An outbreak of fungal meningitis occurred after epidural injections of contaminated compounded methylprednisolone.1,2 The first reported 66 cases occurred in Tennessee, and by December 2012, >590 cases had been reported to the U.S. Centers for Disease Control and Prevention.3 The episode was traced to contaminated steroid produced by the New England Compounding Company, exposing the lax regulations that oversee compounding companies.4–6 The catastrophic episode begs several questions. Why do interventional pain medicine physicians use compounded steroids? Are there standards and organizations that regulate the compounding of steroids? How can contaminated steroids be avoided? What is the future in terms of accreditation and regulation of compounding companies?
WHY DO INTERVENTIONAL PAIN MEDICINE PHYSICIANS USE COMPOUNDED STEROIDS?
Pain physicians order compounded steroids for several reasons. The availability of the commercial depot steroids may be interrupted as in the case of betamethasone in 2007.7 Betamethasone has the smallest particle size among the depot steroids, which is viewed as an advantage with unintentional intraarterial injection during epidural injections.7 Physicians also have the impression that compounded steroids are less expensive. However, the average wholesale prices of the compounded and commercial steroids are basically the same (Table 1).
The most important reason clinicians use compounded steroids is to avoid the question of neurotoxicity from the preservatives in commercial steroid preparations. These include benzyl alcohol, polyethylene glycol (PEG), myristyl γ-picolinium chloride (MGPC), and benzalkonium chloride (BKC; Table 1).7,8 The impression that benzyl alcohol causes neurolysis has arisen from a case report of a 24-year-old primigravida who developed flaccid paralysis after unintentional subarachnoid injection of 40-mL 0.9% NaCl that contained 1.5% benzyl alcohol.9 The patient experienced neurologic recovery after 30 hours and complete recovery after 6 months. This episode is in contrast to the absence of a motor block in a patient in whom 40 mL of 2.5% benzyl alcohol was injected in her caudal space for pelvic cancer pain.10
Animal studies showed no neurotoxicity from benzyl alcohol. Histologic examinations of the brain and meninges of adult dogs after cisterna magna injection were not different between saline and 0.9% benzyl alcohol.11 In immature dogs, no effect was seen after injection of 0.2-mL 0.9% benzyl alcohol. Clonic seizures occurred in the dogs injected with 0.45% or 7% benzyl alcohol, and death resulted after 9% benzyl alcohol.11
Regarding PEG and MGPC, demyelination, axonal disorganization, and endoneural collagen formation were noted in 42% to 50% of rat sciatic nerves when injected with methylprednisolone or its suspension (which contains PEG and MGPC).12 The changes were not noted after chloroprocaine and needle puncture. In an isolated nerve preparation, we showed that 30% PEG decreased the amplitudes of the compound action potentials of the A, B, and C fibers.13 The compound action potentials were abolished with 40% concentration, but recovered within a 2-hour washout. Regarding MGPC, the intravitreal injection of 1 mL of 0.38, 0.76, or 1.52 mg/mL MGPC resulted in morphologic damage of the retina. The changes consisted of disarrayed and swollen retinal fibers 24 hours after injection and loss of retinal layers at 6 weeks.14 The conjunctival application of 10 µL of 0.01% or 0.1% BKC, every day for 1 week, resulted in 31% decrease in stromal nerve fiber density with the 0.01% concentration and 60% decrease with the 0.1%.15
Aside from BKC, the preservatives that caused neurotoxic lesions were several-fold their concentrations of these compounds in the commercial depot steroids (Table 1). The collective data on the animal studies exonerate the preservatives in the commercial depot steroids as being neurotoxic when injected into the epidural space. In clinical practice, the steroid is diluted with 1 to 3 mL saline or local anesthetic before epidural injection, further decreasing the concentrations of the preservatives.
The histologic changes after epidural injection of triamcinolone or its vehicle in cats included minor inflammatory changes in the spinal nerve roots and meninges. The changes were not different from those seen in the control (no dural puncture) or the lidocaine groups.16 A dog study showed some histologic evidence of neuronal damage in the animal’s spinal cord after intrathecal injection of methylprednisolone and triamcinolone, but the changes were not different from saline.17 On the other hand, there was dose-related evidence of arachnoiditis when betamethasone was injected intrathecally in sheep.18 No changes were noted in the meninges or neural tissue with 1-mL injection. There was mild focal inflammation and patchy subarachnoid fibrosis with 2 mL, and florid subarachnoid fibrous proliferation with 8 mL.18 The subarachnoid space in sheep is small, one third that of humans, so the authors concluded that the risk of arachnoiditis from subarachnoid betamethasone is low. These studies should be viewed in the context of the low incidence of unintentional subarachnoid injection during epidural placements. Also, repeated intrathecal methylprednisolone injections for postherpetic neuralgia did not result in signs and symptoms of arachnoiditis.19
ARE THERE STANDARDS AND ORGANIZATIONS THAT REGULATE THE COMPOUNDING OF STEROIDS?
The standards for the compounding of medications are noted in the United States Pharmacopeia 797.20 In this handbook, the responsibilities of compounding personnel and risk categories of the drugs are noted. The amounts of acceptable particulate matter in the surrounding environment or microbial contamination are mandated. The problem is that the standards are not uniformly followed. Compounding companies are not required to adhere to the standards set in United States Pharmacopeia 797. The Food and Drug Administration (FDA) defers to the state where the compounding company is located to regulate the practice of pharmacy and perform inspections. The state may adopt the standards in their entirety, incorporate portions of the standards, make their own official policies and procedures, or take no definitive action. It is when public health is threatened (e.g., fungal meningitis outbreak) that the FDA investigates the episode and makes recommendations.
A private organization, the Pharmacy Compounding Accreditation Board (PCAB), was set up to evaluate the compounding companies. Accreditation by the PCAB provides an independent validation that the compounding company meets nationally accepted quality control, quality assurance, and quality improvement standards and that the company voluntarily participates in offsite and on-site evaluation processes. A PCAB visit to the compounding company includes inspection of the facilities and equipment, chemicals and compounds, the compounding process, beyond-use dating, packaging and labeling, and the company’s quality assurance plan. The visits are every 3 years, and the compounding company is notified ahead of time. Unfortunately, only 2% of the 7500 compounding companies in the United States participate in the PCAB voluntary accreditation program.5 The accredited companies, listed by state, are available on the agency’s website (http://www.pcab.org).
WHAT IS THE FUTURE IN TERMS OF ACCREDITATION AND REGULATION OF COMPOUNDING COMPANIES?
To their credit, more compounding companies have sought accreditation by the PCAB since the fungal meningitis episode. Where 4 to 5 companies used to apply per month, 15 to 20 companies are now applying every month (Joe Cabaleiro, personal communication, 2013). The PCAB is presently deliberating whether they will make more frequent and random unannounced visits of the accredited companies.
The fungal meningitis episode has led to the introduction of bills in the House of Representatives to improve the oversight of the compounding companies. One bill, sponsored by Congressman Edward J. Markey of Massachusetts and others, is called the Verifying Authority and Legality in Drug (VALID) Compounding Act of 2012. It has several provisions including the following:
- Preservation of state regulatory authority for traditional small compounding pharmacy activities. These companies must meet specific conditions to be exempted from FDA regulations.
- Compounding companies that are operating as drug manufacturers are regulated by the FDA as drug manufacturers.
- The bill allows some compounding companies, including hospital pharmacies or community pharmacies, to request waivers to enable them to compound drugs before the receipt of a valid prescription.
- In the event of a drug shortage or to protect public health, the FDA may waive for 1 year, the requirement to compound drugs solely for individual patients with valid prescriptions.
- To protect public health, the FDA may waive the requirement to compound drugs only if they are not similar to commercially available drugs.
- The FDA is to create and maintain a “Do Not Compound” list of drugs that are not safe or effective when compounded and to make the list available to the public and state regulators.
- The FDA is given clear authority to inspect any compounding pharmacy that receives any waiver under the act. Compounding pharmacies that become aware of adverse reactions or potential safety problems with drugs that they distributed must report to the FDA. Compounded drugs must be labeled to ensure that recipients know that the FDA has not tested the drug for safety or effectiveness and to provide a means to report serious adverse drug reactions.
Another bill was introduced by Congresswoman Rosa L. DeLauro of Connecticut. The DeLauro bill, called the “Supporting Access to Formulated and Effective (SAFE) Compounded Drugs Act of 2012,” plans to amend the existing Federal Food, Drug, and Cosmetic Act. The bill includes the following provisions:
- The physician will inform the patient that the drug being used is a compounded drug and that the drug is clearly labeled as a “non-FDA approved compounded drug product.”
- The Secretary of Health and Human Services shall maintain a database of information on compounding pharmacies that are licensed in >1 state.
- The Secretary shall determine the minimum standards for safe production of compounded drug products.
- The owner of the compounding company shall inform the Secretary of Health and Human Services the state(s) in which the company is licensed.
Unfortunately, both bills languished in committees partly because the bills were not bipartisan. The sponsors plan to reintroduce the bill in the 2013 session of Congress. However, the House Energy and Commerce Committee is presently investigating the New England Compounding Company case, and it is not likely to proceed with legislation until their investigation is complete. In the Senate, a bipartisan group of senators just introduced a bill requiring compounding companies to be under the supervision of the FDA. The sponsors of the bill include Senators Tom Harkin (D-Iowa), Lamar Alexander (R-Tenn.), Al Franken (D-Minn.), and Pat Roberts (R-Kan.). The salient features of the bill include the following:
- The compounding companies must register with the FDA and tell the agency the products that they have made, make products in compliance with good manufacturing practices and under a pharmacist’s supervision, and investigate and report adverse events.
- The FDA may identify categories of drugs that currently cannot be safely compounded.
- The line between compounding manufacturers and traditional manufacturers is preserved by prohibitions on the wholesale distribution of compounded products.
- The FDA upon receiving a complaint from a state regulatory agency about a pharmacy in another state must relay that information to the relevant state pharmacy board within 15 days.
A controversial provision of the Senate bill is the exemption of some compounding companies from FDA supervision. The bill needs refinement based on input from stakeholders including the FDA, International Academy of Compounding Companies, and organizations representing the interest of the public. It is not clear what the approved bill will look like if one is to be approved during this session of Congress. Just as important as the final provisions of Senate bill is a bill in the House of Representatives with bipartisan input.
While legislative and regulatory changes are being debated, pain medicine practitioners will continue to use compounded medications. It will take time before compounding companies gain back the trust of physicians and their patients. At this time, PCAB accreditation can assure both stakeholders of a sterile and safe medication preparation. Regulations of compounding companies should be based on national standards because these companies sell their products beyond the state where they are located. A bipartisan effort is needed to correct the present unacceptable situation. Leaving the supervision of the compounding companies to the states where they are located, many of which are having fiscal challenges, is a setup for a repeat of this preventable national disaster.
Name: Honorio T. Benzon, MD.
Contribution: This author wrote the manuscript.
This manuscript was handled by: Spencer S. Liu, MD.
The author acknowledges the assistance of the following: Jane Regalado, PharmD, and Ms. Lei Tang of Northwestern Memorial Hospital in researching the average wholesale prices of the different commercial depot steroids; Joe Cabaleiro, Executive Director of PCAB for giving the author the data on the increased number of applications for accreditation and the plan of PCAB on random visits; Avenel Joseph of Congressman Markey’s office for providing the author a version of the VALID Compounding Act of 2012; Sarah Ryan Dodge-Palmer, Vice-President of Government Affairs, International Academy of Compounding Pharmacists (IACP) for providing the author a copy of the DeLauro bill and updating the author on the developments in the Senate Health, Education, Labor, and Pensions (HELP) Committee.
1. Pettit AC, Kropski JA, Castilho JL, Schmitz JE, Rauch CA, Mobley BC, Wang XJ, Spires SS, Pugh ME. The index case for the fungal meningitis outbreak in the United States. N Engl J Med. 2012;367:2119–25
2. Kainer MA, Reagan DR, Nguyen DB, Wiese AD, Wise ME, Ward J, Park BJ, Kanago ML, Baumblatt J, Schaefer MK, Berger BE, Marder EP, Min JY, Dunn JR, Smith RM, Dreyzehner J, Jones TFTennessee Fungal Meningitis Investigation Team. . Fungal infections associated with contaminated methylprednisolone in Tennessee. N Engl J Med. 2012;367:2194–203
3. Kuehn BM. Hospital faces uncertainty as it copes with surge of patients with fungal meningitis. JAMA. 2013;309:219–21
4. Outterson K. Regulating compounding pharmacies after NECC. N Engl J Med. 2012;367:1969–72
5. Wilson LE, Blythe D, Sharfstein JM. Fungal meningitis from injection of contaminated steroids: a compounding problem. JAMA. 2012;308:2461–2
6. Drazen JM, Curfman GD, Baden LR, Morrissey S. Compounding errors. N Engl J Med. 2012;367:2436–7
7. 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
8. Candido KD, Knezevic I, Mulakel J, Knezevic NN. Enhancing the relative safety of intentional or unintentional methylprednisolone administration by removing polyethylene glycol. Anesth Analg. 2011;113:1487–9
9. Craig DB, Habib GG. Flaccid paraparesis following obstetrical epidural anesthesia: possible role of benzyl alcohol. Anesth Analg. 1977;56:219–21
10. Kenny M. Relief of pain in intractable cancer of the pelvis. Br Med J. 1947;2:862–3
11. DeLand FH. Intrathecal toxicity studies with benzyl alcohol. Toxicol Appl Pharmacol. 1973;25:153–6
12. Wood KM, Arguelles J, Norenberg MD. Degenerative lesions in rat sciatic nerves after local injections of methylprednisolone in sterile aqueous suspension. Reg Anesth. 1980;5:13–5
13. Benzon HT, Gissen AJ, Strichartz GR, Avram MJ, Covino BG. The effect of polyethylene glycol on mammalian nerve impulses. Anesth Analg. 1987;66:553–9
14. Zemel E, Loewenstein A, Lazar M, Perlman I. The effects of myristyl gamma-picolinium chloride on the rabbit retina: morphologic observations. Invest Ophthalmol Vis Sci. 1993;34:2360–6
15. Sarkar J, Chaudhary S, Namavari A, Ozturk O, Chang JH, Yco L, Sonawane S, Khanolkar V, Hallak J, Jain S. Corneal neurotoxicity due to topical benzalkonium chloride. Invest Ophthalmol Vis Sci. 2012;53:1792–802
16. Delaney TJ, Rowlingson JC, Carron H, Butler A. Epidural steroid effects on nerves and meninges. Anesth Analg. 1980;59:610–4
17. Abram SE, Marsala M, Yaksh TL. Analgesic and neurotoxic effects of intrathecal corticosteroids in rats. Anesthesiology. 1994;81:1198–205
18. Latham JM, Fraser RD, Moore RJ, Blumbergs PC, Bogduk N. The pathologic effects of intrathecal betamethasone. Spine (Phila Pa 1976). 1997;22:1558–62
19. Kotani N, Kushikata T, Hashimoto H, Kimura F, Muraoka M, Yodono M, Asai M, Matsuki A. Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med. 2000;343:1514–9
20. The U.S. Pharmacopeia Convention. United States Pharmacopeia, 27th rev., and The National Formulary, 22nd ed. 2004 Rockville, MD The U.S. Pharmacopeia Convention:2350–70