RENEW OR SUBSCRIBE TO PPM
Subscription is FREE for qualified healthcare professionals in the US.
10 Articles in Volume 14, Issue #2
How Safe Is Epidural Steroid Injection? Examining Drug-Related Factors
How Important Is Evidence-Based Medicine in Epidural Injection for Low Back Pain?
Current Access to Opioids—Survey of Chronic Pain Patients
Opioid Prescribing Part 2: Appropriate Documentation of Follow-up Visits
Neuropathic Pain: A Literature Review
Translating Chronic Pain Research Into Practice: Chronic Pain and the Brain
Intractable Pain: Time To Understand and Use the Term (Again)
Are Antibiotics a Treatment Option for Low Back Pain?
Genetic Mutations in Cytrochrome P 450 2D6
Light Exercise May Lead To Faster Recovery After Concussion

How Safe Is Epidural Steroid Injection? Examining Drug-Related Factors

While the frequency of serious complications due to ESI is undefined, certain pharmaceutical characteristics of corticosteroids (ie, particulate vs nonparticulate) are thought to contribute to overall risk.

Epidural steroid injection (ESI) has been a treatment modality for low back pain (LBP) and neck pain, with and without radiculopathy, for decades.1 This procedure involves administration of corticosteroids into the epidural space around the spinal cord and nerves. LBP is the second most common symptom-related reason for physician office visits in the United States, and ESI has become the most commonly performed intervention to treat LBP.1,2 The beneficial effects of ESI are proposed to include decreased production of inflammatory mediators, depressed nerve conduction, and dilution of local concentrations of endogenous inflammatory cytokines.1,3 Although the majority of controlled studies of ESI for LBP and neck pain document a moderate and transient benefit from ESI,1 there is controversy over whether these benefits are long-term.2

While considered minimally invasive, ESI can cause serious adverse events, including neurologic injury, embolization, bleeding, and infection.1 Risk depends in large part on technique, including interlaminar versus transforaminal injection, which theoretically have different risk of dural puncture. Examples of serious adverse events include inadvertent injection of drug into a vein or artery, which can result in debilitating or fatal infarction of the brainstem or spinal cord.4 However, it also can be related to characteristics of the corticosteroid used in ESI.5 Other drug-related concerns with ESI were highlighted by the 2012 outbreak of fungal meningitis in patients who received contaminated corticosteroids produced at a compounding pharmacy.6

Frequency of Serious Adverse Events

These rare, but potentially devastating, complications of ESI have an undefined incidence rate because clinical trials generally have not been well-designed and epidemiologic safety data have not been routinely collected.1 Available review articles highlight the infrequent nature and difficulty of quantifying the risk of severe adverse events, despite large sample sizes. For example, one 7-year retrospective review in which 4,265 ESIs were administered to 1,857 patients reported no major complications.7 The majority of data describing disastrous complications from ESI come from case reports.8-21 Findings from evidence reviews have been nonspecific, stating only that the risk of major complications is low and that causative factors mostly are related to physical technique (eg, needle placement) and the formulations of injected steroids.1,22

In the absence of trials designed to detect rare adverse events due to ESI, some useful data have come from a national survey of physician members of the American Pain Society (APS).23 Of 1,340 surveyed physicians, 21.4% responded, revealing 78 total ESI complications in patients receiving cervical transforaminal ESI. Serious complications included 16 brain infarcts, 12 spinal cord infarcts, and 2 combined brain/spinal cord infarcts; death occurred in 13 cases. Corticosteroids were used in 70 of the cases with reported complications. The reported corticosteroids included triamcinolone, betamethasone, and methylprednisolone, which were associated with 10%, 11%, and 79% of complications, respectively.

Pharmaceutical Characteristics of Corticosteroids

While the frequency of serious complications due to ESI is undefined, certain pharmaceutical characteristics of corticosteroids are thought to contribute to overall risk.1,24 For example, the size of aggregated drug molecules may affect the likelihood of embolization following inadvertent injection into vertebral or foraminal arteries.25 Corticosteroids considered more likely to aggregate and potentially embolize are termed particulate corticosteroids. In contrast, those less likely to embolize are termed non-particulate corticosteroids. The latter contain particles smaller than red blood cells and exhibit low propensity to aggregate or pack; they are therefore advocated by some as the corticosteroids of choice in ESI to reduce embolization risk.24,25 Among corticosteroids commonly used in ESI, particulate corticosteroids include methylprednisolone and triamcinolone.23,25,26 Dexamethasone generally is agreed to be non-particulate, while the classification of betamethasone has varied.23,27 Corticosteroids reported in the APS survey all were considered particulate by the authors.23

Microscopic analysis of steroid preparations has assessed pharmaceutical characteristics of corticosteroids used in ESI.25 Particles of triamcinolone and betamethasone equaled or exceeded the diameter of red blood cells and exhibited aggregation, with the largest particles exceeding the median red blood cell size by 12 times, indicating potential for embolization. Those of methylprednisolone acetate were smaller than red blood cells and did not aggregate, although they were densely packed, leaving potential for embolization. Because of this potential, methylprednisolone is generally categorized as particulate. Particle characteristics were most favorable in dexamethasone, which showed sizes 5 to 10 times smaller than red blood cells and no aggregation. The absence of case reports associating dexamethasone with ESI complications substantiates this finding.23,28 In fact, injection of dexamethasone directly into the carotid artery of 8 rats did not cause any injury, whereas injection with methylprednisolone acetate (Depo-Medrol) or methylprednisolone sodium succinate (Solu-Medrol) in 15 of 19 rats caused cerebral hemorrhage (Figure 1).2

Trials comparing outcomes of particulate versus non-particulate steroids have been limited, with inconsistent safety outcomes.30-34 Of 5 retrospective and prospective studies, 2 reported no complications—1 study of 159 patients receiving dexamethasone or triamcinolone for cervical transforaminal epidural injection, and another study of 60 patients receiving dexamethasone or methylprednisolone in lumbar translaminar epidural injection (though 1 patient lost to follow-up inadvertently received intrathecal injections).30,31

Other pharmaceutical characteristics presumed to increase risk of injury include the presence of the neurotoxic preservatives polyethylene glycol (PEG) and benzyl alcohol.1 However, controversy exists regarding which is the offending agent.35 Concentrations of PEG in corticosteroid preparations approximate 2.8% to 3% of the solution; animal studies have shown changes in nerve conduction only at concentrations of 20% and greater.4 Additionally, benzyl alcohol is present in some preparations at concentrations of 0.9%, though injection of up to 9% produced only transient changes in animal models.36 Some available corticosteroid preparations contain either or both of these preservatives—some preparations of methylprednisolone acetate contain PEG or benzyl alcohol, whereas some preparations of betamethasone, triamcinolone, and dexamethasone sodium succinate contain benzyl alcohol but not PEG.37-40

In 2011, the US Food and Drug Administration (FDA) acknowledged the connection between corticosteroids and severe injury in ESI by requiring an update of triamcinolone’s safety labeling.41 The revised label states that the product is intended for intra-articular and intralesional use only, and recommends against other routes of administration, including epidural. In addition, the adverse events section of the label was updated to reflect information on reports of serious complications including spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke.40 Although the post-marketing safety data that prompted the labeling change have not been published or released by the FDA,42,43 numerous case reports detailing triamcinolone-related serious adverse events—including spinal epidural lipomatosis, cauda equina syndrome, paraplegia, calcification, spinal cord infarction, intracranial hypotension, and pneumocephalus—have been published.8-15 Some of these adverse events also have been reported with methylprednisolone and betamethasone.16-19

Drug characteristics are one of many considerations, including physical technique, to address risks associated with ESI. Ultimately, the selection of the type and dose of steroid used in ESI has long been based on clinician preference, and no consensus exists on the optimum regimen.3,44

Sterility Risks of Compounded Corticosteroids

Other risks of ESI were recently highlighted by the use of contaminated corticosteroids. Despite the increased risk of contamination of preservative-free drugs, clinicians often prefer compounded corticosteroids for ESI to avoid potential neurotoxicity from preservatives in commercial products.5 These risks were brought to the forefront in October 2012, when a fungal meningitis outbreak in Tennessee was traced to 3 contaminated lots of methylprednisolone acetate produced by the New England Compounding Center (NECC). Following epidural administration, more than 750 cases of fungal infection and 64 deaths were reported into late 2013.45

Traditional compounding is defined as the preparation of a drug for an individual patient pursuant to a physician’s prescription, which is intended to serve patients whose needs are not met by FDA-approved products.46 Because of this patient-specific nature, FDA does not oversee such compounding and defers to state law; accordingly, these compounders are not required to prove safety and efficacy to FDA or comply with their standards of good manufacturing practices. However, compounding facilities such as NECC constituted a hybrid compounding model that did not fit FDA regulations of pharmaceutical manufacturers or state boards of pharmacy regulations.47 Despite the absence of direct FDA regulation, outsourcing compounders should still operate in accordance with chapter 797 of the United States Pharmacopeia (USP), which outlines standards for sterile compounding.48,49 Unfortunately, not all states harmonize their laws and regulations with USP 797 and some lack adequate resources to provide consistent oversight.50,51

The NECC fungal meningitis outbreak represents an ever-present threat to the safety of patients receiving ESI. NECC maintained its facilities in conditions deficient for sterile compounding.52 This insufficient quality control may be present at compounding facilities that fail to incorporate adequate standards; in fact, 12 serious outbreaks have occurred in recent years, with half of implicated facilities being unable to ensure product sterility.46 Thus, aside from systemic regulatory inadequacies, the onus sometimes falls on the compounding facility.

As a result of the NECC fungal meningitis outbreak, improvements to regulatory and safety surveillance systems are underway. The Drug Quality and Security Act (DQSA) was signed into law in November 2013, amending the Federal Food, Drug, and Cosmetic Act.53-55 The legislation distinguishes pharmacies that voluntarily register as “outsourcing facilities” from traditional pharmacy compounding. Outsourcing facilities will be subject to oversight similar to that of manufacturers and will be required to report to FDA information regarding adverse events and the type of drugs that are compounded.54 The DQSA also provides for the institution of a track-and-trace pedigree system, which will require placement of product identifiers on individual drug packages over the next 10 years.55 This will help identify potentially unsafe drugs and expedite their removal from the drug supply chain.

Other related bills have been proposed, but until further regulatory changes occur, compounded products should be used with caution.56 The quality of compounded drugs can be assured by outsourcing services to compounders accredited by the Pharmacy Compounding Accreditation Board, which provides independent analysis and verification that a compounder meets accepted quality standards and submits to regular inspections.48 The contracting facility also can make considerations regarding the adequacy of the compounder’s services, as recommended in guidelines commissioned by the American Society of Health-System Pharmacists and recommendations from the journal Hospital Pharmacy.47,57 At an individual level, clinicians also must be aware when their facility obtains compounded drugs.46 Reports have documented that a lack of such awareness is common, and may prevent recognition of associations between adverse events and use of compounded drugs. Lastly, the benefit of preservative-free corticosteroids in ESI should be weighed against the risk of potential contamination if USP 797 standards are not strictly followed.

Summary

Serious complications with ESI are rare, and although numerous reports describe serious and fatal complications, the true incidence of these events is unknown. The risks for embolization and neurotoxic complication are thought to be linked with corticosteroids that are categorized as particulate and that contain preservatives, respectively; however, outcomes data from well-designed clinical trials are limited to substantiate these claims. The DQSA recently was enacted to improve oversight of outsourcing compounding facilities and traceability of compounded products. Clinicians should be aware when compounded products are used in ESI, should weigh the risks and benefits of using preservative-free corticosteroids, and should scrutinize the selection of outsourced compounding facilities.

 

Last updated on: April 14, 2015
close X
SHOW MAIN MENU
SHOW SUB MENU