Alcohol and Flagyl = disulfiram rxn? Where’re the data, dood?!

I think probably the first “real” counseling point any pharmacy student learns is “Don’t drink alcohol with Flagyl!” If it’s not the first thing, it’s easily the second or third. In fact, I’ve seen this hand-written on prescription labels for added emphasis, even though the auxiliary labels that print out already say it. You don’t often see “Take with food” hand-written, even though it would probably provide more real-world benefit to the patient than the standard “Don’t drink alcohol” mantra.

“Heresy!” you shout. Well, hear me out…

You see, there’s almost no data to support the assertion that alcohol and metronidazole combine to create a disulfiram-like reaction. It’s crazy, I know. How could this age-old advice be wrong? The reason this is drilled into pharmacy and med students’ heads is because the conventional wisdom is old. It got here because “everyone knows” that ethanol + metronidazole = A Bad Time. Even though there’s no meaningful evidence to support this conclusion.

Regular readers know my distaste (hah!) for metronidazole. In fact, I missed out on my best friend’s 21st birthday drunkfestcelebration because of it. As it turns out, I missed out for naught. Alas.

Exhibit A is a meta-analysis of published anecdotes, “Do Ethanol and Metronidazole Interact to Produce a Disulfiram-Like Reaction” published in The Annals of Pharmacotherapy. Exhibit B is a double-blind, placebo-controlled study out of Finland, also published in TAOP entitled “Lack of Disulfiram-Like Reaction with Metronidazole and Ethanol” which is a bit more science-y and a little less meta-analysis-y.

This is a long entry, so here’s a ToC.

  1. Bits and bobs from Exhibit A
  2. Bits and bobs from Exhibit B
  3. Final thoughts

Bits and bobs from Exhibit A (Back to top)

The first account of a metronidazole-ethanol interaction was noted in 1964. At that time, folks wondered if Flagyl could be used to curb alcohol abuse. A sort of proto-Antabuse, if you will. 8 of 17 studies found it to be marginally effective. But only marginally, and only 2 of the 8 positive studies were double-blind, and these 2 studies were statistically significant only when dropouts had been excluded.

My commentary after each quote.

revealed six case reports involving a total of eight patients. Tunguy-Desmerais reported on a two-year-old child taking acetaminophen and amoxicillin for pharyngitis. After a febrile seizure, ulcerative gingivostomatitis was diagnosed, phenobarbital–vitamin B6 syrup was added, and oral metronidazole was started. The next evening, the child was flushed but not febrile and, because both the analgesic and phenobarbital–vitamin B6 syrup contained ethanol, a metronidazole–ethanol reaction was considered likely.

I’m not an expert in pediatric liver function, but I do know that it takes longer for children to metabolize EtOH than it does for an adult. And the flushing is certainly a side effect of plain old alcohol consumption. Going right for the metronidazole-ethanol “reaction” seems a little too convenient, and more than a little irresponsible.

 

Another report involved three patients: a woman prescribed rectal metronidazole following hysterectomy, who became nauseous, pale, and dyspneic 36 and 60 hours postoperatively and was discovered to have taken a large amount of whiskey just prior to each episode; an 18-year old patient being treated with amoxicillin and metronidazole for pelvic inflammatory disease who experienced nausea, flushing, and headaches each evening after drinking ethanol; and a man who, after a 1g dose of metronidazole and a shared bottle of wine at his evening meal, vomited violently.

  1. Taking whiskey in a post-operative state is probably not advisable regardless of the circumstance. Hysterectomy, while relatively common, isn’t a walk in the park.
  2. Metronidazole can nausea and even vomiting all by itself. It doesn’t need any help from alcohol.
  3. See #2. 1g is a lot of metronidazole all at once, especially if you’re unused its GI effects. Would the man have vomited even if he’d not had a bottle of wine? We can’t be sure, but you can bet that it wouldn’t have been mentioned in the literature if it hadn’t. It would have been chalked up to a bad reaction to the medication.

 

Plosker reported a reaction following intravaginal use of metronidazole. This case involved a female pharmacist who, after two or three cocktails (each contained ~1 oz of (vodka), inserted a single vaginal suppository of metronidazole 500 mg and went to sleep. She awakened an hour later with a burning sensation in her stomach, nausea, and a severe headache accompanied by a cold sweat, which she believed was a metronidazole–ethanol reaction.

I could go for the easy ad hominem attack here, but it doesn’t serve any real purpose — and in any case, I am on my way towards showing that EtOH and metronidazole is not necessarily the End of the World. That said, the burning sensation and nausea could have been from the medication itself. Flagyl can cause this type of reaction, even when it’s not administered orally.

 

A potentially serious reaction involved a 16-year-old male who, nine days after resection of an hepatic echinococcal cyst, developed a staphylococcal infection. He was treated initially with intravenous vancomycin, followed by a combination of intravenous nafcillin, clindamycin, and gentamicin. This regimen was then changed to intravenous trimethoprim/sulfamethoxazole (TMP/SMX) and intravenous metronidazole, in addition to his chronic therapy with albendazole, docusate sodium, and ferrous sulfate. After 12 hours and for the following 60 hours until the TMP/SMX was switched to oral therapy, he vomited and experienced flushing, which was attributed to a metronidazole interaction with the alcohol in intravenous TMP/SMX.

Attributing these side effects to the EtOH in the TMP/SMX is easy. It’s also irresponsible, because a mechanism of action had been proposed by this point in time, but not substantiated. (Exhibit B will cover this more.) This reaction is not completely out of the question — metronidazole can indeed increase the levels of intracolonic alcohol dehydrogenase — but it’s still irresponsible to put down, for certain, that this was the cause of the boy’s distress. I wonder if the heavy antibiotics he was on could have contributed to this. It seems possible that by mowing down his normal intestinal flora, he’s in a position to experience these effects anyway.

 

Another potentially serious reaction reported by Harries et al. also involved intravenous metronidazole, this time combined with cefotaxime and papaveretum in a patient who had been drinking heavily and stabbed in the chest and abdomen. A chest drain was inserted and 500 mL of blood was drained; peritoneal lavage produced clear fluid only and the patient was admitted for observation. Four hours after an initial improvement, he became short of breath and nauseous; he vomited, had a headache, and was profoundly acidotic. This metabolic disturbance was attributed to a metronidazole–ethanol interaction.

Drunken guy stabbed in the chest and abdomen. Chest drain removes half a liter of fluid, and four hours later the patient complains of nausea, vomits, has a headache, and is acidotic. And then it’s attributed to a metronidazole-ethanol interaction.

I could think of a few things that’re more likely to have caused this. Can you? He’s been stabbed and he’s probably developing a hangover spring readily to mind.

 

This last one is a real doozy:

Toxicity due to an ethanol–metronidazole interaction appeared on the death certificate of a 31-year-old woman. Cina et al. described the case of an alcohol abuser who had been in frail health for four years following a serious car accident involving severe chest, abdominal, and closed head injuries. After being assaulted by a man, the patient had collapsed and died. Medications found at the scene included propoxyphene, acetaminophen, naproxen, metaxalone, carisoprodol, amitriptyline, hydroxyzine, vitamins, and cough syrup. No metronidazole or empty metronidazole container was found and she had not recently been prescribed metronidazole by her doctor. Because high concentrations of ethanol and acetaldehyde were found, assays were performed for disulfiram and metronidazole. There was no discussion of the methodology that reportedly found metronidazole in her serum, despite the fact that this was not one of the drugs found at the scene. In addition, there was no discussion about whether any of the other drugs in her possession, for which she was apparently not tested, may have cross-reacted in the metronidazole assay. It was concluded that she had probably ingested metronidazole without the knowledge of her physician and had discarded the bottle before she died.

I think the idiocy here speaks for itself. “It was concluded that she had probably ingested metronidazole without the knowledge of her physician and had discarded the bottle” my ass. Flagyl ain’t a drug people are likely to abuse.

Indeed the common thread throughout these cases has been the assumption that metronidazole and ethanol are the culprits without any real testing to verify whether or not this is the case. This study was published in 2000, and while there was a proposed mechanism of action for this EtOH-metronidazole reaction, there was no real evidence yet to support the proposed mechanism. There are also possible — and I would be so bold as to suggest more probable — causes for each of these adverse events, and I have done my best to explain them.

Now on to Exhibit B which talks about the science of the proposed alcohol-metronidazole interaction.

Bits and Bobs from Exhibit B (Back to top)

Disulfiram works its magic by inhibiting the hepatic low aldehyde dehydrogenase (ALDH) which increases blood acetaldehyde concentrations after alcohol is consumed. This is exactly like “Asian flush” — a common, genetic condition wherein those affected are unable to effectively metabolize alcohol completely leading to flushing, nausea, and a quickened pulse.

It was theorized that metronidazole may have a similar effect on ALDH. However, studies have shown that this is not true in rats. So, what about people?

Well, it doesn’t do it in humans, either. In fact, it had the opposite effect. Metronidazole caused a reduction in acetaldehyde production, opposite to the effect of disulfiram(!). Indeed, in Exhibit B, the graphs show (probably clinically insignificant) that the participants in the double-blind, placebo-controlled, alcohol-metronidazole study that the blood alcohol levels for the participants taking metronidazole were slightly lower than their placebo-controlled counterparts between the 40 and 80 minute marks:

Blood ethanol concentrations during metronidazole therapy

None of the participants noted any dyspnea, flushing, vertigo, or headache during the test. Interestingly, the heart rates for the metronidazole group tended to be about 10bpm lower than the control group throughout the test. I don’t know that this is clinically significant, but it is interesting:

Blood ethanol concentrations during metronidazole therapy

Final thoughts (Back to top)

So we’ve got some age-old advice that doesn’t stand up when tested properly, and we have a proposed mechanism of action that doesn’t hold up to closer scrutiny, either. Where does that leave us?

It leaves us with a couple things… Some people experience GI distress while on Flagyl. Sometimes they vomit. Sometimes they drink alcohol and vomit. Sometimes they drink alcohol and don’t vomit. That tells us that:

  1. Flagyl is hard on the stomach. It’s a difficult medication to tolerate for a good percentage of folks, regardless of its effect on blood acetaldehyde levels.
  2. Flagyl is not a disulfiram-like drug, and should not be referred to as such.
  3. Flagyl will not absolutely cause the vomiting associated with Antabuse when consumed in conjunction with alcohol. Pharmacists should stop counseling that it will.
  4. Adverse events are too often attributed to metronidazole because it is convenient, and “everyone knows” that alcohol and Flagyl are a recipe for disaster.
  5. Flagyl remains an unpleasant drug to take; its side effects are real and often severe, and should not be downplayed.
  6. Patients should be educated about these side effects, and how to minimize them. Avoiding alcohol is one way to do this. Taking it with food is probably more effective. Doing both is obviously better than doing just one of the two.

It is my suspicion that early researchers thought there was a link between metronidazole and alcoholism due to the medication’s side effects. Taste perversion. Smell perversion. These things will cause folks to avoid certain foods for the duration of the drug therapy. Alcohol is one of those things. It’s coincidental, and its usefulness in the real world is questionable.

323 thoughts on “Alcohol and Flagyl = disulfiram rxn? Where’re the data, dood?!

  1. I was prescribed Metronidazole 500 mg three times a day for 10 days by my Dentist for gum disease. Imagine my distraught when he told me I couldn’t have any alcohol given the fact I am in the middle of my vacation. We are also in the middle of a two week heat wave with temperatures nearing 40C. I am in the second day of my medicine.

    Luckily I found this site, tried out a beer last night with no ill effects and followed it with 5 more. There was absolutely no ill effect of any kind I could note.

  2. Thanks, RJS. Looks like you’re no longer tracking these posts, but after being on flagyl for 5 days and rehashing the same monologue everyone else heard from the pharmacist, I also decided to look deeper online beyond the Yahoo Answers and WebMD. So last night I had 4 drinks over 2 hours and was perfectly fine. No nausea…..no heightened sense of inebriation (beyond what 4 drinks normally does)…..no cruddy feeling the next morning…..etc.

    In defense of my doctor, he did say the hype over the interaction was overkill and that if I wanted a glass of wine, just take it easy and see how I feel afterwards. But with the Pharmacists fear spell, I didn’t even consider having a drink for the first 5 days.

    As many have indicated, it all depends on your own biochemistry and internal makeup. So if you want a drink, take it easy and see how you react. There is probably a good chance you’ll be just fine.

    Finally an online blog that actually helped :)

  3. THANKS AFTER 3 DAYS ON IT i AM DIEING FOR A GLASS OF WINE AFTER A HECKIC DAY AT THE BANKI KNOW MANY YEARS AGO I TOOK THIS MEDICINE AND i KNOW I DRANK WITH IT BUT DONT RECALL ANY WARNINGS. BUTI WAS SO FREAKED OUT ABOUT HAVING A DRINK. I DONT PLAN TO OVER DUE IT TONIGHT BUT SO FAR I FEEL FINE. THANKS DENISE

  4. I'm 73 w/m taking 500 metro tid. After reading promising posts, I had 1oz white wine with dinner yesterday eve. 2 hours later, I experienced tachycardia (120+bpm)and aryth. I have history of intermittent palps and take 4mg inderal bid even though cardiologist doesn't consider palps a concrern. When the tach started, I popped one 4mg inderal and one .5 mg loarzepam immediately. Settled to normal rythm in about 45min; plse in 80s; one hour later 60s. Can't say for sure that wine and metro did it but damned if I want to go through that again. Today I have lingering soreness left center abdomen??

  5. Ya'll are funny, I was prescribed 7 days and I wanted to drink on Friday(5th day) and Saturday night (96th) but didn't. However on the 7th day I just quit taking the medicine and had drinks. I never got sick! They say you can get sick the day after but I didn't. I probably could have take the last day of meds and been fine. Hope it worked in 6 days…

  6. Type your comment here. Last night was day 9 of 10 day metro 500mg 4X per day. Read this blog yesterday afternoon and decided the alcohol affect was way overblown. Had a glass of wine slowly over half an hour with no ill effects. Had another glass and after an hour no ill effects. Had a couple shots of Gentleman Jack (for science) just to prove the theory false. No ill effects and woke up feeling fine this morning.

  7. Can't image these comments are still being tracked, but since I found this post after my doctor prescribed flagyl and the pharmacist offered an extreme alcohol interaction warning, I thought I'd add another personal experience data point…

    I've been taking flagyl for the last 8 days (almost done… yay!), and yesterday I finally went for it and had a couple of glasses of wine. I felt fine drinking and shortly after, but yesterday evening, I was miserable. I gradually became more and more nauseous, developed a sick headache, and had severe stomach cramping.

    Today (because “once bitten” apparently doesn't apply to me), I drank 2/3 of a bottle of wine in the afternoon. This evening, the same nausea and cramping is creeping back up on me (no headache so far).

    Definitely not the worst thing I've ever felt, but I think I'll hold off on any more wine until I'm a couple of days clear of the flagyl.

  8. I have been taking metronidazole 400 mg 3x a day for 1 week, and i had half a bottle of wine last night. No problems..

  9. I am taking 500 MG Flagyl three times per day. Pharmacist told me not even to use listerine/scope, or alcohol-based products on my face. After finding this forum, I tried the listerine, no problem. I then drank a glass and a half of wine, then a beer, and a few hours later another Flagyl prior to going to bed. No side effects or sickness whatsoever. Thanks for this article and forum.

  10. This blog is great like everyone else on this med just wanted wine soooooo bad. Could not find any other info really talking about this till I came across this site. So I’m on 500mg 2x’s a day. I got all excited after reading the blogs called the hubby and said stop by wine store on way home!!!! Well let me say after 2 glasses this awful feeling came over me and I just made it to the toliet where I puked for a hour….yay good times!!! So lesson learned do not drink on this crap…suck it up and just finish the meds!!!

  11. DOH! Exciteable Post button!

    I was just prescribed Flagyl (500mg 3x a day) and I’m about to take a week’s vacation on a beach. I was feeling really depressed that I had to avoid alcohol for the entire week. I’ll try having a drink near the end of the week to see; I’m still pretty bummed that I can’t party, but hopefully one drink won’t kill me. Thanks again!

  12. I am on a course of flagyl right now (day four) 400mg three times a day. I have been drinking my usual amount of wine daily (too much – max 18 glasses per day). No side-effects of any kind. I actually looked this up because it seemed so bizarre that I was given so many warnings but felt no side-effects.

  13. So. I completed my last dose last night around 6pm. After 7 days twice daily on metro, ive never been a big drinker but i am dying for a margarita today on the 4th of july. Should i risk it?

  14. having four vodka rasberries plus two bottles of wine 28 hours after flagyl and i feel ok no issues but i did ask god to protect me😀amen

  15. This article and thread is awesome! I suffer chronically with diverticulitis. I have been having flare ups quite often and always seem to be on Flagyl and Cipro. I’m trying to figure out my triggers and change my diet which has been such a challenge. Having to be on antibiotics so often has made it difficult to enjoy 2 island vacations this year. I too begin experimentin with my tolerance when taking Flagyl and consuming. I’ve been doing pretty well with moderate consumption. When I found this site I rejoiced in knowing others are struggling with the same dilemma. Loved your article. Hilarious!

  16. Thank you RJS for some scientific info on this topic instead of just the over-the-top medical warnings. I’m currently a biology major and found some of the supposed methods of interaction a little hokey, not to mention some of the bad experience reviews to be lacking in common sense.

    I’m currently on flagyl (500mg 2x daily- day 4 of 5) and curious to test this mystery on myself. I’ve had no side effects thus far, not even a single flagyl burp. So tonight, to celebrate the kick off of my last semester, I’m going to skip my evening dose and go have a few beers, maybe even a shot of fireball (known to contain propylene glycol) if I feel brave. I’ll report back if I survive this doom and gloom pseudoscience and tell you how it went. Cheers!

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