In April 2014, the U.S. Food and Drug Administration (FDA) issued a drug safety communication entitled “FDA requires label changes to warn of rare but serious neurologic problems after epidural corticosteroid injections (ESI) for pain.”1 In May 2015 an expert panel convened by the FDA published their recommendations to prevent neurologic complications after ESI.2 The purpose of this article is to review the FDA warning and to summarize the expert panel recommendations.*
2009: The FDA begins evaluating serious neurologic events (SNE) associated with ESI. Cases in the medical literature and FDA adverse event reporting system (FAERS) included stroke, paralysis, spinal cord infarction, seizures, nerve injury, brain edema, loss of vision, and death.
2011: The FDA Safe Use Initiative facilitated the formation of an external advisory committee. The working group was to develop recommendations for minimizing risk of SNE with ESI.
2014 May: FDA Drug issues a Safety Communication requiring label change to warn of SNE after ESI.
2014 Nov.: FDA confers with the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee to discuss the necessity of further regulatory actions. Concerns were raised by the FDA advisory committee regarding particulate steroids (methylprednisolone, triamcinolone, betamethasome) in suspension having a higher risk for SNEs than nonparticulate steroids (dexamethasome) in solution, but there was not clear agreement on the best course of action from the advisory committee. The FDA did not modify the safety communication warning.
2015 May: The FDA Safe Use Initiative multidisciplinary and national organization working group publishes their consensus report and recommendations in a paper entitled "Safeguards to Prevent Neurologic Complications after Epidural Steroid Injections".2 This report addresses numerous potential safety issues including sedation level, technique, use of fluoroscopy or other imaging guidance, injection of contrast prior to injection of steroid and avoidance of particulate steroids for injection, particularly in the cervical region.
2015 Oct: FDA publishes "Serious Neurologic Events after Epidural Glucocorticoid Injection—The FDA’s Risk Assessment,"3 explaining their rationale for not differentiating the warning for particulate versus non-particulate steroids.
Both the FDA and the external consensus panel were confronted with numerous confounding variables and a striking lack of scientific data to illuminate the myriad issues surrounding SNE after ESI. The FDA recognized potential causes of SNE including technique-related issues such as intrathecal injection, epidural hematoma, direct nerve or spinal cord injury, and embolic infarction. Patient- and procedure-related contributors included selection criteria, anatomy, spinal level, approach (interlaminar or transforaminal), the degree of patient sedation, and use of fluoroscopy. A central question was the role of glucocorticoid preparations themselves including particulate steroid suspensions and non-particulate solutions. The vast majority of SNEs with infarction were associated with particulate steroid suspensions, which was supported by two animal studies. The FDA database with 1.3 million Medicare ESIs found that 80% utilized suspensions thereby making the relative frequency of this rare event with the different steroid preparations unclear. The use of solutions increased from 5% to 15% in younger patients and 4% to 9% in Medicare recipients between 2009 and 2013. However, there were SNEs with both suspensions and solutions during that review period.
The Safe Use Initiative consensus group was charged with reviewing the existing scientific evidence and assembling clinical considerations aimed at reducing the risk of severe neurologic complications after ESI. The members of the Safe Use Initiative committee consisted of experts from many disciplines and stakeholder national medical organizations, and the consensus group generated their specific clinical practice parameters without any decision-making input from the FDA.
The group concluded that adherence to specific practice recommendations should lead to a reduction in the incidence of neurologic injuries after ESI.
The FDA Warning:1
Facts, information for patients, information for health care professionals
- Injectable corticosteroids include methylprednisolone, hydrocortisone, triamcinolone, betamethasone, and dexamethasone.
- Corticosteroids are not approved by the FDA for injection into the epidural space. Information for Patients:
- Rare but serious problems have occurred after injection of corticosteroids into the epidural space of the spine to treat neck and back pain and radiating pain in the arms and legs. These serious problems include loss of vision, stroke, paralysis, and death.
- The effectiveness and safety of injection of corticosteroids into the epidural space of the spine have not been established, and the FDA has not approved corticosteroids for this use.
- Discuss the risks and benefits of ESI with your health care professional along with the benefits and risks associated with other possible treatments.
- Seek emergency medical attention if you experience any unusual symptoms after receiving ESI, such as loss of vision or vision changes, tingling in your arms or legs, weakness or numbness of your face, arm, or leg on one or both sides of the body, dizziness, severe headache, or seizure.
- Report any side effects following ESI to the FDA MedWatch program using the information in the “contact FDA” box: Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.
Information for Health Care Professionals:
- Rare but serious neurologic events have been reported with ESI including spinal cord infarction, paraplegia, quadriplegia, cortical blindness, stroke, and death.
- These serious events have been reported with and without the use of fluoroscopy.
- The effectiveness and safety of epidural corticosteroid administration have not been established, and the FDA has not approved corticosteroids for this use.
- Discuss with patients the risks and benefits of ESI and other possible treatments.
- Counsel patients to seek emergency medical attention immediately if they experience symptoms after receiving ESI such as loss of vision or vision changes, tingling in arms or legs, sudden weakness or numbness of face, arm, or leg on one or both sides of the body, dizziness, severe headache, or seizure.
- Report adverse effects following ESI to the FDA MedWatch program using the information in the “contact FDA” box.
Statements and Clinical Considerations of the Safe Use Working Group2
- Cervical interlaminar ESIs are associated with a rare risk of catastrophic neurologic injury.
- Transforaminal ESI using particulate steroid is associated with a rare risk of catastrophic neurovascular complications.
- All cervical interlaminar ESIs should be performed using image guidance with appropriate AP, lateral, or contralateral oblique views and a test dose of contrast medium.
- Cervical transforaminal ESI should be performed using contrast medium under real-time fluoroscopy or digital subtraction imaging, using an AP view before injecting any substance that may be hazardous to the patient.
- Cervical interlaminar ESI are recommended to be performed at C7-T1, but preferably not higher than C6-C7 level.
- No cervical interlaminar ESI should be undertaken at any segmental level without reviewing, prior to the procedure, prior imaging studies showing adequate epidural space for needle placement at the target level.
- Particulate steroids should not be used in therapeutic cervical transforaminal injections.
- All lumbar interlaminar ESIs should be performed using image guidance with appropriate AP, lateral,or contralateral oblique views and a test dose of contrast medium.
- Lumbar transforaminal ESI should be performed using contrast medium under real-time fluoroscopy or digital subtraction imaging using an AP view before injecting any substance that may be hazardous to the patient.
- A nonparticulate steroid (e.g., dexamethasone) should be used for the initial injection in lumbar transforaminal epidural injections.
- There are situations where particulate steroids could be used in the performance of lumbar transforaminal epidural steroid injection.
- Extension tubing is recommended for transforaminal ESIs.
- A face mask and gloves must be worn during the procedure.
- The ultimate choice of what (interlaminar vs. transforaminal ESI) to use should be made by the treating physician by balancing potential risks vs. benefits with each technique for each given patient.
- Cervical and lumbar interlaminar ESIs can be performed without contrast in patients with documented contraindication to the use of contrast (e.g., significant history of contrast allergy or anaphylactic reaction).
- Transforaminal ESIs can be performed without contrast in patients with documented contraindication to use, but in these circumstances particulate steroids are contraindicated and only preservative-free, particulate-free steroids should be used.
- Moderate to heavy sedation is not recommended for ESI but if light sedation is used, the patient should remain able to communicate pain or other adverse sensations or events.
The FDA drug safety communication is important to help clinicians and patients understand the FDA perspective and database experience with epidural steroid injections. Between 1997 and 2014, a total of 90 serious and sometimes fatal neurologic events were reported to the FDA Adverse Reporting System (FAERS) excluding contaminated compounded products. Statistics for Medicare and IMS Health suggested almost two million ESIs were performed from 2009 to 2013. Thus, clearly these catastrophic adverse events are rare. Both the advisory committee and FDA concurred that these events do occur. The FDA acknowledges ambiguity surrounding the effectiveness of ESI in their information for patients and information for health care professional sections of the warning.4-5 In November 2014, after the warning had already been released, the FDA asked their advisory committee on Anesthetic and Analgesic Drug Products whether a contraindication was warranted to restrict the injection of glucocorticosteroids into the epidural space.3 The FDA considered the advisory committee feedback and decided not to modify the warning which states that the "effectiveness and safety of injection of corticosteroids into the epidural space of the spine have not been established, and the FDA has not approved corticosteroids for this use." The FDA also did not find that the available data warranted either a contraindication or warning focused on cervical transforaminal injection of particulate steroid suspension preparations. There was a concern that data did not support labeling non-particulate steroid solutions safer than particulate steroid suspensions and that such labeling might encourage practitioners to use solutions even though their relative safety and effectiveness remain an open question.3 The Safe Use expert panel overwhelmingly felt that particulate steroids were the culprit in transforaminal approaches.6 The FDA safety warning urges clinicians to discuss the risks and benefits of ESIs and alternative therapy with patients presumably as a part of the pre-procedure informed consent process.
The multispecialty external working group from the FDA Safe Use Initiative contended with numerous scientific obstacles and clinical uncertainties inherent in the data surrounding ESI. There were 13 organizations voting to agree, disagree, or abstain with the clinical recommendations. The largest degree of disagreement was 11 in agreement and 2 disagreeing or unable to reach consensus (85% agree). The document is clinically oriented and the recommendations are quite specific including some that may not be ubiquitously followed by all at present. There was a focus on the particulate steroid suspensions as being a major harmful factor in spinal cord infarctions, and the group recommended to restrict particulate steroid suspension use, particularly in the cervical region.2 Recommendations include the use of particulate versus nonparticulate steroid formulations, imaging prior to and during the procedure, radiocontrast test doses, degree of sedation, approach, etc.
The Safe Use Initiative working group consensus recommendations were published in an anesthesiology journal although ESIs are also performed by specialists from other disciplines. Areas not addressed in the recommendations include the use of a local anesthetic test dose, patient selection criteria, the anticoagulated patient, chlorhexidine in alcohol for skin preparation, and the use of specific needle types.
The two documents begin from the position that significant neurologic injury may rarely occur after ESI. They diverge as a function of different areas of focus. The FDA’s job was to warn patients and doctors of these rare events. The FDA did not endorse the use of ESIs for chronic pain, a specific approach (transforaminal versus interlaminar), a specific formulation (particulate steroid suspension or non-particulate steroid solution), or the use of fluoroscopy or other type of imaging. The Safe Use Initiative working group complimented the FDA warning by delineating clinically substantive relevant recommendations which could reduce SNE after ESI. Although research is needed to clarify issues, the low incidence of these events may preclude detection in even very large studies. The SafeUse Initiative authors conclude "Our hope is that these clinical considerations will help every practitioner who performs epidural injections of steroids to become familiar with the risk of neurologic complications and to adopt the best safeguards to avoid complications and provide the safest care for their patients".3
Dr. Christie reports no financial disclosures related to this article or topic.
Dr. Christie is Associate Clinical Professor in the Department of Anesthesiology at the University of South Florida College of Medicine in Tampa, FL. She is a member of the APSF Editorial Board and the APSF Committee on Education and Training.
- Food and Drug Administration. FDA Drug Safety Communication: FDA requires label changes to warn of rare but serious neurologic problems after epidural corticosteroid injections for pain. April 23, 2014 (http://www.fda.gov/DrugsSafety/ucm394280.htm).
- Rathmell JP, Benzon HT, Dreyfuss P et al. Safeguards to prevent complications after epidural steroid injections. Consensus opinions from a multidisciplinary working group and national organizations. Anesthesiology 2015:122:974–984.
- Racoosin JA, Seymour SM, Cascio L, Gill R. N Engl J Med 2015. DOI:10.1056/NEJMp1511754.
- Friedy JL, Comstock BA et al. A randomized trial of epidural glucocorticoid injections for spinal stenosis. N Engl J Med 2014;371:11–21.
- Cohen SP, Bicket MC, Jamison D, Wilkinson I, Rachmell JP. Epidural steroids: a comprehensive, evidence-based review. Reg Anesth Pain Med 2013;38:175–200.
- Benzon HT, Huntoon MA, Rathmell JT. Improving the safety of epidural steroid injections. JAMA 2015;313:1713–1714.