September 01, 2010
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Preservative noted as possible key to intra-articular injection corticosteroid chondrotoxicity

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Jason L. Dragoo, Md
Jason L. Dragoo

PROVIDENCE, R.I. — Intra-articular corticosteroid injections with betamethasone combinations for knee inflammation relief should be used with caution due to a significant chondrotoxic effect, according to a California orthopedic investigator. Also, he noted that caution should be used with anesthetic corticosteroid combinations that use lidocaine until further studies can be performed to establish their safety.

“Corticosteroids have been used for years to provide short-term relief of inflammation within the joint,” said Jason L. Dragoo, MD, assistant professor at Stanford University. “There have been a number of studies showing their efficacy at decreasing pain symptoms; however few studies examined their effects on cartilage.”

Dragoo noted that there are no guidelines for the use of corticosteroids for intra-articular injection. “There is some evidence of chondrotoxicity in the literature for these corticosteroids. However, there are no current in vitro studies which evaluate these effects over the length of their duration using a physiologically relevant model.”

Four common corticosteroids

For his investigation, Dragoo analyzed the properties of four of the most popular corticosteroids in use today: triamcinolone acetonide; methylprednisolone acetate, betamethasone sodium acetate and betamethasone sodium phosphate combination; and dexamethasone sodium phosphate. They used a customized bioreactor which allowed a continuous infusion pump to constantly allow ingress and egress of the medications to juvenile human chondrocytes throughout the duration of the study.

“Single injection doses of each corticosteroid were used and were delivered at the average duration of residence time within the joint,” Dragoo said. “There was a 14-day trial performed to make sure there was no cell death due to the culture method itself.”

Preservative

Dragoo found that single-dose injections of betamethasone sodium acetate (Celestone Soluspan, Merck) were significantly toxic compared to the 9-day control chondrocytes. The other three medications were not chondrotoxic compared to their relative controls.

“A 14-day time controlled trial also showed that Soluspan continued its chondrotoxicity and that none of the other medications exhibited toxicity,” he said.

He noted that the chondrotoxicity of Celestone Soluspan was increased in conjunction with the local anesthetic lidocaine “Also, all of the corticosteroids had increased chondrotoxicity when mixed with lidocaine, suggesting that there is some interaction with the medications and lidocaine, seeing that the lidocaine only group had no significant toxicity in itself,” Dragoo said.

Merck’s response

Merck officials responded to Dragoo’s assertions in a statement to Orthopedics Today: “While Merck welcomes continued research in the area of anti-inflammatory medicine, Dr. Dragoo’s recent investigation into an association between chondrotoxicity and commonly used corticosteroids was conducted in an in vitro model. Well-conducted in vivo or human studies would add to this area of knowledge and potentially inform clinical decisions. Merck stands behind the safety of Celestone Soluspan, which has been used clinically for more than 40 years. Celestone Soluspan Injectable Suspension is indicated as adjunctive therapy for short-term administration in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis of osteoarthritis.”

Dragoo hypothesized which factors would make this one medication chondrotoxic — the medication itself, preservatives used, the pH, or the crystallinity.

“The preservative benzalkonium chloride is found in Celestone and is not in any of the other corticosteroids commonly used,” Dragoo said. “A recent report by Davis and colleagues has shown decreased chondrocyte viability at a dose of 10 mcg which is 1/20 of the dose in a typical concentration of Celestone, and in this study it led to 99% chondrocyte death. Also in this study, when betamethasone was tested alone, without its preservative, it was not toxic. The hypothesis would be that this benzalkonium chloride leads to a disassociation of the lipid bilayers leading to leakage of cellular contents and cell death.”

In a discussion following the presentation, Dragoo pointed out, “Our research was very specific to intra-articular injections and by no means are we concluding that Celestone is harmful for extra-articular injections.” – by Lee Beadling

Reference:

  • Jason L. Dragoo, MD, can be reached at 450 Broadway St., Pavilion A, 2nd Floor MC 6120 Redwood City, CA 94063; 650-723-5643: e-mail: jdragoo@stanford.edu. He serves as a consultant for Smith & Nephew Endoscopy, iBalance, Ossur, Genzyme, and ConMed Linvatec.

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