Metronidazole-Induced Neuropathy: A Burning Truth

Chad G. Wenzel, MD; Thomas S. Achey, PharmD; Brian A. Fischer, MD, PhD

Introduction

Case Presentation

Diagnostic Approach Discussion

References

• Metronidazole is a commonly utilized antibiotic; considered a Top 200 drug based on prescriptions

• It is typically well-tolerated and used to treat a broad spectrum of infections across all ages

• Side effects are usually minimal • Similar to other antimicrobials (eg. GI

symptoms), and are usually dose-dependent • Normally resolve with drug discontinuation

• Prior case reports demonstrate neuropathy as a potential side effect – mostly seen with higher doses • Neuropathy often requires doses between 12

and 228 grams of metronidazole • It oftentimes persists long after drug

discontinuation

• 45 year old female without relevant PMHx presented with burning and excruciating pain in a stocking-and-glove distribution

• Pain present for four days prior to hospitalization • Recently prescribed metronidazole (750 mg orally

three times daily) for suspected bacterial cholecystitis

• Patient self-discontinued antibiotic at onset of pain after three days of use (consumed 7.5 grams total)

• Clinical Examination • Temp 99.0 F, P 135, RR 40, BP 137/66 • Extreme pain and hypersensitivity present on

palpation of hands and feet • No sensation deficits or other neurological findings present • No skin pallor, blistering, rash, or other skin abnormalities

• Labs significant for: • WBC: 22,000 cells/uL • Creatinine kinase 188 u/L • Lactate: 10.3 mmol/L

• EMG: mixed axonal and demyelinative polyneuropathy of both ulnar nerves

• Metronidazole-induced, long-nerve, painful neuropathy is an extremely rare side effect, and had previously occurred with doses between 12 and 228 grams.

• Interestingly, our patient received significantly less drug than other patients

• Temperature anesthesia, decreased tactile sensation, autonomic neuropathy, and mild extremity neuropathy are more common neuropathies associated with the drug

• Other associated drugs include isoniazid, dapsone, vinca alkaloids, taxane derivatives, amiodarone, digoxin, and cimetidine • Evaluate for axonal degeneration, demyelination, or nerve damage to aid in diagnosis • Etiology is currently idiopathic with some theories under investigation, including RNA synthesis

inhibition or modulation of GABA sensitivity • Multiple pain management regimens have been

trialed in patients presenting with these iatrogenic adverse events

• Resolution of pain is dependent on nerve tissue healing; many patients only have partial resolution Management and Treatment

• Immediate: Aggressive pain management with intravenous fentanyl and ketamine

• Acute: Pregabalin titration up to 450 mg/day, short course of intravenous ketorolac, and transition to oral narcotics (long and short acting)

• Long-term: Addition of imipramine, with titration to 50mg/day, continued pregabalin, and weaned oral opioids over the following 2 months

• Additional options: topical lidocaine or capsaicin ointment, tramadol, or venlafaxine

• Takeuchi, Hiroaki, et al. "Metronidazole neuropathy: a case report." Psychiatry and Clinical Neurosciences 42.2 (1988): 291-295.

• Kapoor K, Chandra M, Nag D, et al. Evaluation of metronidazole toxicity: a prospective study. Int J Clin Pharmacol Res 1999;19:83-88

• Kumar, Hitender, et al. "Rapid onset peripheral neuropathy: A rare complication of metronidazole." Journal of the Indian Academy of Clinical Medicine 13.4 (2012): 346-348.

• Alport, Adina R., and Howard W. Sander. "Clinical approach to peripheral neuropathy: anatomic localization and diagnostic testing." CONTINUUM: Lifelong Learning in Neurology 18.1, Peripheral Neuropathy (2012): 13-38.

• Kulkarni, Girish B., et al. "Sural nerve biopsy in chronic inflammatory demyelinating polyneuropathy: Are supportive pathologic criteria useful in diagnosis?." Neurology India 58.4 (2010): 542.

• A diagnosis of exclusion in the setting of known pre-exposure to an offending agent

• Must exclude vitamin deficiencies, diabetes, trauma, autoimmune, and infectious sources

• Nerve biopsy can be done in cases of uncertainty • Biopsies show axonal demyelination and

degeneration in the presence of neuropathic pain

Nerve biopsy stained for myelin and axons shows

predominant myelin loss (A) with relative preservation of axons (B); in contrast, figures C and D show a greater degree of axonal dropout (D) than demyelination (C).