Systematic Review of the Efficacy of Particulate Versus Nonparticulate Corticosteroids in Epidural Injections

Accepted Manuscript Systematic Review of the Efficacy of Particulate vs Non particulate Corticosteroids in Epidural Injections Priyesh Mehta, D.O., Isaac Syrop, M.D., Jaspal Ricky Singh, M.D., Jonathan Kirschner, M.D PII:

S1934-1482(16)31195-9

DOI:

10.1016/j.pmrj.2016.11.008

Reference:

PMRJ 1825

To appear in:

PM&R

Received Date: 16 February 2016 Revised Date:

13 November 2016

Accepted Date: 16 November 2016

Please cite this article as: Mehta P, Syrop I, Singh JR, Kirschner J, Systematic Review of the Efficacy of Particulate vs Non particulate Corticosteroids in Epidural Injections, PM&R (2016), doi: 10.1016/ j.pmrj.2016.11.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Systematic Review of the Efficacy of Particulate vs Non particulate Corticosteroids in Epidural Injections

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Weill Cornell Medical College, New York, NY USA

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Hospital for Special Surgery, New York, NY USA

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Priyesh Mehta D.O.1, Isaac Syrop M.D. 2, Jaspal Ricky Singh M.D.3, Jonathan Kirschner M.D4

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Correspondence To: Priyesh Mehta D.O.

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535 East 70th St.

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Telephone Number: 617-548-8603 Email: [email protected]

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Abstract

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Objective: To systematically analyze published studies in regards to the comparative efficacy of

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particulate versus non-particulate corticosteroids for cervical and lumbosacral epidural steroid injections

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(ESI) in reducing pain and improving function.

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Type: Systematic Review

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Literature Survey: MEDLINE (Ovid), EMBASE, and Cochrane databases were searched from the period of

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1950 to December 2015.

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Methodology: Criteria for inclusion in this review were: 1) Randomized controlled trials and 2)

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Retrospective studies comparing particulate versus non-particulate medication in fluoroscopically

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guided injections using a transforaminal (TF) or interlaminar (IL) approach. Each study was assigned a

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level of evidence (I-V) based on criteria for therapeutic studies. A grade of recommendation (A, B, C, or I)

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was assigned to each statement. Categorical analysis of the data was reported when available, with

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success defined by the minimal clinically important difference (MCID) for appendicular radicular pain – a

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reduction of at least 2 on the Visual Analog Scale (VAS). When data was available, additional categorical

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analysis included the proportion of individuals with a reduction in pain of at least 50%, 70% or 75%.

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Follow-up was included at all reported intervals from 2 weeks to 6 months.

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Synthesis: Three cervical ESI and 6 lumbar ESI studies were found to be suitable for review. Out of the 3

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cervical ESI studies, 2 were retrospective studies with grade III level of evidence and 1 was a randomized

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controlled trial with grade II evidence. Out of 4 lumbar ESI studies using a TF approach, the 2

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randomized double-blinded controlled trials were grade I evidence and 2 retrospective studies were

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grade II and III level of evidence. One randomized controlled trial using the lumbar IL approach was level

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II evidence. One retrospective cohort study using the lumbar TF, IL and caudal approach was level III

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evidence.

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Conclusions: There is no statistically significant difference in terms of pain reduction or improved

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functional outcome between particulate and non-particulate preparations in cervical ESI and therefore,

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the authors recommend using non-particulate steroid when performing cervical TFESI (Grade of

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Recommendation: B). In patients with lumbar radiculopathy due to stenosis or disc herniation, TFESI

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using particulate versus non-particulate is equivocal in reducing pain (Grade of Recommendation: B)

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and improving function (Grade of Recommendation: C) and therefore the authors recommend the use

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of non-particulate steroids for lumbar TFESI in patients with lumbar radicular pain (Grade of

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Recommendation: B). There is insufficient information to make a recommendation of one steroid

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preparation over the other in lumbar ILESI (Grade of Recommendation: I). Given the lack of strong data

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favoring the efficacy of one steroid preparation over the other, and the potential risk of catastrophic

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complications, all of which have been reported with particulate steroids, non-particulate steroids should

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be considered as first line agents when performing ESIs.

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Introduction

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There are several options of corticosteroids available for both transforaminal epidural steroid injections (TFESI) and interlaminar epidural steroid injections (ILESI). The corticosteroids are divided

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between particulate (triamcinolone, methylprednisolone, betamethasone) and non-particulate

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(dexamethasone) formulations.

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Since first described in 2002 by Houten and Errico, there have been 13 reported cases of spinal cord ischemia and posterior circulation infarction following cervical ESI (1-11) and an additional 19 cases

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associated with lumbosacral ESI (12-23). Specifically, reports on spinal cord ischemia after

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transforaminal injections have raised concerns about the potential for embolization of particulate

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corticosteroids during the procedure. Proposed mechanisms involve direct injury to the artery of

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Adamkiewicz or other radiculomedullary arteries in the intervertebral foramen, and intra-arterial

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corticosteroid injection with distal embolization (24). Distinct from the most widely agreed upon

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mechanism of injury – particulate size resulting in embolization – new research demonstrates an

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alternative mechanism of injury. As demonstrated in a mouse model, several particulate steroids have

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an immediate and massive effect on microvascular perfusion because of formation of RBC aggregates

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associated with the transformation of RBCs into spiculated RBCs (25). In 2011, the FDA required a label

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change for Triamcinolone stating it should not be used for ESIs. Following the label change, multiple

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organizations published recommendations using non-particulate steroids as first line agents for ESIs.

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Nonetheless, particulate steroids continue to be used because of a theoretical advantage of pain relief

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secondary to delayed clearance from the spinal canal (26-28). The objective of this review is to

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systematically analyze published studies regarding particulate verse non-particulate corticosteroids for

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cervical and lumbosacral ESIs in reducing pain and improving function.

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Methods

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MEDLINE (Ovid), EMBASE, and Cochrane databases were searched from the period of 1950 to December 2015 using the following key words: epidural steroid injection, transforaminal epidural

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steroid injection, interlaminar epidural steroid injection, dexamethasone, triamcinolone,

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methylprednisolone, betamethasone, particulate, and non-particulate. The references cited in these

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studies were also screened. Only articles published in English were included. Criteria for inclusion in this

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review were: 1) randomized controlled trials (RCTs) and retrospective studies; 2) fluoroscopically guided

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injections using a TF or IL approach; 3) only studies comparing particulate versus non-particulate

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medication.

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Studies meeting these criteria were appraised for quality. A quality checklist was used for initial

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screening. This was modeled after the 2009 PRISMA statement: Preferred Reporting items for

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Systematic Reviews and Meta-Analyses (29). The checklist included 27 items within the categories of

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title, abstract, introduction, methods, results, discussion, and funding. Only those studies that included a

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majority of these items were reviewed.

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Each study was assigned a level of evidence (I-V) based on criteria set by Wright for therapeutic studies (30). Table 1 illustrates the criteria used to assign levels of evidence. RCTs are assigned either a

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level I or a level II based on this system. Each study is summarized with a description of the study

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population, type of intervention, medications used, method of blinding, outcome measures recorded,

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follow-up duration, summarized results with particular attention to categorical analysis, medical

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complications, and study limitations. If the authors did not perform a categorical analysis yet data was

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available, categorical analysis was conducted. Success was defined by the minimal clinically important

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difference (MCID) for appendicular radicular pain – a reduction of at least 2 on the Visual Analog Scale

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(VAS) (31). When data was available, additional categorical analysis included the proportion of

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individuals with a reduction in pain of at least 50%, 70% and 75%.

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The Jadad score was used to assess bias in the RCT publications (32). This score is on a 5-point

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scale, based on adequate randomization, adequate blinding and accounting for loss to follow up within

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studies (Table 3, 4, 5, 6). The principle summary measures were related to pain, either the numeric rating scale (NRS),

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VAS, verbal integer scale (VIS) and/or McGill pain questionnaire at baseline and follow up. Additional

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summary measures included satisfaction and function/disability, scored by Oswestry disability index

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(ODI), Roland-Morris (R-M) disability questionnaire and/or Activities of Daily Living (ADL) assessment

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performed at baseline and follow up. Follow up included all reported time intervals at 2 weeks to 6

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months.

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In the Discussion section of the article the studies are appraised and a recommendation statement is made based on the summary of the studies. A grade of recommendation (A,B, C, or I) is

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assigned to each statement based on the Grades of Recommendation set by Wright et al in 2005 (30)

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(Table 2).

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Results

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Three cervical and six lumbar studies were found to be suitable for review. Two abstracts reporting on

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particulate and non-particulate used in lumbar TFESI were excluded on the basis of not meeting

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inclusion criteria and PRISMA screening (33, 34) (Figure 1).

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Cervical TFESI Particulate verse Non-particulate

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Shakir et al (35) compared dexamethasone with triamcinolone for cervical TFESI in subjects with

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neck and limb pain due to cervical stenosis or disc herniation. The authors retrospectively reviewed 441

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patients treated with between 1 and 3 cervical TFESI from C4-C7. All injections were performed by the

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same physician using 40mg of triamcinolone or 15 mg of dexamethasone. The primary outcome was a

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10-point self-reported NRS scale within 2 weeks before the injection compared to 4 weeks post

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injection. The mean reduction in pain score for those treated with triamcinolone was 2.33 and for those

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treated with dexamethasone was 2.38, both satisfying an MCID of 2 or more. However, the authors

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report no statistically significant difference in the variance between the two groups for the patient self-

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reported pain score. Furthermore, using data extrapolated from the study, based on an MCID of 2 or

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more on the NRS scale, the triamcinolone group demonstrated a 57% improvement compared to the

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dexamethasone group of 61% improvement, and as calculated using the Pearson chi squared test, there

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is no statistically significant difference between the two groups (for p=0.05; chi squared=0.32 with 3

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degrees of freedom; two-tailed p=0.92). Medical complications included 1 subject with a deep vein

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thrombosis, later found to have Factor V Leiden disorder, and 3 subjects with superficial

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thrombophlebitis. Limitations of the study include its retrospective design, lack of dose equivalency

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between the two steroid groups, and susceptibility to selection bias with a single clinical site and single

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physician. Level III (Retrospective)

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Lee et al (36) studied the effect of dexamethasone and triamcinolone for cervical TFESI. The authors retrospectively reviewed 159 patients with pain or tingling sensation in the limb and performed

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a cervical TFESI injection at the levels C4-C7 with either 40mg of triamcinolone or 10mg of

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dexamethasone. Pain improvement on a 5-point scale (no pain; much improved; slightly improved; same

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as before; aggravated) was recorded within 4 weeks following injection. At this time interval, ‘no pain’

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and ‘much improved’ were classified as effective, while the other pain groups were classified as

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ineffective. Those subjects who were deemed effective were followed until symptoms recurred. Overall,

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cervical TFESI was effective in 76.1% of patients within 4 weeks, however there was no statistically

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significant difference between triamcinolone (80.4%) and dexamethasone (69.4%). Additionally, there

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was no statistically significant difference between the groups when examining median symptom-free

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interval. Based on the data reported, categorical analysis of MCID of 2 or more on a pain scale was

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unable to be determined. Medical complications were not included in the study. Limitations of the study

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include retrospective in design, no functional outcome measure, and no long-term follow-up. Level III

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(Retrospective)

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Dreyfuss et al (37) performed a RCT comparing cervical ESI using dexamethasone versus

triamcinolone in thirty patients with unilateral nerve root compression at a single segmental level

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diagnosed by MRI. All patients were treated with a single injection between C5-C7 using a TF approach.

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Patients either received 12.5mg of dexamethasone or 60mg of triamcinolone. The primary outcome

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measure was the VAS at 4 weeks post-injection, and secondary outcome measures included a patient

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specified functional outcome score at 4 weeks. Based on the mean VAS at baseline and 4 weeks, both

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groups exhibited a statistically significant improvement, however there was no significant difference

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between the two groups. Furthermore, based on the author’s categorical analysis, described as at least

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a 50% relief of pain, there was no statistically significant difference between dexamethasone (60%) and

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triamcinolone (67%). Based on the data reported, categorical analysis of MCID of 2 or more on a pain

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scale was unable to be determined. Although the triamcinolone group demonstrated a significant

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restoration of four patient-specified activities of daily living, as compared to dexamethasone, a validated

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functional outcome measure was not used. Medical complications were not included in the study. The

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main limitation of the study is a small sample size, with a power of 7%. Level II (RCT, non-blinded).

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Lumbar TFESI Particulate versus Non-particulate Denis et al (38) compared dexamethasone with betamethasone for lumbar TFESI in subjects

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with radicular pain due to disc herniation or foraminal stenosis confirmed with CT-scan or MRI. The

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authors randomized 56 subjects into two groups: 27 patients were administered 6mg of betamethasone

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sodium acetate and 29 received 7.5mg of dexamethasone sodium phosphate. Both mixtures were

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combined with 0.25 mL of 0.9% saline for a total volume of 1ml. TFESIs were given at 1 or 2 adjacent

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levels depending on the radicular pain pattern in patients and based on decision of the treating

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physician. The primary outcome was pain reduction on a VAS. Secondary outcomes were functional

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improvements as measured by the ODI and number of complications. These outcomes were measured

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at 1, 3 and 6 month after the injection. Following TFESI’s, both groups showed statistically significant

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VAS decreases over time and statistically significant decrease in ODI at 3 and 6 months. There was no

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statistically significant difference on the VAS as measured at all time intervals between the groups.

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Additionally, categorical analysis by the authors, with success defined as 50% and 75% improvement of

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VAS between baseline and 3 months, failed to show a statistically significant difference between

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dexamethasone (59% at 50% success; 24% at 75% success) and betamethasone (33% at 50% success;

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22% at 75% success). Based on the data reported, categorical analysis of MCID of 2 or more on the VAS

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was unable to be determined. As for functional outcomes, there was no statistically significant

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difference in ODI score at both 3 months and 6 months, with the difference at 6 months at the limit of

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statistical significance (p=0.05). Furthermore, following a multivariate regression analysis of 17

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demographic and clinical variables, the results remained non-statistically significant between the two

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groups at all time periods for pain, while the difference became statistically significant at 6 months in

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favor of dexamethasone for functional improvement. The main limitation of the study is a small sample

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size with limited power in detecting a difference between steroids. Medical complications were minor

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and typically resolved within minutes to days. The most serious complication was post-dural puncture

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headache, resolved with a blood patch. Level I (RCT, double-blinded).

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Kennedy et al (39) studied subjects with lumbosacral radicular pain due to an MRI confirmed

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single level herniated disc below L3. The authors randomized 78 subjects to either 1.5ml of

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dexamethasone phosphate (10mg/ml) or 1.5ml of triamcinolone acetonide (40mg/ml). Both the subject

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and treating physician were blinded to the intervention. The primary outcome of NRS pain score,

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number of injections, and surgical rates were recorded at 2 weeks, 3 months and 6 months. Secondary

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outcome included the ODI. All the subjects showed statistically significant improvements in pain and

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function at 2 weeks, 3 months and 6 months. However, at 2 weeks, 3 months and 6 months there was

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neither a statistically significant difference in categorical pain relief, defined by the authors as more than

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50% reduction in pain, between dexamethasone (32%, 73%, 73%) and triamcinolone (43%, 73%, 76%),

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nor a difference in mean ODI between dexamethasone (27%, 68%, 71%) and triamcinolone (35%, 68%,

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65%). Based on the data reported, categorical analysis of MCID of 2 or more on the NRS pain score was

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unable to be determined. There was a statistically significant difference in the number of injections

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received, with 17.1% of the dexamethasone group receiving three injections compared to 2.7% of the

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triamcinolone group. Medical complications were not included in this study. The main limitation of the

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study is a small sample size, with a power deficient to find small differences in effectiveness between

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corticosteroids preparations, as well as lack of confounder control. Level I (RCT, double-blinded).

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phosphate/betamethasone acetate and triamcinolone in 2,634 subjects with radicular pain secondary to

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disc herniation and fixed lateral recess or foraminal stenosis. TFESIs were retrospectively reviewed at

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the L4-5, L5-S1 and S1-2 levels. Primary outcome measures included pain NRS score and R-M disability

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questionnaire at 2 weeks and 2 months. Pain relief and R-M scores improved after both dexamethasone

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and particulate steroids at 2 weeks and 2 months. With continuous outcomes, dexamethasone was

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significantly superior to the particulate steroids in both pain relief and functional recovery at 2 months.

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Based on categorical analysis of pain, defined by the authors as at least a 50% reduction in pain, there

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was neither a statistically significance difference at 2 weeks between dexamethasone (40%) and

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particulate steroids (43%), nor at 2 months between dexamethasone (52%) and particulate steroids

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(44%). Additionally, based on categorical analysis of function, defined by the authors as reduction in R-

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the data reported, categorical analysis of MCID of 2 or more on the pain NRS score was unable to be

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determined. Medical complications were not included in this study. The main limitations of the study

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include its retrospective design and significant number of subjects lost to follow up. Level III

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(Retrospective)

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Park et al (41) randomized 106 subjects with MRI confirmed lumbar radicular pain to receive TFESIs with either 7.5mg of dexamethasone or 40mg of triamcinolone. Outcome measures included

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VAS, McGill Pain Questionnaire and Revised ODI performed at 4 weeks. Mean pain scores improved

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significantly in both groups at 4 weeks. The triamcinolone group achieved a statistically significant larger

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reduction in mean VAS (71%) compared to dexamethasone (40%). Based on data extrapolated from the

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study, categorical analysis with success defined as more than a 50% reduction in VAS at 4 weeks,

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showed a 100% success rate in the triamcinolone group compared to a 35% success rate in the

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dexamethasone group. Using the Pearson chi squared test, the difference between the groups at 50%

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reduction was statistically significant (for p=0.05; chi squared=52.06 with 3 degrees of freedom; two-

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tailed p<0.0001). Similarly, categorical analysis, with success defined as more than a 70% reduction in

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VAS at 4 weeks, showed a 53% success rate in the triamcinolone group compared to a 9% success rate in

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the dexamethasone group. Using the Pearson chi squared test, the difference between the groups at

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70% reduction was statistically significant (for p=0.05; chi squared=24.36 with 3 degrees of freedom;

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two-tailed p<0.0001). Furthermore, based on data extrapolated from this study, categorical analysis,

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with MCID defined as VAS reduction of at least 2, showed a 100% success rate in the triamcinolone

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group. There was no statistically significant difference between the groups with respect to the McGill

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Pain Questionnaire or ODI at 4 weeks. Medical complications were not included in this study.

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Limitations of the study include non-blinded treating physicians and no corroboration of the significant

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improvements in pain VAS with the McGill Pain Questionaire or the ODI . Level II (RCT, non-blinded)

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Lumbar ILESI Particulate versus Non-particulate Kim and Brown (42) studied 60 patients with lumbar radicular symptoms. Subjects were

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randomized into two groups, 15mg of dexamethasone or 80mg of methylprednisolone acetate using an

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IL approach. The primary outcome measure was VAS at 1 to 2 months. Both groups had a significant

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decrease in mean VAS by 2 months, with 87% in the methylprednisolone group and 90% in the

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dexamethasone group showing a decrease in pain. There was no statistically significant difference

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between the two groups. Categorical analysis was not performed by the authors nor is data available to

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extrapolate. Medical complications were included as a secondary outcome, with none reported

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immediately following injection or at 1 to 2 month follow up. The main limitation of the study is both a

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lack of categorical analysis and power. Level II (RCT, non-blinded)

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Lumbar IL/TF/Caudal-ESI Particulate verse Non-particulate

Kim et al (43) examined dexamethasone and triamcinolone for lumbar ESI performed via 3

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different approaches: IL, TF and caudal. The intra-individual comparison study included 162 patients

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with lumbar radiculopathy secondary to stenosis or disc herniation. Each underwent lumbar ESI using

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10mg of dexamethasone and had previously had a lumbar ESI using 40mg of triamcinolone acetonide

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within the previous 1-year. Primary outcomes included degree of relative satisfaction on a 5-point scale

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(much better than dexamethasone, better, same as dexamethasone, worse, much worse), injection-free

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interval and injection frequency recorded at 6 months. The relative satisfaction with triamcinolone

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(63%) was significantly better than that with dexamethasone (18%) in the same patient, and the

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injection-free interval of triamcinolone (92 days) was significantly longer than that of dexamethasone

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(77 days). Categorical analysis was neither performed by the authors nor was data available to

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extrapolate. There were no serious medical complications reported. Limitations of this study include

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retrospective cohort design and no pain or functional assessment. Level III (retrospective cohort)

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Discussion Lumbar and cervical TFESIs and ILESIs are widely used to treat patients with radicular pain (44,45). The safety of these procedures has been challenged due to 32 published reports of serious neurological

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events, including infarction of the brainstem, cerebellum, and spinal cord, all involving the

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administration of particulate corticosteroids (12-23). None of the 32 complications involved non-

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particulate steroids. It is hypothesized that spinal cord infarction due to embolization of particulate

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steroids and mechanical disruption of radiculomedullary arteries are possible mechanisms of spinal cord

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injury in patients undergoing cervical and lumbar epidural procedures (49).

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In vitro studies looking at particle size under light microscopy showed triamcinolone particles to be 12 times larger than RBCs, compared to dexamethasone particles that were approximately 10 times

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smaller than RBCs, with limited particle aggregation (49). The difference in particulate size has led to

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the presumed mechanism of steroid particle causing distal embolization. Anatomical variations of the

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radiculomedullary arteries, specifically the artery of Adamkiewicz, can lead to increased risk of vascular

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injury and neurological complications (50). The artery of Adamkiewicz typically originates at the

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intervertebral foramina between T6-L2 (51, 52), but has been reported extending to the S2 level (53,

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Different from the presumed, but not proven mechanism of embolization and occlusion of end

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arterioles from the steroid particle itself, Laemmel et al elucidates an alternate mechanism – the

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formation of spiculated RBCs causing steroid-induced vascular compromise (25). Through an in vivo

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murine model and in vitro experiments on human RBCs, the study showed that unlike the non-

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particulate steroid dexamethasone, particulate steroids, including triamcinolone, methylprednisolone

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and prednisolone caused often immediate and complete cessation of capillary blood flow, with RBC

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aggregates and alteration of RBC morphologic structure into spiculated RBCs (25). This study is the first

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published mechanism showing particulate steroid causing vascular compromise.

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Given the discord pertaining to the exact cause of the 32 reported neurologic events following ESI, and the potential role of particulate steroids in causing adverse events, there is a controversy regarding

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the use of particulate versus non-particulate steroids in ESIs. In 2009, the FDA created a Multisociety

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Pain Workgroup (MPW) to address safety concerns with ESIs. The MPW was an interdisciplinary expert

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panel charged with making recommendations on decreasing the risk of ESIs (55). The FDA in 2011

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announced a safety labeling change for triamcinolone, warning that triamcinolone “is not for epidural

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use and to add information to the warning section that epidural use is not recommended” (56).

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Additionally, in 2014 the FDA released an announcement stating, “serious neurological events, some

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resulting in death, have been reported with epidural injection of corticosteroids” and called into

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question whether a contraindication was warranted to restrict the injection of glucocorticoids into the

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epidural space (57).

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In 2015 the MPW group published their consensus opinions identifying seventeen clinical

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considerations when performing TF and IL injections, including the use of non-particulate steroid,

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anatomic considerations, and the use of radiographic guidance with scientific evidence for each clinical

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consideration (55). The FDA reviewed the consensus opinions of MPW and in December 2015, the FDA

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released a statement in the New England Journal of Medicine indicating “the FDA does not currently

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support either a contraindication” to the injection of glucocorticoids into the epidural space or a

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“warning focused only on cervical transforaminal injection of suspension glucocorticoids.” In addition

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they state, “although many experts believe the risk is greatest with suspensions, the available data do

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not support comparative safety labeling implying that solutions are safer” (58). Given the discourse

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between the FDA and MPW, a systematic review of the literature examining the efficacy of particulate

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versus non-particulate steroids in reducing pain and improving function is of particular interest.

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Cervical TFESI The results of the RCT by Dreyfuss et al (37), as well as data from two retrospective studies examining cervical TFESI (35,36), are congruent (Table 3). There is no statistically significant difference

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in terms of pain reduction on VAS between particulate and non-particulate preparations in cervical ESI.

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Functional outcome measures were not adequately assessed to make specific conclusions. Therefore,

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based on the results of this review, as well as the knowledge of 13 reported cases of spinal cord

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ischemia following the administration of particulate steroid, the authors recommend using non-

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particulate steroid when performing cervical TFESI (Grade of Recommendation: B).

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Lumbar TFESI

There are three RCTs (38,39,41) and one retrospective study (40) comparing the efficacy of

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particulate versus non-particulate steroids in lumbar TFESIs (Table 4). These studies were limited by

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small sample size, disparities between continuous and categorical data results, and less stringent

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inclusion criteria. Park et al (41) showed a reduction in pain in favor of particulate steroids and El-

322

Yahchouchi et al (40) showed a reduction in pain in favor of non-particulate steroids. Each study had

323

limitations preventing generalizability. Park et al (41) showed a significant reduction in pain in favor of

324

particulate, as demonstrated by a robust categorical analysis using the VAS; however, the authors failed

325

to corroborate these results with the McGill pain questionnaire, a validated pain score that includes a

326

VAS. El-Yahchouchi et al (40) showed a reduction in pain, non-particulate, using continuous outcome

327

measures, however when using a categorical analysis, there was no difference between particulate and

328

non-particulate. Interestingly, Denis et al (38), when using a multivariate regression, did in fact show a

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functional improvement in favor of non-particulate; however, these results were not supported by the

330

other three lumbar TFESI studies.

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Therefore, based on the results of this review, in patients with lumbar radiculopathy due to stenosis or disc herniation, TFESI using particulate versus non-particulate is equivocal in reducing pain (Grade of

334

Recommendation: B) and improving function (Grade of Recommendation: C). Attention again must to

335

given to the 19 reported cases of infarction following the administration of particulate steroid in lumbar

336

ESI. While safeguards can be implemented to enhance the safety of these injections such as real-time

337

fluoroscopy, digital subtraction imaging, anesthetic test dose and others, the authors of this review

338

agree with the MPW recommendations. The authors recommend the use of non-particulate steroids for

339

lumbar TFESI in patients with lumbar radicular pain (Grade of Recommendation: B).

340 341 342 343 344

Lumber ILESI

345

particulate steroids in lumbar ILESI (Table 5). This RCT found no significant difference between the two

346

groups when examining pain. As there is only one study, there is insufficient information to make a

347

recommendation of one steroid preparation over the other in lumbar ILESI (Grade of Recommendation:

348

I).

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To date, there is only one study, by Kim and Brown (42), evaluating particulate and non-

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Conclusion

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There is limited evidence to support particulate versus non-particulate steroids for cervical and lumbar

355

epidural use in reducing pain or improving function. Given the lack of strong data favoring the efficacy

356

of one over the other, and the potential risk of catastrophic complications, all of which have been with

357

particulate steroids, non-particulate steroid preparations should be considered as first line agents when

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performing ESIs. Further studies are necessary to compare corticosteroid preparations in safety and

359

efficacy, though ethical reasons may limit prospective studies involving particulate steroids. If

360

particulate steroids are used, standard safety guidelines should be adhered to. Registries can be an

361

important way to collect outcome data and may be facilitated with the use of an electronic medical

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record.

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4. 5. 6. 7.

8. 9. 10. 11. 12. 13. 14. 15.

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18. Chang Chien GC, Candido KD, Knezevic NN. Digital subtraction angiography does not reliably prevent paraplegia associated with lumbar transforaminal epidural steroid injection. Pain Phys 2012;15:515– 23. 19. Glaser SE, Shah RV. Root cause analysis of paraplegia following transforaminal epidural steroid injections: The ’unsafe’ triangle. Pain Phys 2010;13:237–44. 20. Somayaji HS, Saifuddin A, Casey AT, Briggs TW. Spinal cord infarction following therapeutic computed tomography-guided left L2 nerve root injection. Spine 2005;30:E106–8. 21. 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. 22. Lenoir T, Deloin X, Dauzac C, Rillardon L, Guigui P. Paraplegia after interlaminar epidural steroid injection: a case report Rev Chir Orthop Reparatrice Appar Mot 2008;94:697–701. 23. AbdeleRahman KT, Rakocevic G. J Clin Anesth. 2014 Sep;26(6):497-9. doi:10.1016/j.jclinane.2014.03.010. Epub2014 Sep 4. 24. Gharibo C, Koo C, Chung J, Moroz A. Epidural steroid injections. An update on mechanisms of injury and safety. Tech Reg Anesth Pain Manag 2009; 13:266-71. 25. Laemmel E, Segal N, Mirshahi M, Azzazene D et al. Deleterious effects of intra-arterial administration of particulate steroids on microvascular perfusion in a mouse model. Radiology 2016;279(3):731-740. 26. Benzon HT, Chew TL, McCarthy RJ, Benzon HA, Walega DR. Comparison of the particle sizes of different steroids and the effect of dilution: A review of the relative neurotoxicities of the steroids. Anesthesiology 2007;106:331–8. 27. Cole BJ, Schumacher HR Jr. Injectable corticosteroids in modern practice. J Am Acad Orthop Surg 2005;13:37–46. 28. Provenzano DA, Fanciullo G. Cervical transforaminal epidural steroid injections: should we be performing them? Reg Anesth Pain Med. 2007;32:168; author reply 169-70. 29. Moher D. Liberati A. Tetzlaff J. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLOS Medicine. July 2009;6(7) e1000097. 30. Wright JG. Levels of evidence and grades of recommendation. AAOS Bull 2005;5:18-19. 31. Childs JD, Piva SR, Fritz JM. Responsiveness of the numeric pain rating scale in patients with low back pain. Spine 2005;30:1331-4. 32. Jadad AR, Moore RA, Carroll D. Jenkinson C, Reynolds DJM, Gavaghan DJ et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17(1):1-12. 33. O'Donnell C, Cano W, D'Eramo G. 128. Comparison of Triamcinolone to Dexamethasone in the Treatment of Low Back and Leg Pain via Lumbar Transforaminal Epidural Steroid Injection. Spine J. 2008;8(5 Supplement):65S. 34. Collighan N, Gupta S, Richardson J, Cheema S. Re: Comparison of the effectiveness of lumbar transforaminal epidural injection with the particulate and nonparticulate corticosteroids in lumbar radiating pain. Pain Med Malden Mass. 2011;12(8):1290-1; author reply 1292. 35. Shakir A, Ma V, Mehta B. Comparison of pain score reduction using triamcinolone vs. dexamethasone in cervical transforaminal epidural steroid injections. Am. J. Phys. Med Rehabil 2013;92:768-775. 36. Lee JW, Park KW, Chung SK. Cervical transforaminal epidural steroid injection for the management of cervical radiculopathy: a comparative study of particulate verse non-particulate steroids. Skeletal Radiol 2009;38:1077-1082. 37. Dreyfuss P, Baker R, Bogduk N. Comparative effectiveness of cervical transforaminal injections with particulate and nonparticulate corticosteroid preparations for cervical radicular pain. Pain Medicine 2006;7(3):237-242. 38. Denis I, Claveau G, Filiatrault M. Randomized double-blind controlled trial comparing the effectiveness of lumbar transforaminal epidural injections of particulate and nonparticulate corticosteroids for lumbosacral radicular pain. Pain Medicine 2015;16:1697-1708. 39. Kennedy DJ, Plastaras C, Casey E. Comparative effectiveness of lumbar transforaminal epidural steroid injections with particulate versus nonparticulate corticosteroids for lumbar radicular pain due to intervertebral disc herniation: A prospective, randomized, double-blind trial. Pain Medicine 2014;15(4):548-55 40. El-Yahchouchi CE, Geske J, Carter RE. The noninferiority of the nonparticulate steroid dexamethasone vs the particulate steroids betamethasone and triamcinolone in lumbar transforaminal epidural steroid injections. Pain Medicine 2013;14:1650-1657.

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41. Park, CH, Lee SH, Kim B. Comparison of the effectivenss of lumbar transforaminal epidural injection with particulate and nonparticulate corticosteroids in lumbar radiating pain. Pain Medicine 2010;11:16541658. 42. Kim D, Brown J. Efficacy and safety of lumbar epidural dexamethasone verse methylprednisolone in the treatment of lumbar radiculopathy. Clin J Pain 2011;27:518-522. 43. Kim JY, Lee JW, Lee GY, Lee E, Yoon CJ, Kang HS. Comparative effectiveness of lumbar epidural steroid injections using particulate vs. non-particulate steroid: an intra-individual comparative study. Skeletal Radiol 2016;45(2):169-76 (e-pub prior). 44. Friedly JJ, Chan L, Deyo R. Increases in lumbosacral injections in the Medicare population: 1994 to 2001. Spine 2007;32:1754-60. 45. Manchikanti L, Pampati V, Falco FJ. Assessment of the growth of epidural injections in the Medicare population from 2000-2011. Pain Physician 2013;16E349-64. 46. Manchikanti L, Abdi S, Atluri S et al. An update of comprehensive evidence-based guidelines for interventional techniques in chronic spinal pain. Part II: Guidance and recommendations. Pain Phys 2013;16:S49-283. 47. MacVicar J, Kind W, Landers MH, Bogduck N. The effectiveness of lumbar transforaminal injection of steroids. A comprehensive review with systematic analysis of published data. Pain Med 2013;14:14-28. 48. Bicket MC, Horowitz JM, Benzon HT, Cohen SP. Epidural injections in prevention of surgery for spinal pain: systematic review and meta-analysis of randomized controlled trials. Spine J. 2015;15(2):348-62. 49. Derby R, Lee Sh, Dates ES. Size and aggregation of corticosteroids used for epidural injections. Pain Med 2008;9:227-34. 50. Murthy NS, Maus TP, Behrns Cl. Intraforaminal location of the great anterior radiculomedullary artery (artery of Adamkiewicz): a retrospective review. Pain Med 2010;11:1756-64. 51. Kroszczynski AC, Kohan K, Kurowshi M. Intraforminal location of thoracolumbar anterior medullary arteries. Pain Med 2013;14:808-12. 52. Boll DT, Bulow H, Blackham KA. MDCT angiography of the spinal vasculature and the artery of Adamkiewicz. AJR 2006;187:1054-60. 53. Biglioli P, Roberto M, Cannata A. Upper and lower spinal cord blood supply: the continuity of the anterior spinal aretery and the relevance of lumbar arteries. J Thorac Cardiovasc Surg 2004; 127:1188-92. 54. Lo D, Vallee JN, Spelle L. Unusual origin of the artery of Adamkiewicz from the fourth lumbar artery. Neuroradiology 2002; 44:153-7. 55. Rathmell JP, Benzon HT, Dreyfuss P. Safeguards to prevent neurological complications after epidural steroid injections: Consensus opinions from a multidisciplinary working group and nation organizations. Anesthesiology 2015.122;974-84. 56. FDA-U.S. Food and Drug Administration. Shouulder. Kenalog-10 (triamcinolone acetonide) injection and kenalog 40 (triamcinolone acetonide) injection. Available at: http://www.fda.gov/safety/medwatch/safetyinformation/ucm262876.htm. 57. FDA Drug Safety Communication: FDA requires label changes to warn of rare but serious neurologic problems after epidural corticosteroid injections for pain. Available at: http://www.fda.gov/downloads/Durgs/DrugSafety/UCM 394280.pdf. 58. Racossin JA, Seymour SM, Cascio L. Serious neurologic events after epidural glucocorticoid injection – the FDA’s risk assessment. N Engl J Med 2015;373:2299-2301.

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Table 1: Levels of Evidence for therapeutic studies Criteria Randomized controlled trial - With a significant difference - With no significant difference but narrow confidence intervals Systematic review of Level I randomized controlled trials Prospective cohort study Randomized controlled trials - Poor quality (unblinded evaluators, low power, poor randomization, <80% followup) Systematic Review - Level II Studies - Nonhomogenous Level I studies Case-controlled study Retrospective cohort study Systematic review of Level III studies Case series Expert opinion

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Levels of Evidence Level I

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Level II

Level III

509 510 511 512 513

Table 2: Grades of Recommendation

C

I

516 517 518

AC C

B

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Grades of Recommendation A

514 515

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Level IV Level V

Description Good evidence for or against recommending intervention (ie, Level 1 studies with consistent findings) Fair evidence for or against recommending intervention (ie, Level II or III studies with consistent findings) Conflicting or poor-quality evidence not allowing a recommendation for or against intervention (ie, Level IV or V studies) There is insufficient evidence to make a recommendation

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Table 3: Cervical TFESI Number of Patients Selection Criteria

Interventions

Shakir et al, 2013

Retrospective

441 Patients with cervical radiculopathy from disc protrusion or stenosis

TFESI with 1 mL NRS (1month) of 1% lidocaine + either: A: Dexamethasone 15 mg B: Triamcinolone 40 mg

159 Patients with cervical radiculopathy who failed IL ESI or had previous surgery

TF ESI with NRS (1 month) either: A: Dexamethasone 10 mg B: Triamcinolone 40 mg

Jadad n/a

Retrospective Jadad n/a

Dreyfuss et al, 2006

Randomized

525 526 527 528 529 530

AC C

523 524

30 Patients with unilateral cervical radiculopathy

TF ESI with VAS (1 month) 0.751 mL 4% lidocaine + either: A: Dexamethasone 12.5 mg B: Triamcinolone 60 mg

EP

Jadad 2

TE D

Lee et al, 2009

Outcome Measures Results (Time of Measurements)

Level of Evidence

RI PT

Design

No significant difference in variance of pain or MCID ≥2 between steroids.

III

SC

Reference Year

M AN U

519 520 521 522

No significant difference in proportion of those with pain improvement between steroids.

III

No significant difference in mean pain or >50% reduction between steroids. Significant difference in ADLs in favor of particulate, however not based on a validated functional outcome measure.

II

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Table 4: Lumbar TFESI

Design

Subjects

Interventions

Denis I, et al, 2015

Double blind, randomized

56 pts with lumbar radicular pain

TFESI VAS, ODI (1mon, 3mon, A: 6mon) Dexamethasone 7.5mg B: Betamethasone 6.0mg

No significant difference in mean pain, >50% reduction, >75% reduction, or ODI between steroids. With multivariate regression, significant difference in ODI in favor of dexamethasone.

I

106 Patients with lumbosacral radiculopathy

TFESI with 1 mL ODI, McGill Pain 1% lidocaine Question, VAS (1mon) with either: A: Dexamethasone 7.5 mg B: Triamcinolone 40 mg

Significant difference in mean pain, >50% reduction, and >70% reduction between steroids. MCID of ≥2 in 100% of the particulate group. No significant difference in McGill or ODI between steroids.

II

78 pts with unilateral radicular symptoms secondary to disc herniation< 6 months

TFESI with 2 mL NRS, ODI 1% anesthetic (2wks,3mon,6mon) test dose, then either: A: Dexamethasone 15 mg B: Triamcinolone 60 mg

No significant difference in 50% reduction in pain or ODI between steroids. Significant difference in number of injections in favor of particulate (fewer injections).

I

2,958 patients with lumbosacral radiculopathy secondary to disc herniation, foraminal or lateral recess stenosis

TFESI with NRS, Roland Morris either: disability A: (2wks, 2mon) Dexamethasone 10 mg (1 mL) B: Triamcinolone 80 mg (2 mL) C: Betamethasone 12 mg (2 mL)

Significant difference in mean pain and function at 2 months in favor of particulate. No significant difference in 50% reduction or categorical analysis of function between steroids.

III

Jadad 2

Kennedy DJ et al, 2014

Double blind, randomized Jadad 5

536 537 538 539 540 541

Retrospective Jadad n/a

AC C

ElYahchouchi C et al, 2013

Results

SC

Randomized

EP

Park et al, 2010

TE D

Jadad 4

Outcome Measures (Time of Measurements)

Level of Evidence

RI PT

Reference Year

M AN U

531 532 533 534 535

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Table 5: Lumbar ILESI

Reference Year

Design

Subjects

Interventions

Kim and Brown, 2011

Single blind, randomized

60 pts with lumbosacral radiculopathy ≥ 6 months

ILESI with 10 mL VAS consisting of 2 mL (1-2mon) 0.25% bupivacaine + NS + either: A: Dexamethasone 15 mg B: Methylprednisolone 80 mg

Jadad 3

Outcome Measures (Time Results of Measurements)

Table 6: Lumbar IL/TF/Caudal-ESI

Reference Year

Design

Subjects

Interventions

Outcome Measures (Time of Measurements)

Results

Level of Evidence

Kim et al, 2015

Intraindividual retrospective cohort

162 pts with lumbar radiculopathy secondary to stenosis or herniated disc

ESI with 10 mg dexamethasone and 40 mg triamcinolone

Satisfaction (5-point scale), injection-free interval, injection frequency at 6 months

Relative satisfaction with triamcinolone was significantly better than dexamethasone in the same patient, and injection-free interval of triamcinolone was significantly longer than dexamethasone

III

552 553 554 555 556 557 558 559

EP

551

AC C

550

TE D

Jadad n/a

548 549

M AN U

546 547

II

SC

544 545

No significant difference in mean pain between steroids.

Level of Evidence

RI PT

542 543

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560 561

Figure 1: PRISMA Flow Chart 562 563

Initial results: MEDLINE (Ovid): 2,784 EMBASE: 3,308 Cochrane: 132 n=6,224

RI PT

Review of 564 references of full 565 text inclusions: n=1 566

SC

567

Records after duplicates removed: n=3,645

568

Records screened for relevance: n=3,645

M AN U

569

570 571 572 573 574 Records excluded (did not meet 575 inclusion criteria of English, 576 RCT/retrospective, TF/IL-ESI, 577 part vs. nonpart comparison) 578 579 580 581 582 Records excluded: n=3,602

TE D

Full-text articles assessed for eligibility: n=43

AC C

585 586 587 588 589 590 591 592

EP

Studies included in systematic review: n=9 583 584