Safety assessment and pharmacokinetics of intrathecal methylprednisolone acetate in dogs

Mienke Rijsdijk, Albert J M Van Wijck, Cor J. Kalkman, P. C Willem Meulenhoff, Marjorie Grafe, Joanne Steinauer, Tony L. Yaksh

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

BACKGROUND:: Intrathecal methylprednisolone acetate (MPA) has been used in patients with chronic pain syndromes. Its safety has been debated after reports of adverse events. No systematic preclinical evaluation of MPA has been reported. In the current study, the acute and long-term effects of intrathecal MPA on dog spinal tissue was studied with the injectate reformulated to include minimal adjuvants. METHODS:: Seventeen dogs were implanted with intrathecal catheters and randomized to three groups: vehicle (lidocaine; 4 dogs), MPA 20 mg/ml (human dose; 7 dogs), and MPA 80 mg/ml (maximum deliverable dose; 6 dogs). In parallel with the human protocols, dogs received four injections at 7-day intervals. Clinical observations and plasma methylprednisolone measurements were done before and at intervals after intrathecal delivery. One week (acute) or 6 weeks (long-term) after the last injection, animals were sacrificed and spinal tissues harvested for histopathology. RESULTS:: Other than a brief motor block, no adverse clinical event occurred in any animal. Group A (vehicle) showed minimal histologic changes (median histology-score; acute: 1.3, long-term: 1.0). Group B (MPA 20 mg/ml) had a diffuse inflammatory reaction (acute: 2.0, long-term: 3.0), group C (MPA 80 mg/ml) a severe inflammatory response, with large inflammatory masses (acute: 4.0, long-term: 7.0) The severity of the inflammatory reaction increased significantly with increasing dose at long-term sacrifice (acute P = 0.167, long-term P = 0.014). No neuronal injury, demyelination, or gliosis was seen in any animal. CONCLUSION:: These results, showing dose-dependent intrathecal inflammatory reactions at MPA doses and injectate concentrations comparable to those used in humans, indicate that the continued use of this modality in humans is not recommended.

Original languageEnglish (US)
Pages (from-to)170-181
Number of pages12
JournalAnesthesiology
Volume116
Issue number1
DOIs
StatePublished - Jan 2012

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Pharmacokinetics
Dogs
Safety
Injections
Gliosis
methylprednisolone acetate
Methylprednisolone
Demyelinating Diseases
Lidocaine
Chronic Pain
Histology
Catheters
Wounds and Injuries

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Rijsdijk, M., Van Wijck, A. J. M., Kalkman, C. J., Meulenhoff, P. C. W., Grafe, M., Steinauer, J., & Yaksh, T. L. (2012). Safety assessment and pharmacokinetics of intrathecal methylprednisolone acetate in dogs. Anesthesiology, 116(1), 170-181. https://doi.org/10.1097/ALN.0b013e31823cf035

Safety assessment and pharmacokinetics of intrathecal methylprednisolone acetate in dogs. / Rijsdijk, Mienke; Van Wijck, Albert J M; Kalkman, Cor J.; Meulenhoff, P. C Willem; Grafe, Marjorie; Steinauer, Joanne; Yaksh, Tony L.

In: Anesthesiology, Vol. 116, No. 1, 01.2012, p. 170-181.

Research output: Contribution to journalArticle

Rijsdijk, M, Van Wijck, AJM, Kalkman, CJ, Meulenhoff, PCW, Grafe, M, Steinauer, J & Yaksh, TL 2012, 'Safety assessment and pharmacokinetics of intrathecal methylprednisolone acetate in dogs', Anesthesiology, vol. 116, no. 1, pp. 170-181. https://doi.org/10.1097/ALN.0b013e31823cf035
Rijsdijk, Mienke ; Van Wijck, Albert J M ; Kalkman, Cor J. ; Meulenhoff, P. C Willem ; Grafe, Marjorie ; Steinauer, Joanne ; Yaksh, Tony L. / Safety assessment and pharmacokinetics of intrathecal methylprednisolone acetate in dogs. In: Anesthesiology. 2012 ; Vol. 116, No. 1. pp. 170-181.
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abstract = "BACKGROUND:: Intrathecal methylprednisolone acetate (MPA) has been used in patients with chronic pain syndromes. Its safety has been debated after reports of adverse events. No systematic preclinical evaluation of MPA has been reported. In the current study, the acute and long-term effects of intrathecal MPA on dog spinal tissue was studied with the injectate reformulated to include minimal adjuvants. METHODS:: Seventeen dogs were implanted with intrathecal catheters and randomized to three groups: vehicle (lidocaine; 4 dogs), MPA 20 mg/ml (human dose; 7 dogs), and MPA 80 mg/ml (maximum deliverable dose; 6 dogs). In parallel with the human protocols, dogs received four injections at 7-day intervals. Clinical observations and plasma methylprednisolone measurements were done before and at intervals after intrathecal delivery. One week (acute) or 6 weeks (long-term) after the last injection, animals were sacrificed and spinal tissues harvested for histopathology. RESULTS:: Other than a brief motor block, no adverse clinical event occurred in any animal. Group A (vehicle) showed minimal histologic changes (median histology-score; acute: 1.3, long-term: 1.0). Group B (MPA 20 mg/ml) had a diffuse inflammatory reaction (acute: 2.0, long-term: 3.0), group C (MPA 80 mg/ml) a severe inflammatory response, with large inflammatory masses (acute: 4.0, long-term: 7.0) The severity of the inflammatory reaction increased significantly with increasing dose at long-term sacrifice (acute P = 0.167, long-term P = 0.014). No neuronal injury, demyelination, or gliosis was seen in any animal. CONCLUSION:: These results, showing dose-dependent intrathecal inflammatory reactions at MPA doses and injectate concentrations comparable to those used in humans, indicate that the continued use of this modality in humans is not recommended.",
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