Pain Management

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Key safety considerations when administering epidural steroid injections Laxmaiah Manchikanti*,1,2 & Ramsin M Benyamin3,4

Practice points ●●

Neurological complications of epidural steroid injections include rare, but serious, adverse reactions including spinal cord infarction, paralysis and death.

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An overwhelming proportion of neurological complications is related to cervical transforaminal epidural injections with some complications related to lumbar transforaminal epidural injections, intra-arterial injections and the potential for an embolic mechanism with particulate steroids.

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Because of anatomic variations, cervical transforaminal epidural injections are associated with an extremely high risk of complications, without a proven methodology to prevent these complications. There is also a lack of evidence for their effectiveness in therapy and their lack of accuracy for assisting in making a diagnosis.

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In addition to intra-arterial injections of particulate steroids, arachnoiditis, nerve damage, hemorrhage and epidural abscess have been reported.

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Multiple preventive strategies may be applied including determination of appropriate indications and medical

necessity based on efficacy; understanding the anatomy, pathophysiology and mechanism of injury; safe practices with alternate techniques, alternate drugs and appropriate monitoring; and finally appropriate coding and documentation illustrating specificity and granularity.

SUMMARY Neurological and other complications of epidural steroid injections have been widely discussed in recent years. Consequently, the US FDA issued a warning about serious neurological events, some resulting in death, and consequently is requiring label changes. Neurological adverse events numbering 131, including 41 cases of arachnoiditis, have been identified by the FDA, and 700 cases of fungal meningitis following injection of contaminated steroids. A review of the literature reveals an overwhelming proportion of the complications are related to transforaminal epidural injections, with the majority of them to cervical transforaminal epidural injections. This perspective describes the prevalence of administering epidural injections, complications, pathoanatomy, mechanism of injury and various preventive strategies.

KEYWORDS 

• arachnoiditis • epidural injections • epidural steroids • intra-arterial injection • local anesthetic • neurological complications • nonparticulate steroids • particulate steroids • steroid toxicity

Epidural injections are commonly performed in managing various types of spinal pain by multiple approaches [1–5] . Epidural injection approaches include caudal; lumbar, cervical and thoracic interlaminar; and cervical, thoracic, lumbar and sacral transforaminal epidural injections [2–5] . Just as the growth of epidural injections has been increasing with expanded indications, multiple Pain Management Center of Paducah, Paducah, KY 42003, USA Anesthesiology & Perioperative Medicine, University of Louisville, Louisville, KY, 40292, USA 3 Millennium Pain Center, Bloomington, IL 61701, USA 4 Department of Surgery, College of Medicine, University of Illinois, Urbana-Champaign, IL 61801, USA *Author for correspondence: Tel.: +1 270 554 8373 ext 101; Fax: +1 270 554 8987; [email protected] 1 2

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Perspective  Manchikanti & Benyamin publications warning about the potential for serious complications from such injections also have been increasing [1–2,6] . While epidural injections have been used since 1901 [1,7] , epidural steroids have been used since 1952 by various approaches [1–3,8] . Due to serious complications and complaints, the US FDA issued a drug safety communication warning on 23 April 2014 [9] . The FDA warned that injecting corticosteroids into the epidural space of the spine may result in rare, but serious and adverse events, including ‘loss of vision, stroke, paralysis and death.’ In addition, the FDA warning also commented that injection of corticosteroids into the epidural space of the spine has been a widespread practice for many decades, commonly used to reduce swelling or inflammation. The FDA warning, however, adds that the effectiveness and safety of the drugs for this use have not been established, and that they have not approved corticosteroids for epidural use [9] . The warning and proposed safety recommendations met with significant debate and controversy [10–12] . While neurological complications with vascular injection are a recent phenomenon [6,13–17] , multiple other complications associated with epidural steroid injections, including arachnoiditis, meningitis, epidural abscess, hematoma and drug-related complications, have been described since 1960 [1–2,18–20] . Some of the reports, though few, combined with sensationalized reporting, essentially caused the abandonment of epidural steroid injection usage in Australia in the 1990s [1] . The scare of fungal infections associated with contaminated methylprednisolone acetate in 2012 [20] and neurological complications  [6,13–14] led to the FDA’s actions, safety recommendations and significant debate [9–12,15–17] . Most of the early warnings regarding epidural steroid injections were based on reports of complications following subarachnoid steroid injections causing aseptic meningitis, bacterial meningitis and arachnoiditis. Various other complications, including nerve damage, hemorrhage and epidural abscess, also have been reported. However, the sensationalism and outrage about epidural injections was based on conjecture rather than evidence [1,9–12,15–17] . Furthermore, the present data collection system is not amenable to accurate estimations due to poor voluntary reporting and a coding system that lacks specificity and granularity [3–5,12] . The present Current Procedural Terminology (CPT) coding system uses a single code to indicate subarachnoid, or

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epidural procedures, without regional specificity (i.e., lumbar interlaminar vs caudal approaches) or identification of drugs utilized (i.e., particulate steroids versus other solutions). Furthermore, it is also important to provide an appropriate diagnosis for the procedure such as post lumbar surgery syndrome. Impact of chronic pain With low back and neck pain occupying the top five categories of disability [21] , in conjunction with increasing prevalence [22] and escalating costs  [23,24] , numerous modalities of treatments have been utilized in managing chronic spinal pain, ranging from over-the-counter acetaminophen to complex surgical fusions [2–3,25–33] . Opioid poisoning-related deaths have been reported to be 16,235 in 2012, an increase of 300% since 1999 [33] . In fact, methadone alone contributed to 4418 deaths in 2011 [33] . The 8260 unintentional drug poisoning deaths from heroin in 2013 were a 39% increase from the 5927 seen in 2012 and nearly double the 4400 seen in 2011 [28,33] . Acetaminophen itself has been linked to almost 1000 deaths a year based on data from the US FDA [32] . Further, the chronic use of NSAIDs leads to multiple gastrointestinal (GI), cardiovascular, renal complications and hearing loss. It is estimated that 60 million Americans regularly use NSAIDs, resulting in significant GI complications in up to 2% of users, with 120,000 hospital admissions annually in the USA leading to 16,500 deaths per 1990 estimates [30] . Antiepileptic drugs are used extensively without proven efficacy; their effectiveness is only 7–11% in patients who have a 50% reduction of pain, but they also have been associated with multiple complications [31] . Spinal surgical interventions have been increasing rapidly with fusions increasing 137% from 1998 to 2008, with 497 associated deaths in 1998 and 1012 associated deaths in 2008 [26] . Use of epidural injections Epidural injections are one of the most commonly utilized interventional techniques in managing spinal pain since the invention of caudal epidural injections in 1901 and epidural steroid injections in 1952 [1–3,9–12] . They have been administered to hundreds of millions of patients in the USA and across the globe. Epidural injections showed an overall increase of 106% per 100,000 Medicare fee-for-service beneficiaries with an annual increase of 6%

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Key safety considerations when administering epidural steroid injections  from 2000 to 2013 [4] . However, caudal and/or lumbar interlaminar epidural injections have increased during the same period 11%, with an annual increase of 1%. Compared to these, cervical and thoracic interlaminar epidural injections increased substantially: 119% per 100,000 Medicare fee-for-service beneficiaries, with an annual increase rate of 6% from 2000 to 2013. Transforaminal epidural injections have also increased with cervical and thoracic transforaminal epidural injections increasing overall by 84%, an annual increase of 5%, but, lumbosacral transforaminal epidural injections have increased an astonishing 577% per 100,000 population with an annual increase of 16% from 2000 to 2013. Over the years, caudal and lumbar interlaminar epidural injections, which were the predominant category of procedures, have been replaced by lumbosacral transforaminal epidural injections (three to five). The majority of the complications are related to transfor­a minal epidural injections. The present systems of monitoring are unreliable due to coding systems which do not differentiate among approaches and drugs utilized. Complications of epidural injections While in recent years neurological complications related to intra-arterial injection of particulate steroids have been reported, leading to the FDA warning, there have been a multitude of other complications such as an outbreak of 751 cases of fungal meningitis resulting in 64 deaths associated with contaminated methylprednisolone acetate [20] . Further, the FDA’s Division of Pharmacovigilance (DPV) recently provided FDA Adverse Event Reporting System (FAERS) data and the medical literature has described the serious neurological events of epidural steroid injections  [12] . FAERS data from the DPV has reported 131 adverse neurologic events: this includes 41 arachnoiditis events [12] . The data essentially showed that in addition to neurological adverse events related to vascular complications with intra-arterial steroid injections, there is also a potential association of arachnoiditis with injectable corticosteroids, along with paraparesis/paraplegia, quadriplegia, spinal cord infarction, stroke, thrombosis or thromboembolism, sensory disturbances, nerve injury, blindness, seizures, bowel and bladder dysfunction, and psychological or behavioral changes. In addition to the complications described by the FDA, multiple other complications including

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hemorrhage, epidural hematoma, and epidural abscess have been reported [1–2,18–19] . An outbreak of fungal infection due to preservative-free, injectable methylprednisolone acetate was identified in 2012 [20] . The outbreak involved 17,675 vials of contaminated methylprednisolone acetate, distributed to 76 facilities in 23 states leading to 13,534 potentially exposed patients. There were 751 patients affected: 31% had meningitis, 43% had spinal or paraspinal infection, 20% had concurrent meningitis and spinal/paraspinal infection, 4% had septic arthritis and 1% had a stroke likely due to meningitis Multiple complications related to the pharmacology of steroids also have been described [1,2] . However, in the modern era, the major complications are neurological complications and arachnoiditis  [6,9–17] . Other adverse events and complications include facial flushing and vasovagal reactions; intravascular penetration of the needle with bleeding, dural or subdural punctures with associated complications; meningismus, pneumocephalus and infectious complications including epidural abscess, discitis and meningitis; nerve root trauma and cauda equina syndrome; adrenocortical suppression; and radiation exposure [1–2,19–20,34–36] . Literature review of complications Literature search was performed by utilizing PubMed, Cochrane library, US National Guideline Clearinghouse, for English language, original and review articles published from 1996 through 2014. The search was focused on all types of epidural steroid injections, c­omplications and safety considerations. A general literature review of the use of epidural injections in clinical practice shows very few complications related to the administration of epidural injections with or without steroids. In a prospective evaluation of complications of 10,000 fluoroscopically directed epidural injections [18] , which included 2376 cervical interlaminar epidural injections, 301 thoracic interlaminar epidural injections, 1450 lumbar interlaminar epidural injections, 1395 caudal epidural injections, 1310 lumbar transforaminal epidural injections and 839 caudal epidural adhesiolysis procedures, no major complications were identified. However, there were a significant number of minor incidents with intravascular entry of the needle as the most common complication, followed by dural puncture. McGrath et al. [34] assessed 4265

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Perspective  Manchikanti & Benyamin epidural injections on 1857 patients over 7 years, with 161 cervical interlaminar epidural injections, 123 lumbar interlaminar epidural injections, 17 caudal injections and 3964 lumbar transforaminal epidural injections. They reported 103 minor complications and an overall injection rate complication of 2.4%. Karaman et al.  [35] assessed 1305 episodes of injections in 562 patients. They reported an overall incidence of vascular penetration in 7.4%, an overall rate of minor complications of 11.5%, and no major complications. Neal et al. [37] reported that neurologic complications associated with regional anesthesia and pain medicine are rare, particularly those co­mplications that do not involve hematoma or infection. In contrast, Scanlon et al. [14] reported 78 complications, including 16 vertebral basilar brain infarcts, 12 cervical spinal cord infarcts and two combined brain and spinal cord infarcts related to cervical transforaminal epidural steroid injections. Engel et al.  [6] , in a comprehensive analysis of the published data related to the risks of fluoroscopically guided cervical transforaminal epidural steroid injections, reported 13 deaths and many catastrophic neurological injuries. Atluri et al.  [13] , in assessing complications and recommending alternate approaches, reported multiple cases of neurological complications. In addition, an assessment of injury and liability claims associated with cervical procedures for chronic pain also showed an increasing number of claims related to cervical interventions [38,39] . Cervical interventions were involved in 22% of the chronic pain treatment claims from 2005 to 2008 [38] . Among those patients undergoing cervical procedures, 59% experienced spinal cord damage compared with 11% of patients who had other chronic pain modalities of treatments, with direct needle trauma as the predominant cause. The side effects and complications related to the chemistry or to the pharmacology of steroids are mainly theoretical [1,2] . The major side effects include the suppression of the hypothalamic–pituitary–adrenal axis hypocorticism, Cushing syndrome, osteoporosis, avascular necrosis of the bone, steroid myopathy, epidural lipomatosis, weight gain, fluid retention and hyperglycemia. Prevention of complications The prevention of complications related to epidural steroid injections may be achieved by consideration of various factors. Prevention is threefold: understanding of efficacy, indications

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and medical necessity; pathoanatomy and mechanism of complications; and safe practices with applications of alternate techniques, alternate drug use and appropriate monitoring. ●●Efficacy, indications & medical necessity

Epidural injections are considered to be efficacious in managing multiple pathologies when administered appropriately with proper indications and medical necessity, with assessment of evidence, based on qualitative best evidence synthesis based on high-quality randomized trials with appropriate assessment and cost utility analysis [40–48] . However, there is a lack of trials for thoracic transforaminal epidural injections and a lack of efficacy for cervical transforaminal epidural injections, which are also associated with high risk [2,6,41–42] . However, among others, debate continues with variable evidence for various pathologies ranging from some evidence of efficacy to a lack of efficacy [2,49–50] . Utilizing the best evidence synthesis with five levels of evidence [47] with level I evidence denoting consistent findings among multiple high-quality RCTs and level II evidence denoting consistent findings among multiple lowquality RCTs, or one high-quality RCT, the evidence is level II in managing disc herniation with or without steroids in the cervical, lumbar and thoracic spine [40–42,44] . There is also a potential superiority for steroids demonstrated in managing lumbar disc herniation with up to 1-year followup compared with local anesthetic alone in the lumbar spine with interlaminar and caudal epidural injections [40,42,51] . The evidence is level II for caudal and interlaminar epidural injections of the lumbar, thoracic and cervical spine, as well as lumbar transforaminal epidural injections [2,40– 42,44] . Furthermore, there are no significant differences noted in managing lumbar disc herniation, either with caudal, lumbar interlaminar, or lumbar transforaminal epidural injections [51] . In managing central spinal stenosis, there is level II evidence based on multiple high-quality randomized controlled trials in the cervical and lumbar spine [2,41–42,44,52] . In the lumbar spine, the evidence appears to be superior with lumbar interlaminar epidural injections compared with caudal epidural injections [52] . However, the evidence for lumbar transforaminal epidural injections is limited, in spinal stenosis, with no evidence available for thoracic and cervical transforaminal epidural injections. The evidence for axial discogenic pain without disc herniation, radiculitis, or sacroiliac joint pain has been assessed in high-quality trials

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Key safety considerations when administering epidural steroid injections  showing level II evidence in the lumbar and cervical regions with caudal and interlaminar epidural injections [2,41–42,53] . Furthermore, while there is no evidence for transforaminal epidural injections, lumbar interlaminar epidural injections are shown to be superior to caudal epidural injections in managing lumbar discogenic pain [53] . Finally, the evidence for postsurgery syndrome has been demonstrated to be level II, either with cervical interlaminar injections or caudal epidural injections [2,41–42] . Percutaneous adhesiolysis also has been shown to have level II evidence in managing post lumbar surgery syndrome, lumbar central stenosis and recalcitrant lumbar disc herniation [54–58] . Furthermore, British Pain Society guidelines also have endorsed epidural steroid injections [59] . Multiple systematic reviews utilizing inappropriate methodology [49,50] , and multiple randomized controlled trials utilizing inappropriate assessment and methodology, have shown a lack of efficacy [40,60] . With increasing utilization, multiple policy implications from evidence that was not properly analyzed and synthesized has led to inappropriate conclusions [2–3,61–63] . Multiple political forces, attempting to reduce healthcare costs, have put epidural steroid injections under high levels of scrutiny. Even though complications from epidural injections have been described ever since their introduction into clinical practice, with episodes of arachnoiditis in the 1990s, fungal infections in 2012 and multiple reports of neurological complications related to transforaminal epidural injections, sensationalism and hyperbolic reporting have brought epidural steroid injections center stage without evidence [9–12] . Of the various complications related to epidural injections, the majority of them are minor, but neurological complications with serious adverse reactions including spinal cord infarction, paralysis and death, and arachnoiditis are of critical importance. The literature reports a number of complications related to cervical transforaminal epidural injections, with some complications related to lumbar transforaminal epidural injections, caused by intra-arterial injection of particulate steroids [6,13–14] . There are a large number of case reports of contaminated steroids injected epidurally resulting in meningitis. Arachnoiditis has been reported secondary to overwhelming meningitis, as well as i­ntrathecal injections in a majority of the cases. The data reported have been out of proportion to the severity of the problem, with

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multiple academic and political factors causing the issue to be sensationalized. A total of 131 fatalities have been reported to the FDA due to epidural injections, of which 41 cases were related to arachnoiditis [9,12] . Even if these numbers are quadrupled to 500 cases to account for underestimation, the amount of adverse events over 20 years from epidural injections pales in comparison to the prevalence of deaths due to opioids, acetaminophen, NSAIDs and spinal surgery, all which far exceed the deaths caused by epidural injections  [12–14,26,28,32–33,38–39] . The complication rate from epidural injections continues to be less than 40 per year. However, neurological and other complications of epidural steroids must not be lightly taken or the trauma due to c­omplications be minimized. The essential problem with the present atmosphere is misrepresentation of the evidence, which is not applicable for all epidural injections. Based on utilization data [3–5] , overall cervical and thoracic transforaminal epidurals constitute 2.4% of all epidural injections and less than 5% of all transforaminal epidural injections; however, they contribute to over 99% of the complications related to intra-arterial injection of particulate steroids. These data have been incorrectly extrapolated to all types of epidural injections and have not been convincingly related to any neurological complications with caudal, lumbar, cervical or thoracic interlaminar epidural injections. Unfortunately, there is also a lack of evidence for the efficacy or effectiveness of cervical transforaminal epidural injections with a lack of availability of a­ppropriate p­reventive measures. There is proven efficacy for epidural injections along with safety for caudal, lumbar, cervical and thoracic interlaminar epidural injections [40–42,44] . There is demonstrated efficacy and relative safety for lumbar transforaminal epidural injections with evidence based on high-quality randomized trials with level II evidence in managing lumbar disc herniation [2,40,42–43,51] . There is a lack of published evidence for thoracic transforaminal epidural injections, and the evidence for cervical transforaminal epidural injections is not only lacking, but also is represented by an overwhelming complication rate. It is also important to understand proper evidence-based methodology. There is significant debate related to the inappropriate use of evidence and major conflicts of interest, which are generally ignored by some high level academicians and policy makers.

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Perspective  Manchikanti & Benyamin Appropriate indications and medical necessity have to be established in performing epidural injections which will lead to performing the procedures only when needed and appropriate [2–3,63]. The necessity for interventional techniques with appropriate available evidence with performance of them safely is exemplified by overuse, abuse, of opioid therapy with its adverse consequences of related deaths and increasing use of heroin and marijuana with heroin deaths doubling just in 3 years [27–29,32–33] . This will avoid performance of cervical transforaminal epidural injections specifically with particulate steroids. It will also avoid the use of particulate steroids in high risk patients and, as we discus below, will show appropriate alternate approaches to avoid neurological complications. Further, since there is no evidence for epidural steroid injections with a lumbar interlaminar approach in post lumbar surgery syndrome, and there is no superiority with steroids, these procedures must be performed only by a caudal approach, a cervical interlaminar epidural approach, and a transforaminal approach, if the targeted space cannot be reached by caudal or interlaminar approaches, preferably without particulate steroids. Some have argued that replacing particulate steroids with nonparticulate dexamethasone will avoid an embolization event; however, this will not affect injury from needle trauma, dissection, or spasm of the artery which are the other mechanisms of injury. Theoretically, particulate steroids seem to be more efficacious than nonparticulate steroids or local anesthetic in lumbar disc herniation [16,40–42,44,49,51–54] . ●●Pathoanatomy & mechanism of

complications

While vascular complications can and do occur in all areas of the spine and are of grave concern, based on the literature and expert opinions, these complications occur very frequently following procedures in the cervical spine, specifically with cervical transforaminal epidural injections, and with lesser frequency in lumbar and thoracic transforaminal epidural injections [6,13–14] . Appropriate understanding of the pathoanatomy and mechanism of various complications has significant propensity to avoid complications of epidural injections. While various complications have been reported, including arachnoiditis and vascular complications, the theory of injection of particulate steroids into radicular arteries has been shown to be the most common mechanism

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receiving extensive attention. Common neurological complications following cervical transforaminal epidural injections are based on the lower margin of safety because of the proximity of the artery supplying the brain and the proximity of the spinal cord itself, the random nature of the location of the vascular feeder arteries to the spinal cord within the cervical foramen, the lack of a reliable and proven strategy for avoiding them while performing procedures and injury or transection of these arteries or embolism from injections into them. However, the arterial supply to the thoracolumbar spinal cord follows a regular and recurring path along the vertebra and within the thoracic and lumbar foramen. Thus, critical knowledge of vascular components of the foramen is crucial in avoiding the complications specific to transforaminal epidural i­njections, particularly in the cervical spine. The spinal cord receives it vascular supply from anterior spinal and posterior spinal arteries  [64–67] . The spinal cord and nerve roots are supplied by radicular arteries which travel at each of the vertebral levels through the neuroforamen. At the thoracolumbar regions, these arteries take off from the intercostal and lumbar artery branches, entering the foramina and continue on to supply the anterior spinal artery. The dominant medullary branch that supplies the anterior branch is called the Artery of Adamkiewicz, typically found at the level of T8, with its origin in 85% of individuals on the left side, variable between T9 and L2, even though it has been shown rarely as low as S1. There is a fairly high risk of complications when administering cervical transforaminal epidural injections. This is due to anatomic variations [64–67] . Currently, there is no proven methodology for preventing these complications. Most complications in the thoracic and lumbar regions can be avoided by approaching the f­oramen with an infraneural approach [4,13,64–67] . An intrathecal injection of steroids can cause meningitis and arachnoiditis. Reports of meningitis mostly occur as a result of dural puncture during an epidural corticosteroid injection [19] . However, reports of this happening have overwhelmingly been caused by steroid being contaminated with a fungus [20] . In addition to meningitis leading to arachnoiditis, the chemicals in corticosteroids have also been reported to cause it. While there have been several clinical reports and animal studies concerning the neurotoxicity

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Key safety considerations when administering epidural steroid injections  of intrathecal glucocorticoids [1,68–69] , some have reported no adverse events with four intrathecal injections of methylprednisolone over 7 days for postherpetic neuralgia [70] . There is no consensus why neurological complications occur secondary to vascular trauma or arterial injection. Most believe that particulate steroids cause an embolism and causes a stroke [6,13–14,16] . But many others believe something else is the cause, among them: arterial intimal flaps, arterial dissection, plaque dislodgment that cause an embolism, arterial muscle spasm and embolism from a fresh thrombus after an intima disruption [4,13–14,65] . Supporters of the leading theory of embolic phenomenon have garnered support for this theory because there so many intravascular injections of contrast medium occur, especially cervical transforaminal injections and to a lesser degree, lumbar transforaminals  [67,71] . In addition, case reports of steroids injected into the vertebral artery leading to cerebral and cerebellar trauma have been reported  [6,14,72] . Thus, the embolic hypothesis has been conceived, based on the anatomy of an ascending or deep cervical artery which could result in spinal cord infarction, brain stem or cerebral infarcts, apart from direct injection into the vertebral artery. The majority of the case reports and experimental evidence points to particulate steroids  [6,13–14,72–73] . Methylprednisolone is the most commonly used corticosteroid; it also has the largest particles [6,12–14,72] . Particulates from methylprednisolone, as well as triamcinolone, have a tendency to coalesce into larger aggregates. These aggregates far exceed 100 microns, thus increasing the possibility for an embolism [72] . Above all, the only experimental evaluation available with intra-arterial injection in the rat brain showed cerebral hemorrhage with DepoMedrol and Solu-Medrol, Depo-Medrol carrier; however, without cerebral lesions identified with Decadron or saline groups providing evidence for the postulated mechanism of injury of embolism [73] . Since the majority of the trials have shown a lack of significant superiority with particulate steroids, one can avoid particulate steroids and proceed with local anesthetic alone or nonparticulate steroids with transforaminal epidural injections. In addition to various considerations, multiple attempts may increase the chances of vascular penetration and subsequent injury, as well as high risk postsurgery patients and significant degenerative abnormalities, resulting in

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distortions of the vasculature. However, if appropriate indications are met, alternate techniques must be applied specifically in high risk patients after surgery and when performing procedures close to radiculomedullary arteries. ●●Alternate techniques, drugs & monitoring

The exact mechanism or combination of mechanisms that may contribute to vascular or neural injury is uncertain and expected to be multifactorial. Multiple modifications may be made in performing transforaminal epidural injections, based on embolic theory and other potential theories, including the sustained compressive effect of the injectate producing neural ischemia, and the inflammatory arterial irritability that predisposes the local vasculature to vasospasm from an advanced needle or from the mechanical effect of the injectate itself. These modifications include technical application of an infraneural approach for lumbar transforaminal epidural injections which appears to be safe and effective  [13] . Suggested intra-articular approach for cervical transforaminal epidurals [74] or modified approach  [75–77] , though unreliable, approach based on indications and medical necessity performance. Other modifications include a blunt needle and monitoring (live fluoroscopy and digital substraction angiography [DSA]) techniques, and finally, use of local anesthetic alone or with nonparticulate steroids [78–80] . However, these preventive strategies may not be amenable for testing for effectiveness in preventing complications. Further, it is not known if prevention of adverse effects and embolism based on particulate steroids will prevent all complications. Consequently, major emphasis has been laid on modification of the technique utilizing an infraneural approach in the thoracic and lumbar regions for transforaminal epidural injections, which has been reported to be equally effective as the supraneural approach and also has been devoid of any complications even with injections of particulate steroids [13] . However, unfortunately, a reliable modification of technique in the cervical spine is not available [74–77] . Modifications focused on detecting intravascular uptake and avoiding intravascular injection are based on the philosophy that a needle can be entered into a small artery and identified appropriately with injection of contrast medium under live fluoroscopy or DSA so the needle can be safely removed. Live fluoroscopy and DSA may be utilized, which increase costs and increase

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Perspective  Manchikanti & Benyamin radiation exposures, but they are not proven and reliable strategies [78,79] . Apart from live fluoroscopy and DSA, injection of local anesthetics test doses have been recommended with an appropriate waiting period to monitor the patient for side effects associated with intra-arterial injection of the local anesthetic manifested by seizures, loss of consciousness and transient neurological deficits; however, this is also an unproven strategy. Another technique modification is using blunt needles which may protect against intravascular entry [80] . However, blunt needles are associated with significant difficulties. A modification with a Whitacre needle may be simpler. In addition, a caudal or interlaminar approach may be utilized with a steerable catheter. Recently the FDA Safe Use Initiative considered some recommendations to prevent neurological complications. While these were not approved by the Safe Use Initiative and have not been adopted by the FDA, the Multi-Society Pain Workgroup (MPW) has approved multiple measures [11,16] . It has been described that these measures will increase regulations and are without evidence or clarifications [11,15,17] . Manchikanti et al. [11,17] analyzed these measures and provided an appropriate critique of the major flaws and disadvantages of these recommendations. Among the multiple recommendations, live fluoroscopy, injection of contrast medium, DSA and injection of a test dose of nonparticulate steroids for cervical transforaminals and for initial injections for lumbar epidural injections have been included in these recommendations. Complications of arachnoiditis can be further reduced by avoiding steroids, as there is no evidence of steroids being efficacious in postsurgery syndrome any more than local anesthetic alone. In addition, avoidance of entering the lumbar epidural space with an interlaminar approach except in rare circumstances must be avoided. Pharmacological complications may be avoided by utilizing limited doses of steroids as there is no significant difference based on the amount injected and by following appropriate regulations in reference to the frequency of injections based on the pharmacological profile with limits of 120 mg of methylprednisolone or equivalent dosages per day and repeating the procedures at least after 2 weeks initially for the initial two procedures and repeating them approximately with 3 months’ duration in the therapeutic phase. Overall, steroids, when not proven by evidence, may be avoided to spare all types of complications.

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The crucial and important preventive strategy is appropriate tools for monitoring. At present the monitoring system is inadequately based on voluntary reporting. In addition, the present coding system does not allow for specificity and granularity of the approach utilized (caudal versus interlaminar) and drugs injected (particulate steroids vs other solutions). Appropriate monitoring will improve with modification in coding with replacement codes for epidural injections providing regional specificity and granularity in reference to injection of particulate steroids versus other solutions. In addition, appropriate diagnosis is essential in monitoring for which treatment is provided including comorbid issues such as post lumbar surgery syndrome. Discussion The growth in epidural injections has been enormous, at a rate of 106% per 100,000 feefor-service Medicare population from 2000 to 2013, with transforaminal epidural injections contributing to the majority of the increase [3–5] . With multiple regulations and policy perspectives and lower healthcare spending, a slowdown in growth has been observed from 2011 through 2013 [4] . The number of epidural injections was 4354 per 100,000 Medicare population in 2013 compared with 4740 in 2011 [4] . Multiple mechanisms have been proposed to account for neurological complications following epidural injections secondary to vascular trauma or injection into an artery, with emphasis on the embolism from a particulate steroid theory. The mechanism of arachnoiditis has been related to intrathecal injection of particulate steroids. Even though the exact mechanism or combination of mechanisms that may contribute to vascular or neural injury is uncertain and expected to be multifactorial, based on the available literature, alternate techniques are available for transforaminal epidural injections with an infraneural approach, which basically eliminated any type of intra-arterial injection with or without particulate steroids, thus circumventing the risk in lumbar transforaminal epidural injections except in highrisk cases with disturbed anatomy. However, this is not the case with cervical transforaminal epidural injections due to highly variable arterial circulation and abundant arteries in the foramina at all levels. Avoiding the use of particulate steroids has been advocated, which may be reasonable considering that nonparticulate solutions provide similar

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Key safety considerations when administering epidural steroid injections  effectiveness [41–42,44,49,52–53] in multiple conditions except in lumbar disc herniation at least with the initiation of therapy. Appropriate monitoring, technical modifications including blunt needles (i.e., Whitacre, among others) is also of importance, along with avoidance of multiple risk factors such as disturbed anatomy with severe degenerative disease and postsurgery syndromes, and multiple attempts. There is an urgent need to improve monitoring systems with mandatory reporting and an appropriate coding and documentation system providing regional specificity (cervical vs thoracic) (lumbar interlaminar vs caudal) and identification of the drugs injected (particulate steroids vs other solutions), and proper coding of the diagnosis for which the procedure is performed. Finally, cervical transforaminal epidural injections must not be performed as there is no efficacy, effectiveness, or diagnostic accuracy for these procedures and there is an overwhelming risk of complications. Conclusion Preventing complications from epidural steroid injections may be achieved by a proper application of efficacy, indications and medical necessity; understanding pathoanatomy and mechanism of injury; and by application of alternate techniques. The neurological complications of particulate steroids with intra-arterial injections have not been reported with caudal, lumbar, thoracic, or cervical interlaminar epidural injections. Thus, these injections must be exempted from extrapolation of the evidence from cervical transforaminal epidural injections. Complications may be avoided with reasonable probability with lumbar transforaminal epidural injections. Meanwhile, cervical transforaminal epidural injections must not be performed until appropriate evidence develops and safe pr­eparations of steroids are available. Future perspective The growth of interventional techniques, along with epidural injections, has been enormous since References Papers of special note have been highlighted as: • of interest; •• of considerable interest 1

Bogduk N, Brazenor G, Christophidis N et al. Epidural Use of Steroids in the Management of Back Pain. Report of working party on epidural use of steroids in the management of back pain. National Health and Medical

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the 1990s. The growth of epidural injections has been at a rate of 106% per 100,000 fee-for-service Medicare population from 2000 to 2013 [4] . Cervical and transforaminal epidural injections have contributed significant increases. Lumbar transforaminal epidural injections contributed an increase of only 11% during this period, while cervical and thoracic interlaminar epidural injections have contributed 119% to the growth rate  [3–5] . However, the number of procedures performed in the cervical spine is extremely low compared with the lumbar spine. The majority of the growth comes from lumbar transforaminal epidural injections, which have increased at a rate of 577% from 2000 to 2013. With multiple regulations and policy perspectives and a slowdown in health care spending, a slowdown in growth has been observed from 2008 through 2013. In fact, the rate of epidural injections was 4354 per 100,000 Medicare population in 2013 compared with 4442 in 2008, which gradually increased to 4740 in 2011, with a decrease noted for 2012 and 2013 [4] . With the same factors operating vigorously, it is expected that utilization will be reduced per beneficiary with proper applications of indications and medical necessity. In addition, the evolving literature will stabilize in reference to the efficacy or lack thereof of particulate steroids compared with local anesthetic alone or nonparticulate steroids. This will also be heralded by development of nonparticulate steroids with commercial development rather than compounding, which has been shown to be associated with high risk. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or ­pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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