European Spine Journal

, Volume 28, Issue 1, pp 21–30 | Cite as

Safety of intrathecal route: focus to methylprednisolone acetate (Depo-Medrol) use

  • Joël SchlatterEmail author
  • David Nguyen
  • Michèle Zamy
  • Sofiane Kabiche
  • Jean-Eudes Fontan
  • Salvatore Cisternino
Review Article



Complications of the intrathecal route may cause potential toxicity related to the medical device and properties of the administered drug and/or excipient. A description of clinical and histological effects of polyethylene glycol and miripirium after Depo-Medrol injection, and the adverse reactions of particulate methylprednisolone acetate was conducted. The safety of the intrathecal route with excipients, label and off-label drugs is discussed.


A bibliographic search in Medline, Google, and Cochrane database from 1940 to June 2016 was performed. The keywords included ‘intrathecal methylprednisolone acetate’, ‘miripirium’, ‘myristyl-gamma-picolinium’, ‘side effects’, ‘intrathecal Depo-Medrol’, ‘polyethylene glycol’, and ‘intrathecal devices’ used individually or in combination.


Adverse reactions have been reported with this intrathecal administration route such as arachnoiditis, bladder dysfunction, headache, meningitis. Some pharmaceutical excipients have been associated with specific toxicity issues and with allergic and anaphylaxis reactions. Additives of methylprednisolone acetate formulations such as polyethylene glycol and miripirium chloride can be neurotoxic when injected intrathecally. Polyethylene glycol—an antimicrobial agent widely used in pharmaceutical drugs—has been associated with cardiovascular, hepatic, respiratory, and CNS toxicity.


Intrathecal methylprednisolone acetate (Depo-Medrol) therapy seems not fully safe due to reported adverse events. The use of other forms of corticosteroid therapy free from excipients should be emphasized such as soluble methylprednisolone sodium succinate.


Drug safety Intrathecal injection Methylprednisolone acetate Off-label 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Coombs DW, Saunders RL, Gaylor MS, Pageau M, Leith MG, Shaiberger C (1981) Continuous epidural analgesia via implanted morphine reservoir. Lancet 2:425–426CrossRefGoogle Scholar
  2. 2.
    Onofrio BM, Yaksh TL, Arnold PG (1981) Continuous low-dose intrathecal morphine administration in the treatment of chronic pain of malignant origin. Mayo Clin Proc 56:516–520Google Scholar
  3. 3.
    Kerr JZ, Berg S, Blaney SM (2001) Intrathecal chemotherapy. Crit Rev Oncol Hematol 37(3):227–236CrossRefGoogle Scholar
  4. 4.
    Gilbar PJ (2014) Intrathecal chemotherapy: potential for medication error. Cancer Nurs 37(4):299–309CrossRefGoogle Scholar
  5. 5.
    Varhabhatla NC, Zuo Z (2012) Rising complication rates after intrathecal catheter and pump placement in the pediatric population: analysis of national data between 1997 and 2006. Pain Phys 15(1):65–74Google Scholar
  6. 6.
    Penn RD, York MM, Paice JA (1995) Catheter systems for intrathecal drug delivery. J Neurosurg 83:215–217CrossRefGoogle Scholar
  7. 7.
    Przybyl JS, Follett KA, Caraway D (2003) Intrathecal drug therapy: general considerations. Sem Pain Med 1(4):228–233CrossRefGoogle Scholar
  8. 8.
    Motta F, Antonello CE (2016) Comparison between an Ascenda and a silicone catheter in intrathecal baclofen therapy in pediatric patients: analysis of complications. J Neurosurg Pediatr 24:1–6Google Scholar
  9. 9.
    Kwong YL, Yeung DY, Chan JC (2009) Intrathecal chemotherapy for hematologic malignancies: drugs and toxicities. Ann Hematol 88(3):193–201CrossRefGoogle Scholar
  10. 10.
    Monsivais JJ, Monsivais DB (2014) The long-term safety and efficacy of intrathecal therapy using sufentanil in chronic intractable non-malignant pain. Korean J Pain 27(3):297–300CrossRefGoogle Scholar
  11. 11.
    Oliveira M, Braga S, Passos-Coelho JL, Fonseca R, Oliveira J (2011) Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab. Breast Cancer Res Treat 127(3):841–844CrossRefGoogle Scholar
  12. 12.
    Bonnan M, Ferrari S, Bertandeau E, Demasles S, Krim E, Miquel M et al (2014) Intrathecal rituximab therapy in multiple sclerosis: review of evidence supporting the need for future trials. Curr Drug Targets 15(13):1205–1214CrossRefGoogle Scholar
  13. 13.
    Chotsampancharoen T, Sripornsawan P, Wongchanchailert M (2016) Two fatal cases of accidental intrathecal vincristine administration: learning from death events. Chemotherapy 61(2):108–110CrossRefGoogle Scholar
  14. 14.
    Tournel G, Bécart-Robert A, Courtin P, Hédouin V, Gosset D (2006) Fatal accidental intrathecal injection of vindesine. J Forensic Sci 51(5):1166–1168CrossRefGoogle Scholar
  15. 15.
    Sehgal AD, Gardner WJ (1960) Corticosteroids administered intradurally for relief of sciatica. Cleve Clin Q 27:198–201CrossRefGoogle Scholar
  16. 16.
    Sehgal AD, Gardner WJ (1963) Place of intrathecal methylprednisolone acetate in neurological disorders. Trans Am Neurol Assoc 88:275–276Google Scholar
  17. 17.
    Singh S, Gupta R, Kaur S, Kaur J (2013) Post-herpetic neuralgia: a review of current management strategies. Indian J Pain 27(1):12–21CrossRefGoogle Scholar
  18. 18.
    Kotani N, Kushikata T, Hashimoto H, Kimura F, Muraoka M, Yodono M et al (2000) Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med 343(21):1514–1519CrossRefGoogle Scholar
  19. 19.
    Kikuchi A, Kotani N, Sato T, Takamura K, Sakai I, Matsuki A (1999) Comparative therapeutic evaluation of intrathecal versus epidural methylprednisolone for long-term analgesia in patients with intractable postherpetic neuralgia. Reg Anesth Pain Med 24:287–293Google Scholar
  20. 20.
    Vilmer E, Suciu S, Ferster A, Bertrand Y, Cavé H, Thyss A et al (2000) Long-term results of three randomized trials (58831, 58832, 58881) in childhood acute lymphoblastic leukemia: a CLCG-EORTC report—Children Leukemia Cooperative Group. Leukemia 14:2257–2266CrossRefGoogle Scholar
  21. 21.
    Pinkel D, Woo S (1994) Prevention and treatment of meningeal leukemia in children. Blood 84(2):355–366Google Scholar
  22. 22.
    Matloub Y, Lindemulder S, Gaynon PS, Sather H, La M, Broxson E et al (2006) Intrathecal triple therapy decreases central nervous system relapse but fails to improve event-free survival when compared with intrathecal methotrexate: results of the Children’s Cancer Group (CCG) 1952 study for standard-risk acute lymphoblastic leukemia, reported by the Children’s Oncology Group. Blood 108(4):1165–1173CrossRefGoogle Scholar
  23. 23.
    National Institute of Cancer (2016) Les spécificités des cancers des enfants et des adolescents. Available at: Accessed June 2016
  24. 24.
    Donadieu J, Hill C (2002) Clinical trials in childhood acute lymphoblastic leukemia: a common prognostic classification and a common induction therapy are now warranted. J Pediatr Hematol Oncol 24(6):424–425CrossRefGoogle Scholar
  25. 25.
    Donadieu J, Auclerc MF, Baruchel A, Leblanc T, Landman-Parker J, Perel Y et al (1998) Critical study of prognostic factors in childhood acute lymphoblastic leukaemia: differences in outcome are poorly explained by the most significant prognostic variables. Fralle Group. French Acute Lymphoblastic Leukaemia Study Group. Br J Haematol 102(3):729–739CrossRefGoogle Scholar
  26. 26.
    Donadieu J, Auclerc MF, Baruchel A, Perel Y, Bordigoni P, Landman-Parker J et al (2000) Prognostic study of continuous variables (white blood cell count, peripheral blast cell count, haemoglobin level, platelet count and age) in childhood acute lymphoblastic leukaemia. Analysis of a population of 1545 children treated by the French Acute Lymphoblastic Leukaemia Group (FRALLE). Br J Cancer 83(12):1617–1622CrossRefGoogle Scholar
  27. 27.
    Pui CH, Robison LL, Look AT (2008) Acute lymphoblastic leukaemia. Lancet 371(9617):1030–1043CrossRefGoogle Scholar
  28. 28.
    Pui CH, Mahmoud HH, Rivera GK, Hancock ML, Sandlund JT, Behm FG et al (1998) Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood 92(2):411–415Google Scholar
  29. 29.
    Liu HC, Yeh TC, Hou JY, Chen KH, Huang TH, Chang CY et al (2014) Triple intrathecal therapy alone with omission of cranial radiation in children with acute lymphoblastic leukemia. J Clin Oncol 32(17):1825–1829CrossRefGoogle Scholar
  30. 30.
    Gardner WJ, Goebert HW, Sehgal AD (1961) Intraspinal corticosteroids in the treatment of sciatica. Trans Am Neurol Assoc 86:214–215Google Scholar
  31. 31.
    Goldstein NP, McGuckin WF, McKenzie BF, Mattox VR (1970) Experimental intrathecal administration of methylprednisolone acetate in multiple sclerosis. Trans Am Neurol Assoc 95:243–244Google Scholar
  32. 32.
    Nelson DA, Vates TS Jr, Thomas RB Jr (1973) Complications from intrathecal steroid therapy in patients with multiple sclerosis. Acta Neurol Scand 49(2):176–188CrossRefGoogle Scholar
  33. 33.
    Bernat JL, Sadowsky CH, Vincent FM, Nordgren RE, Margolis G (1976) Sclerosing spinal pachymeningitis. A complication of intrathecal administration of Depo-Medrol for multiple sclerosis. J Neurol Neurosurg Psychiatry 39(11):1124–1128CrossRefGoogle Scholar
  34. 34.
    Roche J (1984) Steroid-induced arachnoiditis. Med J Aust 140(5):281–284Google Scholar
  35. 35.
    Johnson A, Ryan MD, Roche J (1991) Depo-Medrol and myelographic arachnoiditis. Med J Aust 155(1):18–20Google Scholar
  36. 36.
    Rijsdijk M, van Wijck AJ, Meulenhoff PC, Kavelaars A, van der Tweel I, Kalkman CJ (2013) No beneficial effect of intrathecal methylprednisolone acetate in postherpetic neuralgia patients. Eur J Pain 17(5):714–723CrossRefGoogle Scholar
  37. 37.
    Lima RM, Navarro LH, Carness JM, Barros GA, Marques ME, Solanki D et al (2010) Clinical and histological effects of the intrathecal administration of methylprednisolone in dogs. Pain Phys 13(5):493–501Google Scholar
  38. 38.
    Rijsdijk M, van Wijck AJ, Kalkman CJ, Meulenhoff PC, Grafe MR, Steinauer J et al (2012) Safety assessment and pharmacokinetics of intrathecal methylprednisolone acetate in dogs. Anesthesiology 116(1):170–181CrossRefGoogle Scholar
  39. 39.
    Food and Drug Administration (FDA) (2016) Depo-Medrol label information. Accessed June 2016
  40. 40.
    Nelson JW, Lyster SC (1946) The toxicity of myristyl-gamma-picolinium chloride. J Am Pharm Assoc Am Pharm Assoc 35:89–94CrossRefGoogle Scholar
  41. 41.
    Zemel E, Loewenstein A, Lazar M, Perlman I (1993) The effects of myristyl gamma-picolinium chloride on the rabbit retina: morphologic observations. Invest Ophthalmol Vis Sci 34(7):2360–2366Google Scholar
  42. 42.
    Farm G, Erikssohn I (2001) Contact allergy to miripirium chloride in Depo-Medrol. Contact Dermat 44(2):127CrossRefGoogle Scholar
  43. 43.
    Loewenstein A, Zemel E, Lazar M, Perlman I (1991) The effects of Depo-Medrol preservative on the rabbit visual system. Invest Ophthalmol Vis Sci 32(12):3053–3060Google Scholar
  44. 44.
    Mathias CG, Robertson DB (1985) Delayed hypersensitivity to a corticosteroid suspension containing methylprednisolone. Two cases of conjunctival inflammation after retrobulbar injection. Arch Dermatol 121(2):258–261CrossRefGoogle Scholar
  45. 45.
    Knezevic NN, Candido KD, Cokic I, Krbanjevic A, Berth SL, Knezevic I (2014) Cytotoxic effect of commercially available methylprednisolone acetate with and without reduced preservatives on dorsal root ganglion sensory neurons in rats. Pain Phys 17(5):E609–E618Google Scholar
  46. 46.
    Benzon HT, Gissen AJ, Strichartz GR, Avram MJ, Covino BG (1987) The effect of polyethylene glycol on mammalian nerve impulses. Anesth Analg 66(6):553–559CrossRefGoogle Scholar
  47. 47.
    Nelson DA (1988) Dangers from methylprednisolone acetate therapy by intraspinal injection. Arch Neurol 45(7):804–806CrossRefGoogle Scholar
  48. 48.
    Candido KD, Knezevic I, Mukalel J, Knezevic NN (2011) Enhancing the relative safety of intentional or unintentional intrathecal methylprednisolone administration by removing polyethylene glycol. Anesth Analg 113(6):1487–1489CrossRefGoogle Scholar
  49. 49.
    Reed JC (2000) Mechanisms of apoptosis. Am J Pathol 157:1415–1430CrossRefGoogle Scholar
  50. 50.
    Okubadejo GO, Talcott MR, Schmidt RE, Sharma A, Patel AA, Mackey RB et al (2008) Perils of intravascular methylprednisolone injection into the vertebral artery. An animal study. J Bone Jt Surg Am 90(9):1932–1938CrossRefGoogle Scholar
  51. 51.
    Beck-Speier I, Dayal N, Karg E, Maier KL, Schumann G, Schulz H et al (2005) Oxidative stress and lipid mediators induced in alveolar macrophages by ultrafine particles. Free Radic Biol Med 38:1080–1092CrossRefGoogle Scholar
  52. 52.
    Donaldson K, Stone V (2003) Current hypotheses on the mechanisms of toxicity of ultrafine particles. Ann Ist Super Sanita 39(3):405–410Google Scholar
  53. 53.
    Driscoll KE, Carter JM, Hassenbein DG, Howard B (1997) Cytokines and particle-induced inflammatory cell recruitment. Environ Health Perspect 105:1159–1164Google Scholar
  54. 54.
    Akers MJ (2002) Excipient–drug interactions in parenteral formulations. J Pharm Sci 91(11):2283–2300CrossRefGoogle Scholar
  55. 55.
    Golightly LK, Smolinske SS, Bennett ML, Sutherland EW, Rumack BH (1988) Pharmaceutical excipients. Adverse effects associated with inactive ingredients in drug products (Part I). Med Toxicol Adverse Drug Exp 3(2):128–165Google Scholar
  56. 56.
    Sood S, Strachan DR, Tsikoudas A, Stables GI (2002) Allergic otitis externa. Clin Otolaryngol Allied Sci 27(4):233–236CrossRefGoogle Scholar
  57. 57.
    No authors listed (2009) What are excipients doing in medicinal products? Drug Ther Bull 47(7):81–84Google Scholar
  58. 58.
    Fabiano V, Mameli C, Zuccotti GV (2011) Paediatric pharmacology: remember the excipients. Pharmacol Res 63:362–365CrossRefGoogle Scholar
  59. 59.
    Arulanantham K, Genel M (1978) Central nervous system toxicity associated with ingestion of propylene glycol. J Pediatr 93(3):515–516CrossRefGoogle Scholar
  60. 60.
    Gulia S, Gupta S, Singh A (2016) Intrathecal trastuzumab for leptomeningeal carcinomatosis in patients with human epidermal growth factor receptor 2 positive breast cancer. Indian J Med Paediatr Oncol 37(3):196–198CrossRefGoogle Scholar
  61. 61.
    Doorduijn JK, van Imhoff GW, van der Holt B, Schouten HC, Schaafsma MR, MacKenzie MA et al (2016) Treatment of secondary central nervous system lymphoma with intrathecal rituximab, high-dose methotrexate, and R-DHAP followed by autologous stem cell transplantation: results of the HOVON 80 phase 2 study. Hematol Oncol. (epub ahead of print) Google Scholar
  62. 62.
    Safari F, Aminnejad R, Mohajerani SA, Farivar F, Mottaghi K, Safdari H (2016) Intrathecal dexmedetomidine and fentanyl as adjuvant to bupivacaine on duration of spinal block in addicted patients. Anesth Pain Med 31 6(1):26714Google Scholar
  63. 63.
    Tandon S, Singh S, Sharma S, Lahiri AK (2016) Use of intrathecal fluorescein in recurrent meningitis after cochlear implantation. Iran J Otorhinolaryngol 28(86):221–226Google Scholar
  64. 64.
    Antunes P, Perdigão M (2016) The use of intrathecal fluorescein in cerebrospinal fluid leak repair: management from an anesthesiologist’s point-of-view. Acta Anaesthesiol Scand 60(9):1323–1327CrossRefGoogle Scholar
  65. 65.
    Raza SM, Banu MA, Donaldson A, Patel KS, Anand VK, Schwartz TH (2016) Sensitivity and specificity of intrathecal fluorescein and white light excitation for detecting intraoperative cerebrospinal fluid leak in endoscopic skull base surgery: a prospective study. J Neurosurg 124(3):621–626CrossRefGoogle Scholar
  66. 66.
    Saiki JH, Thompson S, Smith F, Atkinson R (1972) Paraplegia following intrathecal chemotherapy. Cancer 29(2):370–374CrossRefGoogle Scholar
  67. 67.
    DeLand FH (1973) Intrathecal toxicity studies with benzyl alcohol. Toxicol Appl Pharmacol 25(2):153–156CrossRefGoogle Scholar
  68. 68.
    Craig DB, Habib GG (1977) Flaccid paraparesis following obstetrical epidural anesthesia: possible role of benzyl alcohol. Anesth Analg 56(2):219–221CrossRefGoogle Scholar
  69. 69.
    Niv D, Whitwam JG, Loh L (1983) Depression of nociceptive sympathetic reflexes by the intrathecal administration of midazolam. Br J Anaesth 55(6):541–547CrossRefGoogle Scholar
  70. 70.
    Hahn AF, Feasby TE, Gilbert JJ (1983) Paraparesis following intrathecal chemotherapy. Neurology 33(8):1032–1032CrossRefGoogle Scholar
  71. 71.
    Swerdlow M (1973) Intrathecal chlorocresol. Anaesthesia 28(3):297–301CrossRefGoogle Scholar
  72. 72.
    Du Pen SL, Ramsey D, Chin S (1987) Chronic epidural morphine and preservative-induced injury. Anesthesiology 67(6):987–988CrossRefGoogle Scholar
  73. 73.
    Rincon F, Mocco J, Komotar RJ, Khandji AG, McCormick PC, Olarte M (2008) Chronic myelopathy due to a giant spinal arachnoid cyst: a complication of the intrathecal injection of phenol. J Neurosurg Spine 8(4):390–393CrossRefGoogle Scholar
  74. 74.
    Malinovsky JM, Lepage JY, Cozian A, Mussini JM, Pinaudt M, Souron R (1993) Is ketamine or its preservative responsible for neurotoxicity in the rabbit? Anesthesiology 78(1):109–115CrossRefGoogle Scholar
  75. 75.
    Gurun MS, Leinbach R, Moore L, Lee CS, Owen MD, Eisenach JC (1997) Studies on the safety of glucose and paraben-containing neostigmine for intrathecal administration. Anesth Analg 85(2):317–323Google Scholar
  76. 76.
    Wang BC, Hillman DE, Spielholz NI, Turndorf H (1984) Chronic neurological deficits and Nesacaine-CE–an effect of the anesthetic, 2-chloroprocaine, or the antioxidant, sodium bisulfite? Anesth Analg 63(4):445–447CrossRefGoogle Scholar
  77. 77.
    Ready LB, Plumer MH, Haschke RH, Austin E, Sumi SM (1985) Neurotoxicity of intrathecal local anesthetics in rabbits. Anesthesiology 63(4):364–370CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.PharmacieHôpital Universitaire Necker - Enfants Malades, APHPParisFrance
  2. 2.Pharmacie, Hôpital Jean Verdier, APHPHôpitaux Universitaires de Paris-Seine-Saint-Denis (HUPSSD)BondyFrance
  3. 3.Pharmacovigilance, Hôpital Saint-Antoine, APHPHôpitaux Universitaires Est ParisienParisFrance
  4. 4.INSERM UMR-S 1144Université Paris Descartes, Faculté de pharmacieParisFrance

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