Methoxyflurane-induced hepatotoxicity following repeated analgesic use: a case report

Abstract

Methoxyflurane is a halogenated ether previously used as a general anesthetic, now reintroduced in subanesthetic doses for analgesia. Although considered safe in low doses, historical data suggest the potential for rare but severe hepatotoxicity. We report a case of methoxyflurane-induced acute liver failure following repeated low-dose exposure, including unsupervised over-the-counter use, which necessitated liver transplantation.

A previously healthy 38-year-old woman with a history of migraine (managed with sumatriptan) and varicose veins developed progressive symptoms of acute hepatitis, including severe epigastric pain, jaundice, and persistent vomiting. These symptoms began three days after she self-administered a third dose of inhaled methoxyflurane, obtained over the counter for post-procedural pain. The initial dose had been administered under supervision during a varicose vein sclerotherapy session, while the subsequent two doses were taken one week apart without medical oversight.

On evaluation, laboratory investigations revealed marked hepatic dysfunction, including hyperbilirubinemia, elevated gamma glutamyl transpeptidase (GGT), and evidence of impaired synthetic function. Coagulopathy was evident, with a significantly prolonged INR. Additional findings included hypoalbuminemia and elevated inflammatory markers. Comprehensive workup excluded viral, autoimmune, and metabolic causes of liver injury. Despite supportive therapy with intravenous fluids and N-acetylcysteine, her liver function continued to decline, and she was referred for liver transplantation. She subsequently underwent orthotopic liver transplantation. Histopathological examination of the explanted liver demonstrated extensive centrilobular necrosis, consistent with drug-induced liver injury likely attributable to methoxyflurane. This case emphasizes that even subanesthetic analgesic doses—especially with repeated or unsupervised use—may trigger immune-mediated hepatic injury analogous to halothane hepatitis. Prompt recognition, exclusion of alternative causes, and early referral for transplantation are essential for optimal outcomes.

Abbreviations: ANA: antinuclear antibody, ASMA: anti-smooth muscle antibody, AMA: anti-mitochondrial antibody, GGT: gamma glutamyl transpeptidase, LKM: liver-kidney microsomal antibody.

Keywords: acute hepatitis; hepatic dysfunction; Methoxyflurane; Toxicity; Transplantation

Citation: Qutob RA. Methoxyflurane-induced hepatotoxicity following repeated analgesic use: a case report. Anaesth. pain intensive care 2025;29(8):1037-1043. DOI: 10.35975/apic.v29i8.2971

Received: June 17, 2025; Revised: July 22, 2025; Accepted: August 02, 2025