treated patients experience sustained ⱖ50% reduction in radicular pain [29]. The calculated CIs for the proportions of successful outcomes indicate that, realistically, approximately one-third to two-thirds of patients with LSS will experience clinically meaningful and sustained reduction in their index radicular pain after undergoing TFESIs. We can now inform our patient that, if we were treating 2 additional patients with an identical spine condition, at least 1 and perhaps 2 of them could expect relief. All of these studies used particulate steroid preparations, and some subjects required multiple TFESIs for sustained relief from radicular pain [26,28]. No studies that assessed TFESIs in LSS have been published that used a nonparticulate steroid preparation. When comparing group data alone, TFESIs and interlaminar epidural steroid injections (ILESIs) appear no different regarding outcome, including rate of surgical decompression [30]. However, categorical differences, or the differences in the proportions of successful outcomes, between these 2 injection techniques are yet unknown. We can now elaborate for our patient that the injection she underwent 4 years earlier, the particular approach and type, is very similar to the investigated injections that yielded the results we quoted her. Use of TFESI particulate steroid preparations are not without inherent risks. Adverse effects are mild and selflimited [31-33]. Catastrophic complications, for example, spinal cord infarction, have been reported in association with lumbosacral TFESIs [34-37]. Depot preparations of steroid, methylprednisolone, triamcinolone, betamethasone, aggregate into clusters of particles larger than red blood cells, which could embolize terminal vessels within the spinal cord [38]. An animal study has also demonstrated that methylprednisolone and its carrier molecule may have a direct neurotoxic effect when injected intravascularly [39]. When performed by adhering to strict procedural technique, TFESIs have not been reported in association with spinal

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cord infarction [24,31,33]. Yet, safeguards can be exercised to reduce the risk of this complication, such as using enough contrast medium under continuous, anterior-posterior fluoroscopic imaging sufficient to detect intravascular uptake [40], use of digital subtraction imaging, use of low-volume extension tubing to minimize needle displacement, and administration of a test dose of local anesthetic before instilling the steroid preparation [37,41]. Regardless, concerns of spinal cord injury have led some investigators to consider nonparticulate steroid preparations [42]. However, dexamethasone has not performed as well against triamcinolone [42]. The onset of these complications has lead the U.S. Food and Drug Administration (FDA) to issue a warning against using particulate steroid preparations in the epidural space. Our patient should be apprised of this labeling to make an informed decision. Yet, this labeling should be cast in proper perspective. It is not based on scientific evidence that confirms that inadvertent intra-arterial injection of particulate steroid during TFESIs is unavoidable. Unintentional spinal cord injury via vascular embarrassment by particulate steroids is avoidable. These injections can be completed without injecting steroid into an artery, or, such uptake can be abolished once detected. Detection by cuing into fluoroscopic aspects requires the proceduralist to comply with all safeguards and standards for safe performance of TFESIs. Categorically, instillation of corticosteroid into the epidural space is an off-label application of this medication. However, such labeling should not preclude offering a TFESI to this patient. Although spinal cord injury has not been observed due to TFESI of dexamethasone, dexamethasone does not appear as effective as triamcinolone, and, when performing by adhering to strict standards, TFESI of particulate steroids has not been observed to occur with spinal cord injury. All things considered, it is reasonable and defensible to repeat the TFESI by using triamcinolone to reinstate pain relief for this patient. Yet, this prescription is only reasonable and defensible provided that it is performed by using the technical features compliant with the safe performance of TFESIs. In this regard, S.S. can be notified that it appears possible or even probable that her radicular pain can be safely relieved by a repeated TFESI by using triamcinolone.

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REFERENCES 1. Kalichman L, Cole R, Kim DH, et al. Spinal stenosis prevalence and association with symptoms: The Framingham Study. Spine J 2009;9: 545-550. 2. Ishimoto Y, Yoshimura N, Muraki S, et al. Prevalence of symptomatic lumbar spinal stenosis and its association with physical performance in a population-based cohort in Japan: The Wakayama Spine Study. Osteoarthritis Cartilage 2012;20:1103-1108. 3. O’Donnell J, O’Donnell A. Prostaglandin E2 content in herniated lumbar disc disease. Spine (Phila Pa 1976) 1996;21:1653-1655. 4. DePalma MJ, Slipman CW. Lumbar radicular pain: An algorithmic methodology. In: Slipman C, Derby R, Simeone F, Mayer T, eds.

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Interventional Spine: An Algorithmic Approach, Philadelphia, PA: Elsevier; 2007, 893-910. Spivak JM. Degenerative lumbar spinal stenosis. J Bone Joint Surg Am 1998;80:1053-1066. Sirvanci M, Bhatia M, Ganiyusufoglu KA, et al. Degenerative lumbar spinal stenosis: Correlation with Oswestry Disability Index and MR imaging. Eur Spine J 2008;17:679-685. Postacchini F. Surgical management of lumbar spinal stenosis. Spine (Phila Pa 1976) 1999;24:1043-1047. Kabayashi S, Uchida K, Takeno K, et al. Imaging of cauda equina edema in lumbar canal stenosis by using gadolinium-enhanced MR imaging: experimental constriction injury. AJNR Am J Neuroradiol 2006;27: 346-353. Igarashi A, Kikuchi S, Konno S. Correlation between inflammatory cytokines released from the lumbar facet joint tissue and symptoms in degenerative lumbar spinal disorders. J Orthop Sci 2007;12:154-160. Delamarter RB, Bohlman HH, Dodge LD, Biro C. Experimental lumbar spinal stenosis: Analysis of the cortical evoked potentials, microvasculature, and histopathology. J Bone Joint Surg 1990;72-A:110-120. Olmarker K, Holm S, Rosenqvist A, Rydevik B. Experimental nerve root compression: A model of acute, graded compression of the porcine cauda equina and an analysis of neural and vascular anatomy. Spine (Phila Pa 1976) 1991;1:61-69. Schonstrom N, Bolender NF, Spengler DM, Hansson TH. Pressure changes within the cauda equina following constriction of the dural sac: An in vitro experimental study. Spine (Phila Pa 1976) 1984; 9:604-607. Botwin K, Brown LA, Fishman M, Rao S. Fluoroscopically guided caudal epidural steroid injections in degenerative lumbar spine stenosis. Pain Physician 2007;10:547-558. Onda A, Yabuki S, Kikuchi S, et al. Effects of lidocaine on blood flow and endoneurial fluid pressure in a rat model of herniated nucleus pulposus. Spine (Phila Pa 1976) 2001;26:2186-2191; discussion 2191-2192. Johansson A, Hao J, Sjolund B. Local corticosteroid application blocks transmission in normal nociceptive C-fibres. Acta Anaesthesiol Scand 1990;34:335-338. Kantrowitz F, Robinson DR, McGuire MB, Levine L. Corticosteroids inhibit prostaglandin production by rheumatoid synovia. Nature 1975; 258:737-739. Haimovic IC, Beresford HR. Dexamethasone is not superior to placebo for treating lumbosacral radicular pain. Neurology 1986;36:15931594. Friedman BW, Esses D, Solorzano C, et al. A randomized placebocontrolled trial of single-dose IM corticosteroid for radicular low back pain. Spine (Phila Pa 1976) 2008;33:E624-E629. Dilke TFW, Burry HC, Grahame R. Extradural corticosteroid injection in management of lumbar nerve root compression. BMJ 1973;2:635637. Carette S, LeClaire R, Marcoux S, et al. Epidural corticosteroids injections for sciatica due to herniated nucleus pulposus. N Engl J Med 1997;336:1634-1640. Valat JP, Giraudeau B, Rozenberg S, et al. Epidural corticosteroid injections for sciatica: A randomised, double blind, controlled clinical trial. Ann Rheum Dis 2003;62:639-643. Breivik H, Hesla PE, Molnar I, Lind B. Treatment of chronic low back pain and sciatica. Comparison of caudal epidural injections of bupivacaine and methylprednisolone with bupivacaine followed by saline. In: Bonica JJ, Albe- Fessard D, eds. Advances in Pain Research and Therapy. vol 1. New York, NY: Raven Press; 1976, 927-932. Bush K, Hillier S. A controlled study of caudal epidural injections of triamcinolone plus procaine for the management of intractable sciatica. Spine (Phila Pa 1976) 1991;16:572-575. Ghahreman A, Ferch R, Bogduk N. The efficacy of transforaminal injection of steroids for the treatment of lumbar radicular pain. Pain Med 2010;11:1149-1168.

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25. Park JW, Nam HS, Cho SK, Jung HJ, Lee BJ, Park Y. Kambin’s triangle approach of lumbar transforaminal epidural injection with spinal stenosis. Ann Rehabil Med 2011;35:833-843. 26. Botwin KP, Gruber RD, Bouchlas CG, et al. Fluoroscopically guided lumbar transformational epidural steroid injections in degenerative lumbar stenosis. An outcome study. Am J Phys Med Rehabil 2002;8: 898-905. 27. Jeong HS, Lee J, Kim SH, Myung JS, Kim JH, Kang HS. Effectiveness of transforaminal epidural steroid injection by using a preganglionic approach: A prospective randomized controlled study. Radiology 2007;245:584-590. 28. Narozny M, Zanetti M, Boos N. Therapetuic efficacy of selective nerve root blocks in the treatment of lumbar radicular leg pain. Swiss Med Wkly 2001;131:75-80. 29. Cyteval C, Fesquet N, Thomas E, Decoux E, Blotman F, Taourel P. Predictive factors of efficacy of periradicular corticosteroid injections for lumbar radiculopathy. Am J Neuroradiol 2006;27:978-982. 30. Smith CC, Booker T, Schaufele MK, Weiss P. Interlaminar versus transforaminal epidural steroid injections for the treatment of symptomatic lumbar spinal stenosis. Pain Med 2010;11:1511-1515. 31. Botwin KP, Gruber RD, Bouchlas CG, Torres-Ramos FM, Freeman TL, Slaten WK. Complications of fluoroscopically guided transforaminal lumbar epidural injections. Arch Phys Med Rehabil 2000;81:10451050. 32. Karaman H, Kavak GO, Tufel A, Yildrim ZB. The complications of transforaminal lumbar epidural steroid injections. Spine (Phila Pa 1976) 2011;36:E819-824.

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33. Huston C, Slipman C, Garvin C. Complications and side effects of cervical and lumbosacral selective nerve root injections. Arch Phys Med Rehabil 2005;86:277-283. 34. Houten JK, Errico TJ. Paraplegia after lumbosacral nerve root block: Report of three cases. Spine J 2002;2:70-75. 35. Huntoon M, Martin D. Paralysis after transforaminal epidural injection and previous spinal surgery. Reg Anesth Pain Med 2004;29:494-495. 36. Somyaji HS, Saifuddin A, Casey ATH, Briggs TWR. Spinal cord infarction following therapeutic computed tomography-guided left L2 nerve root injection. Spine (Phila Pa 1976) 2005;30:E106-E108. 37. Kennedy DJ, Dreyfuss P, Aprill CN, Bogduk N. Paraplegia following image- guided transforaminal lumbar spine epidural steroid injection: Two case reports. Pain Med 2009;19:1389-1394. 38. Derby R, Date ES, Lee JH, Lee SH, Lee CH. Size and aggregation of corticosteroids used for epidural injections. Pain Med 2008;9:227-234. 39. Dawley JD, Moeller-Bertram T, Wallace MS, Patel PM. Intra-arterial injection in the rat brain. Evaluation of steroids used for transforaminal epidurals. Spine (Phila Pa 1976) 2009;34:1638-1643. 40. Smuck M, Fuller BJ, Chiodo A, et al. Accuracy of intermittent fluoroscopy to detect intravascular injection during transforaminal epidural injections. Spine (Phila Pa 1976) 2008;33:E205-E210. 41. Karasek M, Bogduk N. Temporary neurologic deficit after cervical transforaminal injection of local anesthetic. Pain Med 2004;5:202-205. 42. Park CH, Lee SH, Kim B. Comparison of the effectiveness of lumbar transforaminal epidural injection with particulate and nonparticulate corticosteroids in lumbar radiating pain. Pain Med 2010;11: 1654-1658.

Alison Stout, DO, Responds A repeated transforaminal epidural steroid injection (TFESI) is a reasonable plan of care in this patient, but the choice of steroid should reflect consideration of the recent scientific literature. Epidural corticosteroid injections are associated with rare but catastrophic injury to the central nervous system. The risk of this serious complication varies by the route of injection and the region of the spine targeted. A large proportion of these injuries during the transforaminal approach have been attributed to occlusion of an artery that supplies the central nervous system. Specifically, this complication is thought to arise from the injection of a particulate corticosteroid into a radiculomedullary or vertebral artery, which results in an embolic injury and causes permanent and catastrophic ischemic injury to the spinal cord and brain. Evidence of embolic injury to the central nervous system during TFESI first emerged as case reports [1]. For cervical TFESI, a survey of pain physicians has also revealed a total of 78 neurologic complications, including 16 vertebrobasilar brain infarctions, 12 spinal cord infarctions, and 2 combined brain and/or spinal cord infarctions [2]. The actual number of cases and the incidence of central nervous system complication due to intra-arterial injection of particulate steroid is difficult to ascertain. Case reports underestimate the incidence due to medical-legal considerations and a lack in novelty with subsequent cases that result in fewer publications of these events. Alternatively, a survey may overestimate incidence (eg, more than one provider reports the same complication). In an evaluation done for mass media corpo-

ration Bloomberg LP, the FDA data were used to determine the number of adverse events due to ESI. Bloomberg LP found that, between 2004 and 2011, 198 patients experienced serious complications due to ESI [3]. The exact type of epidural injection and the exact injuries were not reported. In addition, the authors of this article cited that, according to government estimates, only 1%-10% of adverse drug events are reported to the FDA. Therefore, this method also cannot determine the true incidence of injury due to intra-arterial injection of particulate steroid during TFESI. The risk of inadvertent intra-arterial injection varies by region of the spine due to anatomic considerations. In the cervical spine, the vertebral artery lies within the intervertebral foramen at every spinal level and is in close proximity to the target for TFESI. The vertebral artery is generally not encountered if the needle is kept in the posterior foramen and the appropriate needle depth is obtained [4]. There, however, is anatomic variability, in which a tortuous vertebral artery may be encountered in the posterior foramen. Also located within the intervertebral foramen are spinal branches of the ascending and deep cervical arteries that supply the anterior spinal artery and the anterior spinal cord. In addition to supplying the anterior spinal cord, these branches anastomose with branches from the vertebral artery and, if injured, could jeopardize brainstem and cerebellar tissues as well. The radiculomedullary arteries enter the foramen posteriorly, usually within the “safe triangle” target for TFESI needle placement [5]. There is anatomic variation of the number ra-

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diculomedullary arteries and at which spinal levels these arteries occur. In a 1971 study of the 62 radicular arteries, only 7 or 8 actually perfused the spinal cord [6]. In the thoracolumbar spine, there usually is a single, large reinforcing radiculomedullary artery, the artery of Adamkiewicz [7]. This artery arises more often on the left and in the thoracic levels, but it can occur as low as L2 or L3 in approximately 1% of patients and more rarely at lower levels [8]. In a cadaveric study, the artery of Adamkiewicz had been found as low as S2 [9]. Despite low rates of occurrence of radiculomedullary arteries at lumbosacral levels, anterior spinal cord injury after TFESI with particulate steroid that results in paraplegia has been reported in several cases [1,10,11]. Analysis of the anatomic evidence and case reports suggests that the risk of encountering the artery of Adamkiewicz is greater at L3 and above. There are several case reports of spinal cord injury after TFESI of particulate steroid at L3 and above, although there is one report of paraplegia after S1 TFESI [10,12]. With evidence that intra-arterial injection of steroid can cause embolic neurologic injury during TFESI, corticosteroid particulate size becomes relevant. Commonly used steroid preparations such as triamcinolone (Kenalog; Bristol-Meyers Squibb, New York, NY), methylprednisolone (Depo-Medrol; Pfizer Inc, New York, NY), and betamethasone (Celestone; Merck and Co, Whitehouse Station, NJ) have been shown to have particles that exceed the caliber of arterioles, and all of these have published cases of paralysis in the literature [1]. Dexamethasone and betamethasone sodium phosphate are the only 2 corticosteroids that do not have either particles or aggregates larger than red blood cells. It has been proposed that the use of these particulate-free steroids for TFESI would lower the risk of embolic injury. Of these, only dexamethasone phosphate (Decadron; Merck) is commercially available. The safety of particulate and nonparticulate corticosteroids has been evaluated in animal models, via direct vertebral artery injection of dexamethasone and methylprednisolone in pigs [13]. The results demonstrated that pigs that received particulate steroid (methylprednisolone) never regained consciousness and had signs of ischemic neurologic injury on autopsy, whereas all those that were administered nonparticulate steroid (dexamethasone) showed no evidence of neurologic injury and no changes were noted on brain magnetic resonance imaging. Therefore, it was concluded that if inadvertent intra-arterial injection were to occur during TFESI, dexamethasone should not result in neurologic injury. In a separate animal study, direct injection of corticosteroid into the carotid artery of rats was used to test the same hypothesis. In addition to Depo-Medrol, this study also compared the effects of Solu-Medrol (Pfizer), which contains the carrier benzyl alcohol, and the Depo-Medrol carrier alone (polyethylene glycol). Solu-Medrol, Depo-Medrol, and its carrier alone all resulted in hemorrhagic brain injury,

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whereas none of the rats injected with saline solution or with Decadron showed any evidence of brain injury [14]. Because the carrier alone resulted in injury and because the type of injury was hemorrhagic rather than embolic, the researchers suggested that injury may not be only due to particulate but rather a chemical vascular injury. However, they also expressed that the “carrier alone” was prepared by spinning down the Depo-Medrol and could have in fact still contained particulate. Although further study is clearly needed, these findings suggest that vascular injury may be due to the particulate corticosteroid or the additives in the carrier. Concern regarding steroid carriers and preservatives in epidural injection dates back to the 1980s. Some researchers published concern of intraspinal neurotoxicity due to propylene glycol, a congener of polyethylene glycol (PEG), which is contained in some steroid preparations. Propylene glycol was shown to be necrotizing to axons, myelin, and connective tissue in animal models, and it was suggested that PEG could cause injury if injected intrathecally [15]. Methylprednisolone contains PEG, whereas triamcinolone acetonide, betamethasone, and dexamethasone do not [1]. Only methylprednisolone contains PEG, therefore, PEG alone could not account for the reported injuries after intra-arterial injection with triamcinolone acetonide (Kenalog) or betamethasone (Celestone). Nonetheless, the potential of vascular injury due to steroid carrier may be a consideration when selecting a steroid for epidural injection. Nonscientific influences have also changed the selection of steroid for epidural use for some physicians. In June 2011, Bristol-Meyers changed the Kenalog package insert to include “not recommended” for epidural use. The company reported it was because of “reports of serious medical events, including death.” Bristol-Meyers did not specify the nature of the injuries or the route of injection, although the presumption is that they were responding to case reports of inadvertent intra-arterial injections that resulted in severe morbidity. Although not founded on scientific evidence, this has caused some physicians to refrain from the use of Kenalog in favor of other particulate steroids, such as methylprednisolone. However, due to the results of the above-mentioned study of intra-arterial injection of methylprednisolone carrier in rats [14], the move away from Kenalog in favor of other particulate steroid may not be advantageous. To date, the evidence indicates that nonparticulate steroid is safer if inadvertently injected intra-arterially, but there is debate regarding the efficacy of nonparticulate corticosteroids. There are 2 studies of TFESI in the cervical spine that do not show a significant difference in efficacy between particulate and nonparticulate steroid [16,17]. Conversely, there is one lumbar TFESI study that showed that pain scores were significantly more improved with triamcinolone versus dexamethasone at 1 month [18]. It is possible that there may be slightly improved results with particulate steroid, although the difference is not overwhelming.

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Despite the difficulty in ascertaining the true level of risk of intra-arterial injection during TFESI when properly performed by an experienced and knowledgeable physician, the risk of resulting injury is reduced presumably to nearly zero with the use of nonparticulate steroid (dexamethasone). When weighing the risks versus benefits, the use of particulate steroid for TFESI is not favored. There is not clear evidence that particulate steroid is superior to nonparticulate steroid. Yet, there is unequivocal evidence that particulate steroid can cause serious harm if injected intra-arterially. Given that the risk is much more relevant at spinal levels above L4, nonparticulate steroid is favored for TFESI in these cases until further evidence of superiority is demonstrated. For TFESI at L4 and below, such as in this case, nonparticulate steroid should be the first choice and particulate steroids be reserved for patients who seem to be nonresponders to a nonparticulate steroid. I would recommend dexamethasone as a first choice. Specifically, I would recommend preservative-free dexamethasone. If she has relief that is only temporary or insufficient after TFESI with dexamethasone, then the use of a particulate steroid injected via a transforaminal or possibly an interlaminar approach could be discussed. The informed consent process would include a discussion of increased risk with particulate steroid and TFESI.

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4. Ma DJ, Gilula LA, Riew KD. Complications of fluoroscopically guided extraforaminal cervical nerve blocks An analysis of 1036 injections. J Bone Joint Surg Am 2005;87:1025-1030. 5. Huntoon MA. Anatomy of the cervical intervertebral foramina: Vulnerable arteries and ischemic neurologic injuries after transforaminal epidural injections. Pain 2005;117:104-111. 6. Lazorthes G, Gouaze A, Zadeh JO, Santini JJ, Lazorthes Y, Burdin P. Arterial vascularization of the spinal cord. Recent studies of the anastomotic substitution pathways. J Neurosurg 1971;35:253-262. 7. Bogduk N, Dreyfuss P, Baker R, Yin W, Landers M, Hammer M, Aprill C. Complications of spinal diagnostic and treatment procedures. Pain Med (Malden, Mass.) 2008:S11-S34. 8. Lo D, Valleé JN, Spelle L, et al. Unusual origin of the artery of Adamkiewicz from the fourth lumbar artery. Neuroradiology 2002;44:153-157. 9. Kroszczynski AC, Kohan K, Kurowski M, Olson TR, Downie SA. Intraforaminal location of thoracolumbar anterior medullary arteries. Pain Med 2013 Feb 25 [Epub ahead of print]. 10. Kennedy DJ, Dreyfuss P, Aprill CN, Bogduk N. Paraplegia following image-guided transforaminal lumbar spine epidural steroid injection: two case reports. Pain Med 2009;10:1389-1394. 11. Thefenne L, Dubecq C, Zing E, et al. A rare case of paraplegia complicating a lumbar epidural infiltration. Ann Phys Rehabil Med 2010;53: 575-583. 12. Houten JK, Errico TJ. Paraplegia after lumbosacral nerve root block: Report of three cases. Spine J 2002;2:70-75. 13. Okubadejo GO, Talcott MR, Schmidt RE, et al. Perils of intravascular methylprednisolone injection into the vertebral artery an animal study. J Bone Joint Surg 2008;90:1932-1938. 14. Dawley JD, Moeller-Bertram T, Wallace MS, Patel PM. Intra-arterial injection in the rat brain: Evaluation of steroids used for transforaminal epidurals. Spine (Phila Pa 1976) 2009;34:1638-1643. 15. Bernat JL. Intraspinal steroid therapy. Neurology 1981;31:168-171. 16. Dreyfuss P, Baker R, Bogduk N. Comparative effectiveness of cervical transforaminal injections with particulate and nonparticulate corticosteroid preparations for cervical radicular pain. Pain Med 2006;7:237242. 17. Lee JW, Park KW, Chung S-K, et al. Cervical transforaminal epidural steroid injection for the management of cervical radiculopathy: A comparative study of particulate versus non-particulate steroids. Skeletal Radiol 2009;38:1077-1082. 18. Park CH, Lee SH, Kim BI. Comparison of the effectiveness of lumbar transforaminal epidural injection with particulate and nonparticulate corticosteroids in lumbar radiating pain. Pain Med 2010;11:1654-1658.

Michael J. DePalma, MD, Rebuts Dr Stout nicely articulates why the intra-arterial injection of particulate steroids must be avoided during TFESIs. In addition, the FDA has cautioned against instillation of particulate steroid into the epidural space. However, when performed properly by experienced physicians following appropriate guidelines, severe complications can be avoided. Therefore, the effectiveness of TFESIs must be taken into consideration. The largest prospective randomized trial to date that compared particulate with nonparticulate steroids for radicular pain via a single TFESI showed that 86.7% (95% CI, 77.9%-96.0%) of patients injected with triamcinolone report a visual analog scale (VAS) score of 0-3 at 1-month follow-up; in contrast, only 35.8% (95% CI, 22.9%-48.7%) of similar patients treated

with dexamethasone experience, after injection, VAS radicular pain of 0-3 [1]. Even the casual reader would be impressed by the definitively more-effective performance of triamcinolone over dexamethasone at 1 month. What needs to be underscored is the overuse of TFESIs. A published report exclaims the drastic increases in TFESIs performed in the United States over the past decade [2]. Within these data are the identities of the groups of physicians who perform these procedures, but absent in the report is whether these clinicians adhered to supported guidelines when performing these procedures [3]. Therefore, our focus ought to remain on how to properly perform an effective procedure rather than to abandon a proven [4] treatment. Failure to comply with defensible

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and recommended standards for technical performance of TFESIs can, and perhaps does, lead to these catastrophic complications. However, this speculation warrants further examination of these potential relationships rather than solely recommending withholding a TFESI of particulate steroid. Substituting a less-effective drug during a TFESI to avoid a rare but grave complication, which may be preventable by using other safety measures, is difficult to accept on scientific grounds. If proper safety measures are not exercised either due to insufficient knowledge or scarce resources to ensure safe TFESIs, the injection ought to be postponed until these measures are available. However, warning against use of a medication when perhaps only its misuse has been implicated in relation to compli-

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cations is less defensible when proper use of the drug has demonstrated effectiveness.

REFERENCES 1. Park CH, Lee SH, Kim B. Comparison of the effectiveness of lumbar transforaminal epidural injection with particulate and nonparticulate corticosteroids in lumbar radiating pain. Pain Med 2010;11:1654-1658. 2. Manchikanti L, Flaco FJE, Singh V, et al. Utilization of interventional techniques in managing chronic pain in the Medicare population: Analysis of growth patterns from 2000-2011. Pain Physician 2012;15:E969E982. 3. Bogduk N, ed. Practice Guidelines. Spinal Diagnostic and Treatment Procedures. San Francisco, CA: International Spinal Intervention Society; 2004. 4. Ghahreman A, Ferch R, Bogduk N. The efficacy of transforaminal injection of steroids for the treatment of lumbar radicular pain. Pain Med 2010;11:1149-1168.

Alison Stout, DO, Rebuts I concur that the study by Park et al [1] of lumbar TFESI for radicular pain showed that triamcinolone (40 mg) is superior to dexamethasone (7.5 mg) for improvement in pain scores at 1 month. It should be noted, however, that there were not significant differences between groups for secondary measures (Oswestry Disability Index [ODI] and McGill Pain Questionnaire). Additionally, statistically significant does not necessarily equate to a clinically significant difference. The superiority of particulate steroid for pain relief in this study is in contrast to 3 other studies that do not show a difference between particulate and nonparticulate steroid at 1-month follow-up [2-4]. In one of the cervical TFESI studies, there was a slight trend favoring triamcinolone (60 mg) over dexamethasone (12.5 mg), which was not statistically significant [2]. Another study for lumbar interlaminar ESI showed no significant difference between methylprednisolone (80 mg) and dexamethasone (15 mg) [4]. All of these studies used a dexamethasone dose equivalent to the triamcinolone dose, but the Park et al study used a lesser dose of each. It is unclear if this could contribute to a difference in results. Several factors in the study by Park et al [1] may have affected the results. Although the study was randomized, there, unfortunately, was a significant difference in baseline pain scores between groups. There were significantly more subjects with higher initial VAS scores in the triamcinolone group. It is possible that higher initial pain levels may result in a greater percentage of improvement. Other baseline characteristics that were not evaluated could also influence results. For example, those with compression due to a herniated disk may have a different response to steroid than those with osseous impingement. In addition, secondary gain, depression, and endocrinologic disorders could affect results and were not assessed. One substantial difference of the Park et al [1] compared to other studies was a lack of blinding. It is difficult

to blind the physician who performs the injection due to the obvious visual difference between particulate and nonparticulate steroid, and none of the studies have attempted this. However, other studies did blind the study personnel who were collecting the follow-up data. The personal preference and beliefs of the person collecting the data in the study by Park et al [1] could have influenced the VAS scores. In closely examining all of the current evidence, there is still not significant proof that particulate is superior to nonparticulate steroid at 1-month follow-up. Future studies comparing types of steroid should account for baseline characteristics that could influence outcomes, utilize blinded and unbiased data collection, and include follow-up to at least 6-12 weeks to better assess for a difference in duration of effect. I also agree that the risk of intra-arterial injection during TFESI is minimized when it is properly performed in adherence to all safety standards. However, “low risk” does not equate to “no risk” in the cervical or lumbar spine. There has been a case of cord infarction after L5 TFESI with triamcinolone despite using all precautionary measures [5]. The researchers report using fluoroscopic verification in 3 planes, digital subtraction angiography, and a test dose of lidocaine. Unfortunately, the patient still experienced a cord infarction from T6-T10 and resulting paraplegia. This illustrates that, despite a lower risk in the lumbar spine and use of proper procedural steps, there is still a risk of catastrophic neurologic injury with TFESI when using particulate steroid. The procedural steps that improve safety, such as digital subtraction angiography, reduce the risk of intra-arterial injection, but are vulnerable to technical and/or interpretation errors. Risks are only further increased when meticulous technique is not practiced. So, in the interest of safety, it may be better to recommend nonparticulate steroid for TFESI, at least at L3

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and above, until there is clear evidence of the superiority of particulate steroid.

REFERENCES 1. Park CH, Lee SH, Kim BI. Comparison of the effectiveness of lumbar transforaminal epidural injection with particulate and nonparticulate corticosteroids in lumbar radiating pain. Pain Med 2010;11:1654-1658. 2. Dreyfuss P, Baker R, Bogduk N. Comparative effectiveness of cervical transforaminal injections with particulate and nonparticulate corticosteroid preparations for cervical radicular pain. Pain Med 2006;7:237-242.

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3. Lee JW, Park KW, Chung S-K, et al. Cervical transforaminal epidural steroid injection for the management of cervical radiculopathy: A comparative study of particulate versus non-particulate steroids. Skeletal Radiol 2009;38:1077-1082. 4. Kim D, Brown J. Efficacy and safety of lumbar epidural dexamethasone versus methylprednisolone in the treatment of lumbar radiculopathy: A comparison of soluble versus particulate steroids. Clin J Pain 2011;27:518-522. 5. Chang Chien GC, Candido KD, Knezevic NN. Digital subtraction angiography does not reliably prevent paraplegia associated with lumbar transforaminal epidural steroid injection. American Academy of Pain Medicine. 2013 Scientific Poster Abstracts. Available at http://www. painmed.org/2013posters/abstract-177/. Accessed May 11, 2013.

David J. Kennedy, MD, Commentary There are several aspects that add complexity to this important conversation. Dr Stout clearly articulated the severe detrimental neurologic effects of inadvertent intra-arterial injection of a particulate corticosteroid. She also pointed out that 3 studies thus far failed to demonstrate a statistically significant difference in the short-term efficacy of particulate and nonparticulate corticosteroids [1-3]. However, these studies did have a trend that favored particulate corticosteroids, and they were all likely underpowered. It would take an estimated 796 patients to truly determine if no differences in efficacy existed between these preparations [1]. Dr DePalma made a compelling argument that the efficacy of nonparticulate corticosteroids may be less than the particulate corticosteroids based on the largest published study to date [4]. Both discussants also considered a variety of appropriate safeguards that may limit the potential of developing a serious complication. Dr Stout was correct in noting that these safeguards may not decrease the risk of an injection to zero. However, it is essential to note that no spine injection, regardless of safeguards implemented or corticosteroid used, has zero risk. Patients, therefore, must be adequately consented to the potential risks. Physicians should also consider the risks and benefits of a given treatment and alternative treatments as well as their relative efficacy when making recommendations. The rate of paralysis as a complication of a TFESI is unclear. To date, 12 cases have been published in the literature, but there were approximately 2 million epidural injections done in the U.S. Medicare population in 2011 alone [5]. Given the frequency of this procedure, this is clearly a rare complication. As a comparison, a recent study showed spine surgical complication rates of 27%, with the majority being “moderately to extremely bothersome” [6]. Because the failure of percutaneous procedures may result in additional treatments, physicians must consider the effects of using a potentially less-effective treatment. For instance, if we assume a 60% efficacy based on published literature for particulate steroids [7], then a mere decrement of 5% efficacy by using either a less-effective corticosteroid or alternative injection route in the 2 million Medicare patients who received an ESI in 2011 could result in 100,000 patients annually undergoing a less-effective treatment. This may, in

turn, result in significantly more medication use, repeated procedures, and even spine surgeries. The ultimate population-based outcome due to less-effective treatments may be more overall morbidity and mortality. This number is only enhanced when one considers that the study by Park et al [4] demonstrated an efficacy difference much greater than 5%, and the Medicare population is only approximately 15% of the U.S. population. Thus, it is in our patient’s interest to use an effective treatment. To date, there is no clarification in the literature of which corticosteroid preparation is the most efficacious, but trends do favor particulate corticosteroids. Unfortunately, the corticosteroid options are being limited for nonscientific reasons, as evidenced by the recent label change on triamcinolone to state “Not for Epidural Use.” By using similar logic, the routine use of alternative injection routes such as caudal epidurals or non–image-guided interlaminar injections as a “safer” alternative may also be less than ideal because analysis of the research results have shown these types of injections to have less efficacy [8,9]. Based on a large volume of research, it is clear that these procedures can be effective when used for appropriate conditions [7,8]. ESIs are indicated for radicular pain that results in functional limitations and the patient has failed or is unable to tolerate appropriate conservative therapies. Unfortunately these injections, although effective, are likely overused, perhaps by clinicians who do not abide by recommended standards. This obviously contributes to more complications. Because overuse does not equal inefficacy, it is essential to assure that these injections are done for appropriate conditions. For instance, there currently is no literature-based indication for a routine series of 3 injections. It is also clear that practitioners must be aware of the potential complications of these procedures, the preprocedure likelihood of developing them as well as techniques that may decrease their likelihood. Given the literature outlined in this article, it may be reasonable to consider nonparticulate corticosteroids as a first-line interventional treatment for TFESI in the lower lumbar spine. Particulates can be used as a second-line medication in attempts to avoid surgery with its known higher complication rates. In this case, the patient

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had previously responded to a particulate corticosteroid, thus it may be reasonable to consider the repeated use of a particulate corticosteroid because this is not a first-line treatment and the patient had previously responded well to the particulate medication. The use of a particulate corticosteroid may necessitate the use of additional safeguards to prevent serious neurologic complications such as an anesthetic test dose, digital subtraction angiography, or an infraneural approach. Additional factors that change the preprocedure probability of developing serious complications include procedural levels at L3 and higher, a history of spine surgery, or preforming multiple procedures at once [10]. Additional safety measures may be required, depending on the patient and the preprocedural possibility of developing a complication. In some cases, such as a cervical TFESI, the risk of particulate corticosteroids may be too high to justify their use. A multicenter research study that compares the efficacy of particulate with nonparticulate corticosteroids is currently in its final stages. The outcomes of this study may change these recommendations; especially if the particulate steroid is found to have either greater efficacy, require fewer injections to achieve the same efficacy, or result in less surgery.

REFERENCES 1. Dreyfuss P, Baker R, Bogduk N. Comparative effectiveness of cervical transforaminal injections with particulate and nonparticulate corticosteroid preparations for cervical radicular pain. Pain Med 2006;7:237-242.

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2. Lee JW, Park KW, Chung S-K, et al. Cervical transforaminal epidural steroid injection for the management of cervical radiculopathy: A comparative study of particulate versus non-particulate steroids. Skeletal Radiol 2009;38:1077-1082. 3. Kim D, Brown J. Efficacy and safety of lumbar epidural dexamethasone versus methylprednisolone in the treatment of lumbar radiculopathy: A comparison of soluble versus particulate steroids. Clin J Pain 2011;27: 518-522. 4. Park CH, Lee SH, Kim B. Comparison of the effectiveness of lumbar transforaminal epidural injection with particulate and nonparticulate corticosteroids in lumbar radiating pain. Pain Med 2010;11:16541658. 5. Manchikanti L, Flaco FJE, Singh V, et al. Utilization of interventional techniques in managing chronic pain in the Medicare population: Analysis of growth patterns from 2000-2011. Pain Physician 2012;15: E969-E982. 6. Mannion AF, Fekete TF, O’Riordan D, Porchet F, Mutter UM, Jeszenszky D, Lattig F, Grob D, Kleinstueck FS. The assessment of complications after spine surgery: Time for a paradigm shift? Spine J. [Epub ahead of print] 7. MacVicar J, King W, Landers MH, Bogduk N. The effectiveness of lumbar transforaminal injection of steroids. 8. Ghahreman A, Ferch R, Bogduk N. The efficacy of transforaminal injection of steroids for the treatment of lumbar radicular pain. Pain Med 2010;11:1149-1168. 9. Kolsi et al., Efficacy of nerve root versus interspinous injections of glucocorticoids in the treatment of disk-related sciatica. A pilot, prospective, randomized, double-blind study. 10. Kennedy DJ, Dreyfuss P, Aprill CN, Bogduk N. Paraplegia following image- guided transforaminal lumbar spine epidural steroid injection: Two case reports. Pain Med 2009;19:1389-1394.

Web Poll Question For the case scenario presented in this Point/Counterpoint, which approach would you recommend? a. perform epidural injection with a particulate corticosteroid b. perform epidural injection with a nonparticulate corticosteroid To cast your vote, visit www.pmrjournal.org

Results of April’s Web Poll For the case scenario presented in The Utility of Routine Screening for Deep Vein Thrombosis Upon Admission to an Inpatient Brain Injury Rehabilitation Unit, would you: 80% - selectively screen based on history, examination findings, comorbidities, and functional status 20% - routinely screen all TBI inpatients for DVT with venous Doppler ultrasound