Diazepam is a benzodiazepine that is available for both oral and intravenous administration; oral diazepam is used predominantly as an anxiolytic agent, while the intravenous form is used as an anticonvulsant. Use of intravenous diazepam has not been linked to serum enzyme elevations during therapy or to clinically apparent liver injury. In contrast, use of the oral form of diazepam has been linked to rare instances of cholestatic liver injury.
Diazepam (dye az' e pam) is a benzodiazepine with particularly potent activity against spread of seizure activity in several animal models. The antiseizure activity of the benzodiazepines is mediated by their ability to enhance gamma-aminobutryic acid (GABA) mediated inhibition of synaptic transmission through binding to the GABA A receptor. The use of diazepam as an anticonvulsant is limited largely to intravenous therapy of status epilepticus. Oral diazepam is not as effective or well tolerated as a therapy for epilepsy as are other benzodiazepines such as clobazam, clonazepam and clorazepate. Diazepam was approved in the United States in 1963 and it is currently widely used to treat acute seizures and status epilepticus. Indications also include premedication before surgical operations and as conscious sedation for minor invasive procedures. Several generic forms of parenteral diazepam are available in ampules of 5 mg/mL. The typical recommended dose for status epilepticus is 5 to 10 mg given intravenously, which can be repeated at 10 to 15 minute intervals until control of seizure activity or to a maximum of 30 mg. Intramuscular administration can be used for premedication before general anesthesia. Common effects of the use of parenteral diazepam include somnolence, confusion, dysarthria, diplopia and coma. Acute overdose of diazepam can cause respiratory arrest and death.
Diazepam, as with other benzodiazepines, is rarely associated with serum ALT elevations, and clinically apparent liver injury from diazepam is extremely rare. In particular, parenterally administered diazepam has not been reported to cause serum enzyme elevations, even with prolonged use as with therapy of tetanus. Furthermore, there have been no convincing case reports of acute liver injury attributable to intravenous diazepam, although there are several case reports of acute liver injury from oral formulations. The onset of injury after oral use ranged from 4 to 12 weeks, and the typical pattern of serum enzyme elevations was cholestatic or mixed. Fever and rash have not been described nor has autoantibody formation. There have been no case reports of diazepam hepatotoxicity since the 1980's.
Likelihood score: E (Unlikely cause of clinically apparent liver injury).
Mechanism of Injury
The liver injury from benzodiazepines is probably due to a rarely produced intermediate metabolite.
Outcome and Management
Patients with hepatic injury due to oral diazepam in the literature recovered completely without evidence of residual or chronic injury. No cases of acute liver failure or chronic liver injury due to diazepam have been described. There is no information about cross reactivity with other benzodiazepines (clobazam, clorazepate, lorazepam or alprazolam), but some degree of cross sensitivity should be assumed.
Case 1. Cholestatic hepatitis due to oral diazepam.
[Modified from: Fors B, Nilsson F. [Hepatitis probably induced by diazepam medication] Lakartidningen 1968; 65: 4528-31. Swedish. PubMed Citation]
A 33 year old woman was started on diazepam (2 mg three times daily) for anxiety and four months later developed symptoms of abdominal pain and jaundice. Serum ALT was 306 U/L, alkaline phosphatase was twice elevated and bilirubin was 4.2 mg/dL. A cholecystectomy was done for suspected cholelithiasis, but the gallbladder and biliary tree were normal. A liver biopsy showed acute hepatocellular injury and cholestasis compatible with drug induced liver disease. Diazepam was stopped and she recovered rapidly and had normal liver tests one month later. Tests for hepatitis A, B and C were not available.
|Medication:||Diazepam (2 mg orally three times daily)|
|Pattern:|| Mixed (R=~4)|
||3+ (jaundice and hospitalization)
|Recovery:||Complete recovery within a month after stopping|
|Other medications:||Birth control pills|
The patient developed an acute hepatitis-like illness four months after starting diazepam. A liver biopsy showed changes typical of drug induced liver disease and the pattern of enzyme elevations and biopsy did not suggest viral hepatitis, serological testing for which was not available at the time. Causality assessment can only rank this example as a “probable” case of diazepam induced liver injury. In view of the wide scale use of diazepam, instances of hepatic injury are very rare, and no cases of severe, prolonged, persistent or fatal liver injury from diazepam have been published.
REPRESENTATIVE TRADE NAMES
Diazepam – Valium®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 25 January 2017
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Fors B, Nilsson F. [Hepatitis probably induced by diazepam medication] Lakartidningen 1968; 65: 4528-31. Swedish. PubMed Citation (24 and 34 year old women developed mild hepatitis with jaundice 1 and 4 months after starting diazepam [bilirubin 11 and 4.2 mg/dL, ALT 434 U/L Alk ~2 times ULN], rapid resolution with stopping).
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Suzuki A, Aso K, Ariyoshi C, Ishimaru M. Acute intermittent porphyria and epilepsy: safety of clonazepam. Epilepsia 1992; 33: 108-11. PubMed Citation (13 year old girl with acute intermittent porphyria worsened on valproate and on phenytoin therapy, but clonazepam led to control of seizures and no worsening of porphyria).
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