Lack of Disulfiram-Like Reaction with Metronidazole and Ethanol

Design

Single-center, double-blind placebo-controlled study

N= 12

Objective

To investigate the possible disulfiram-like properties of metronidazole and ethanol in human volunteers

Study Groups

Metronidazole (n= 6)

Placebo (n= 6)

Inclusion Criteria

Male volunteers; aged 22-32 years; moderate consumers of ethanol (weekly average consumption of ≤100 g); refrain from consuming ethanol for at least 36 hours before taking the first dose of metronidazole or placebo

Exclusion Criteria

Had received any medication for 4 weeks preceding the study or was using any other drugs during the study

Methods

One-half of the volunteers received metronidazole and the other half received a placebo before the test. The dose of metronidazole was 200 mg 3 times daily. The last dose of medication was taken one hour before the actual test. Before blood samples were drawn, volunteers drank 0.4 g/kg of ethanol as a 10% v/v solution in orange juice within 20 minutes. Blood samples for ethanol and acetaldehyde determinations were drawn by the physicians in our research unit every 20 minutes from 0 to 240 minutes.

Volunteers answered a questionnaire every 20 minutes throughout the test, in which the following parameters were measured in a linear scale of 0 (no symptoms) to 10 (severe symptoms): headache, nausea, dyspnea, and vertigo.

Duration

Treatment period before the test: 5 days

Outcome Measures

Baseline Characteristics

All patients (N= 12)

Age, years

Male

Body weight (Mean ± 2SD), kg

Body mass index, kg/m²

Results

Endpoint

Metronidazole (n= 6)

Placebo (n= 6)

• Changes in blood ethanol in metronidazole-treated and placebo groups were not significant (p= ns).
• Objective signs: the differences in changes in heart rate, blood pressure, and facial temperature (i.e., flushing) were not statistically significant between the 2 groups (p= ns).
• Subjective signs: no one in either group had any adverse symptoms after ethanol ingestion measured in the following parameters: headache, nausea, dyspnea, and vertigo.

Adverse Events

See results

Study Author Conclusions

This study shows that metronidazole does not have an effect on blood acetaldehyde concentrations when ingested with ethanol and does not have any objective or subjective disulfiram-like properties. However, it is possible that disulfiram-like reactions can occur in some subgroups and by other mechanisms than the inhibition of hepatic ALDH.

InpharmD Researcher Critique

Although the results showed no disulfiram reaction was reported, this small study was not powered to draw a conclusion regarding the metronidazole-related disulfiram-like effects associated with ethanol intake.

Disulfiram-like Reaction With Metronidazole: An unsuspected culprit

Design

Case presentation

A 14-year-old Caucasian female received metronidazole oral suspension 110 mg (7.3 mg/kg/dose) every 6 hours administered via feeding tube for treatment of Clostridium difficile-associated diarrhea. On day 2 of concomitant metronidazole and steroid therapy (5-day course of oral Prednisone Intensol), the patient experienced severe discomfort and abdominal distention accompanied by new-onset tachycardia suggesting the possible disulfiram-like reaction between the alcohol-containing steroid solution and metronidazole. After the steroid solution was discontinued, the symptoms resolved and the patient slept well. 

Study Author Conclusions

The patient in this case did not experience some of the traditional symptoms (e.g., flushing, vomiting) of a disulfiram-like reaction; however, this may have been secondary to her developmental delay and inability to verbalize nausea. She did not experience any life-threatening reactions from the simultaneous use of prednisone and metronidazole; however, significant discomfort could have been avoided if an alternate agent was used. The abdominal pain resolved after switching to the non-alcohol-containing prednisolone solution.

If the interaction between metronidazole and alcohol-containing medications occurs, it may
be initially unrecognized, potentially resulting in patient discomfort or harm. It is important for healthcare professionals to identify these potential drug-drug interactions so that alternative medications may be utilized and offending agents can be avoided or replaced. 

Do Ethanol and Metronidazole Interact to Produce a Disulfiram-Like Reaction?

Design

Case reports

N= 6

Case presentation

Patient 1: 

A two-year-old child was diagnosed with ulcerative gingivostomatitis and received phenobarbital–vitamin B6 syrup, and oral metronidazole. The child was flushed with no fever the next evening suggesting a metronidazole-ethanol disulfiram-like reaction due to the alcohol-containing medications (the analgesic and phenobarbital–vitamin B6.

Patient 2:

A woman was admitted for a hysterectomy. At 36 and 60 hours post-operation, following receiving rectal metronidazole, she became nauseous, pale, and dyspneic and was discovered to have taken a large amount of whiskey just prior to each episode.

Patient 3:

An 18-year-old patient was receiving amoxicillin and metronidazole for pelvic inflammatory disease and experienced nausea, flushing, and headaches following each episode of drinking alcohol.

Patient 4:

Another man who was treated 1-g dose of metronidazole had severe nausea/vomiting after having a shared bottle of wine at his evening meal.

Patient 5:

A female consumed 2-3 alcoholic drinks (each contained ~1 oz of vodka) and used a single vaginal suppository of metronidazole 500 mg and went to sleep. An hour later she awakened with a burning sensation in her stomach, nausea, and a severe headache accompanied by a cold sweat suspecting metronidazole–ethanol reaction.

Patient 6:

A 16-year-old male received intravenous trimethoprim/sulfamethoxazole (TMP/SMX) and intra- venous metronidazole, in addition to his chronic therapy with albendazole, docusate sodium, and ferrous sulfate to manage his staphylococcal infection following hepatic echinococcal cyst surgery. He experienced flushing and vomiting suggesting a metronidazole interaction with the alcohol in intravenous TMP/SMX.

Study Author Conclusions

Previously published reviews of the medical literature before 1982 found no convincing evidence to support the existence of a disulfiram-like reaction between metronidazole and ethanol, and this review of case reports since that time has found nothing to contradict their findings. The testimony of patients who admit to concurrent use of these two agents, apparently without consequences, may add weight to this view, but none of the above represents proof that such a reaction could not occur. Since the clinical consequences of drug-related adverse events can be serious, patients should continue to be advised to avoid ethanol during metronidazole therapy until more conclusive evidence is available.