Metronidazole - shouldn't we be concerned that the question of carcinogenic potential hasn't been settled?

[Alfred001]

Perhaps my search of the literature has been inadequate, but as best as I can tell, the situation with metronidazole is that it was conclusively demonstrated to be carcinogenic in animals, genotoxic in humans in vitro and in vivo and "reasonably anticipated to be a human carcinogen" and in spite of this, the drug continues to be in wide use with seemingly no urgency to run a study to settle the question of its carcinogenic potential in humans. Am I missing something or is this insane?

You can maybe say there's no evidence of carcinogenicity in humans, but absence of evidence is not evidence that it's not carcinogenic, not if adequately powered, well designed studies haven't been done. And in fact, as shown in one of the passages I quote later, a "limited-correlation" has been found.

How is it safe for humans to be taking this drug that has so strongly been suggested to be potentially carcinogenic and has not been proven not to be? Shouldn't we stop giving this to people?

Again, perhaps I'm missing some significant literature?

Here's what I looked at:

Association of Metronidazole with Cancer: A Potential Risk Factor or Inconsistent Deductions? (2018 review article)

Quote

Conclusion: Due to potent carcinogenic behaviour, use of MTZ for animals' treatment and its uses in animal food products is prohibited in USA and European countries; however its clinical use in human population is still increasing. Therefore, regular research studies are required to explicate its mechanism/s involved in carcinogenesis.

 

A review on metronidazole: an old warhorse in antimicrobial chemotherapy (2019)

Quote

 

A teratogenic effect of metronidazole could not be established (Koss et al.

2012), but it was found to be carcinogenic in rodents after extended

durations of highly dosed treatment. In man, results were less clear

and often conflicting (Dobiás et al. 1994). With regard to short-

term treatment with metronidazole, originally no correlation

between metronidazole intake and cancer was found (Falagas

et al. 1998), but more recent studies report on a limited correl-

ation (Friedman et al. 2009). As a consequence, metronidazole

is officially classified as ‘reasonably anticipated to be a human

carcinogen’.

 

 

[John Cuthber]

Alcohol, sunlight, silica and the fumes from diesel engines are known human carcinogens.
Do you suggest that we ban them?

Or do you think we should consider the benefits as well?

[exchemist]

2 hours ago, Alfred001 said:

Perhaps my search of the literature has been inadequate, but as best as I can tell, the situation with metronidazole is that it was conclusively demonstrated to be carcinogenic in animals, genotoxic in humans in vitro and in vivo and "reasonably anticipated to be a human carcinogen" and in spite of this, the drug continues to be in wide use with seemingly no urgency to run a study to settle the question of its carcinogenic potential in humans. Am I missing something or is this insane?

You can maybe say there's no evidence of carcinogenicity in humans, but absence of evidence is not evidence that it's not carcinogenic, not if adequately powered, well designed studies haven't been done. And in fact, as shown in one of the passages I quote later, a "limited-correlation" has been found.

How is it safe for humans to be taking this drug that has so strongly been suggested to be potentially carcinogenic and has not been proven not to be? Shouldn't we stop giving this to people?

Again, perhaps I'm missing some significant literature?

Here's what I looked at:

Association of Metronidazole with Cancer: A Potential Risk Factor or Inconsistent Deductions? (2018 review article)

 

A review on metronidazole: an old warhorse in antimicrobial chemotherapy (2019)

 

No, it's not insane and yes, you are missing something. Nobody takes metronidazole for more than about 2 weeks in a course of treatment. It tends to be used to treat serious protozoan or bacterial infections that would otherwise be very debilitating or ultimately lethal, and then stopped. Nobody takes this stuff prophylactically. I've used it twice, in both cases to treat giardiasis I picked up on travels in the Far East. One was a 3 day course and the other 7 days.

There is no drug on Earth that has no risks attached to it. The evidence for metronidazole being carcinogenic in practice is very weak, whereas its benefits are great. Taking it out of the medical arsenal would certainly result in more deaths, and would thus be counterproductive.   

[Alfred001]

18 hours ago, exchemist said:

No, it's not insane and yes, you are missing something. Nobody takes metronidazole for more than about 2 weeks in a course of treatment. It tends to be used to treat serious protozoan or bacterial infections that would otherwise be very debilitating or ultimately lethal, and then stopped. Nobody takes this stuff prophylactically. I've used it twice, in both cases to treat giardiasis I picked up on travels in the Far East. One was a 3 day course and the other 7 days.

There is no drug on Earth that has no risks attached to it. The evidence for metronidazole being carcinogenic in practice is very weak, whereas its benefits are great. Taking it out of the medical arsenal would certainly result in more deaths, and would thus be counterproductive.   

I've cited evidence of a possible correlation, you've just flatly stated there is no increased risk when the course of treatment is short, providing no evidence, even though I've already referenced a study that found "limited correlation" with a short course specifically and never mentioned a long course of metro.

Additionally, there's a cohort study (Beard et al. 1988) which found the incidence of lung cancer (bronchogenic carcinoma) was significantly increased in women exposed to metronidazole, and the excess remained after an attempt to adjust for smoking.

So what's your evidence for your claim?

[StringJunky]

Virtually no treatment is harmless. 

[exchemist]

1 hour ago, Alfred001 said:

I've cited evidence of a possible correlation, you've just flatly stated there is no increased risk when the course of treatment is short, providing no evidence, even though I've already referenced a study that found "limited correlation" with a short course specifically and never mentioned a long course of metro.

Additionally, there's a cohort study (Beard et al. 1988) which found the incidence of lung cancer (bronchogenic carcinoma) was significantly increased in women exposed to metronidazole, and the excess remained after an attempt to adjust for smoking.

So what's your evidence for your claim?

What claim would that be?

[Alfred001]

3 minutes ago, exchemist said:

What claim would that be?

That the risk indicated by the studies I cited does not apply to short courses of treatment.

25 minutes ago, StringJunky said:

Virtually no treatment is harmless. 

Yes, but most drugs we use are not suspected to be carcinogens.

[exchemist]

2 hours ago, Alfred001 said:

That the risk indicated by the studies I cited does not apply to short courses of treatment.

Yes, but most drugs we use are not suspected to be carcinogens.

That’s not what I claimed. If it had been, it would have made no sense for me to go on and discuss the balance of risk.

[Alfred001]

3 minutes ago, exchemist said:

That’s not what I claimed. If it had been, it would have made no sense for me to go on and discuss the balance of risk.

So how much does a 14 day course of metronidazole, commonly used for H pylori therapy, increase a person's cancer risk? Presumably you know, since you claim the risk-reward balance breaks in favor of using metronidazole rather than alternative antibiotics that don't have a suspected cancer risk associated.

[StringJunky]

10 minutes ago, Alfred001 said:

So how much does a 14 day course of metronidazole, commonly used for H pylori therapy, increase a person's cancer risk? Presumably you know, since you claim the risk-reward balance breaks in favor of using metronidazole rather than alternative antibiotics that don't have a suspected cancer risk associated.

I'll take the risk if its H.Pylori. would you rather have a statistical risk of cancer or have a tangible risk of ulcers, and potentially stomach cancer, oesophageal cancer, throat cancer, bad teeth, smelly breath, using antacids by the ton... and generally feeling unwell? This is what weighing up risk vs benefit looks like. The mechanism is there and understood.

Edited July 9, 2023 by StringJunky

[Alfred001]

5 minutes ago, StringJunky said:

I'll take the risk if its H.Pylori. would you rather have a statistical risk of cancer or have a tangible risk of ulcers, and potentially stomach cancer, oesophageal cancer, throat cancer, bad teeth, smelly breath, using antacids by the ton... and generally feeling unwell? This is what weighing up risk vs benefit looks like. The mechanism is there and understood.

#1 How can you say that when you don't know what the risk of cancer is from a 14 day course of metronidazole? Is it lower or higher than that of H pylori? H pylori raises risk of gastric cancer (it is actually inversely correlated with esophageal cancer and is not implicated in any of the other things you mentioned), which cancers does metro raise the risk of? Is it only one or multiple?

The point is that we don't know, because AFAIK (and I'll be happy to be corrected on this, as I said in the OP, I've not exhaustively reviewed the literature), there has not been a large study with long followup to test for this, which is my whole point. We have evidence of a correlation with cancer, but we don't have a study to establish or refute a causal connection, yet the drug is prescribed en masse.

#2 Why take the risk when you could use other antibiotics that don't have a suspected link with cancer?

[StringJunky]

12 minutes ago, Alfred001 said:

#1 How can you say that when you don't know what the risk of cancer is from a 14 day course of metronidazole? Is it lower or higher than that of H pylori? H pylori raises risk of gastric cancer (it is actually inversely correlated with esophageal cancer and is not implicated in any of the other things you mentioned), which cancers does metro raise the risk of? Is it only one or multiple?

The point is that we don't know, because AFAIK (and I'll be happy to be corrected on this, as I said in the OP, I've not exhaustively reviewed the literature), there has not been a large study with long followup to test for this, which is my whole point. We have evidence of a correlation with cancer, but we don't have a study to establish or refute a causal connection, yet the drug is prescribed en masse.

#2 Why take the risk when you could use other antibiotics that don't have a suspected link with cancer?

That's only correct if the acid reflux is periodic. Chronic acid reflux is not periodic.

Quote

Acid reflux, especially when it’s only a periodic condition, does not increase the risk of esophageal or stomach cancer. However, when acid reflux becomes chronic, it results in the esophagus being regularly exposed to stomach acid which can increase the risk of esophageal cancer. Chronic acid reflux is called Gastroesophageal Reflux Disease, commonly referred to as GERD.

https://www.compassoncology.com/blog/does-acid-reflux-cause-gi-cancer#:~:text=Acid reflux%2C especially when it's,the risk of esophageal cancer.

Quote

Abstract
Barrett’s oesophagus is an acquired precancerous condition that develops from mucosal injury incurred due to chronic gastro‐oesophageal reflux. The aim of this study was to determine if bile and/or acid components of the refluxate can induce DNA damage in vitro. The oesophageal cell lines FLO‐1 and HET1‐A were exposed to primary bile salts, individually or as a mixture, and the secondary bile salt sodium deoxycholate, in neutral or acidified media. Cells were then examined in the comet assay to measure DNA strand breaks. Cell viability was also monitored. Acidified media induced DNA damage in a pH‐ and time‐dependent manner. The primary bile compounds sodium glycocholate, glycocholic acid, sodium taurocholate and taurochenodeoxycholate, as an equimolar mixture (100 µM), caused a small but significant (P < 0.028) elevation in DNA damage, but only at neutral pH in FLO‐1 cells. Sodium deoxycholate (100 µM) caused a significant (P < 0.008) elevation in DNA damage in both cell lines, but again only at neutral pH. These data suggest that specific components of gastro‐oesophageal refluxate are capable of causing DNA damage and may participate in the genesis and progression of Barrett’s oesophagus via this mechanism.

https://academic.oup.com/mutage/article/19/4/319/1221558

 

Edited July 9, 2023 by StringJunky

[mistermack]

19 minutes ago, StringJunky said:

I'll take the risk if its H.Pylori. would you rather have a statistical risk of cancer or have a tangible risk of ulcers, and potentially stomach cancer, oesophageal cancer, throat cancer, bad teeth, smelly breath, using antacids by the ton... and generally feeling unwell? This is what weighing up risk vs benefit looks like. The mechanism is there and understood.

Do you know if there's a test for H.Pylori, that doesn't involve the camera etc down the throat? I've had acid reflux problems and severe heartburn for years. Some years ago, I had the camera down the throat, and it was the worst experience of my life. (I have an extreme gagging reflex when anything goes near the back of my throat, even a hair).

I assumed that they would take a sample for testing for H.Pylori as a matter of course, but the doctor working the camera said to the nurse that he couldn't see anything nasty, and the nurse asked him if he was going to take a sample, and he said he couldn't see any point. If I could have spoken, I would have insisted, because it had been bugging me for years whether I had it, but of course, I had the tubes down my throat, and couldn't speak at all. I could have hit him, but I was powerless. And once they had finished, there was no point in telling him what I thought, because nothing in the world would induce me to have that procedure again.  But if there was a non-invasive test, I'd love to take it to know if I had that bug, or not.

I take one Opremazole a day, and it does reduce the need for antacids, but not altogether. 

[Alfred001]

 

21 minutes ago, StringJunky said:

That's only correct if the acid reflux is periodic. Chronic acid reflux is not periodic.

No, periodic acid reflux does not result in an inverse relationship with esophageal cancer and H pylori does not cause GERD. Like I said, studies show either no correlation or an inverse correlation between H pylori and Barrett's. H pylori, as it advances, causes a decrease in acid output, not an incrase, as a consequence of gastric atrophy.

10 minutes ago, mistermack said:

Do you know if there's a test for H.Pylori, that doesn't involve the camera etc down the throat? I've had acid reflux problems and severe heartburn for years. Some years ago, I had the camera down the throat, and it was the worst experience of my life. (I have an extreme gagging reflex when anything goes near the back of my throat, even a hair).

I assumed that they would take a sample for testing for H.Pylori as a matter of course, but the doctor working the camera said to the nurse that he couldn't see anything nasty, and the nurse asked him if he was going to take a sample, and he said he couldn't see any point. If I could have spoken, I would have insisted, because it had been bugging me for years whether I had it, but of course, I had the tubes down my throat, and couldn't speak at all. I could have hit him, but I was powerless. And once they had finished, there was no point in telling him what I thought, because nothing in the world would induce me to have that procedure again.  But if there was a non-invasive test, I'd love to take it to know if I had that bug, or not.

I take one Opremazole a day, and it does reduce the need for antacids, but not altogether. 

Yes, there are stool and breath tests for H pylori that are quite sensitive and specific.

Omeprazole is a first generation PPI, there are newer and more potent drugs such as esomeprazole and rabeprazole and another drug, more potent than those, vonoprazan, which AFAIK has only been approved by the FDA for H pylori therapy, I don't think it's been approved for GERD yet, but I may be wrong on that.

Edited July 9, 2023 by Alfred001

[StringJunky]

If you search 'h pylori stool test kit' there's quite a few. They detect pylori antigens. Superdrug and boots do them.You could also go to a chemist and see if they provide that specific testing service. I would try the latter first as you will have on-hand advice.

Just now, StringJunky said:

If you search 'h pylori stool test kit' there's quite a few. They detect pylori antigens. Superdrug and boots do them.You could also go to a chemist and see if they provide that specific testing service. I would try the latter first as you will have on-hand advice.

Also, if you have significant belly fat, that can contribute significantly, I find. The mass of fat there constantly presses on the stomach and when the top sphincter opens to release air, the sudden added pressure causes it to squirt acid out.

[exchemist]

1 hour ago, Alfred001 said:

So how much does a 14 day course of metronidazole, commonly used for H pylori therapy, increase a person's cancer risk? Presumably you know, since you claim the risk-reward balance breaks in favor of using metronidazole rather than alternative antibiotics that don't have a suspected cancer risk associated.

It increases it by 2/10ths of F-all, to judge by the studies you cite.  

Edited July 9, 2023 by exchemist

[Alfred001]

5 minutes ago, exchemist said:

It increases it by 2/10ths of F-all, to judge by the studies you cite.  

That's precisely my point. Maybe now that I've stated it for the 100th time you'll understand what I'm saying.

[exchemist]

8 minutes ago, Alfred001 said:

That's precisely my point. Maybe now that I've stated it for the 100th time you'll understand what I'm saying.

Good, so there's no burning issue, then and doctors can go on prescribing it for serious infections where there is no good alternative.  I'm glad that's settled. 

Edited July 9, 2023 by exchemist

[John Cuthber]

What's special about cancer?
Plenty of drugs have a variety of ways of killing you.
https://bnf.nice.org.uk/drugs/metronidazole/#side-effects

And you need to balance the risk of side effects with the risks of not taking the medication.

[Sensei]

On 7/8/2023 at 6:13 PM, John Cuthber said:

Alcohol, sunlight, silica and the fumes from diesel engines are known human carcinogens.
Do you suggest that we ban them?

One of your unique posts that I can agree with..

9 hours ago, Alfred001 said:

Yes, but most drugs we use are not suspected to be carcinogens.

Drinking Technetium-99[m] is widely used medial technique..

https://www.google.com/search?q=Technetium-99[m]

[exchemist]

22 hours ago, Sensei said:

One of your unique posts that I can agree with..

Drinking Technetium-99[m] is widely used medial technique..

https://www.google.com/search?q=Technetium-99[m]

My father had a bone scan using this, to check whether his (very slow-moving) prostate cancer was progressing. All rather absurd, as he was 90 at the time and showing no symptoms. I had to take him to the hospital and wait while they dosed him, left it to migrate into the bones and then tested him.  But while I was waiting I was very intrigued to find Tc99m was used. I had not even realised excited states of radioisotopes were a thing - though of course it makes sense.   

[Alfred001]

On 7/9/2023 at 7:22 PM, exchemist said:

Good, so there's no burning issue, then and doctors can go on prescribing it for serious infections where there is no good alternative.  I'm glad that's settled. 

Are you seriously this dense?

On 7/9/2023 at 6:26 PM, Alfred001 said:

#1 How can you say that when you don't know what the risk of cancer is from a 14 day course of metronidazole? Is it lower or higher than that of H pylori? H pylori raises risk of gastric cancer (it is actually inversely correlated with esophageal cancer and is not implicated in any of the other things you mentioned), which cancers does metro raise the risk of? Is it only one or multiple?

The point is that we don't know, because AFAIK (and I'll be happy to be corrected on this, as I said in the OP, I've not exhaustively reviewed the literature), there has not been a large study with long followup to test for this, which is my whole point. We have evidence of a correlation with cancer, but we don't have a study to establish or refute a causal connection, yet the drug is prescribed en masse.

#2 Why take the risk when you could use other antibiotics that don't have a suspected link with cancer?

 

Edited July 11, 2023 by Alfred001

[exchemist]

9 minutes ago, Alfred001 said:

Are you seriously this dense?

 

Most people don't seem to think I'm dense: but I suppose it's all relative. With you I struggle because I don't understand why you seem so anxious about this issue. The links you provided seem to me to show only a very tentative, and possibly non-existent, association with cancer in humans under the conditions of use for this drug in practice, viz. short regimes of treatment lasting only a few days. Plenty of drugs have been associated with cancer. Here's a report of a meta-analysis of some of them: https://pubmed.ncbi.nlm.nih.gov/24310915/

I would agree it might be nice, if the time and resources were available, to conduct some long term follow-up, but it would need to be over decades, and require a very large sample (thousands) of people who like me were once prescribed this drug for a few days. But this would not be easy and it would have to be prioritised relative to other research projects.

What I miss from you, perhaps because I'm so dense, is what makes you think the risk with metronidazole sticks out as a matter of urgent concern, compared to all the other drugs that have also been associated with cancer.  

[CharonY]

Helicobacter infections are associated with a potentially four to  eight fold increase in stomach cancer. For metronizadole there is no clear linkage, hence no numbers. That is where the designation comes from. It is plausible due to the animal studies, but so far no human cohorts have found a difference between users and non-users. If a linkage was found, the designation would shift.

[Alfred001]

On 7/11/2023 at 10:42 PM, exchemist said:

Most people don't seem to think I'm dense: but I suppose it's all relative. With you I struggle because I don't understand why you seem so anxious about this issue. The links you provided seem to me to show only a very tentative, and possibly non-existent, association with cancer in humans under the conditions of use for this drug in practice, viz. short regimes of treatment lasting only a few days. Plenty of drugs have been associated with cancer. Here's a report of a meta-analysis of some of them: https://pubmed.ncbi.nlm.nih.gov/24310915/

I would agree it might be nice, if the time and resources were available, to conduct some long term follow-up, but it would need to be over decades, and require a very large sample (thousands) of people who like me were once prescribed this drug for a few days. But this would not be easy and it would have to be prioritised relative to other research projects.

What I miss from you, perhaps because I'm so dense, is what makes you think the risk with metronidazole sticks out as a matter of urgent concern, compared to all the other drugs that have also been associated with cancer.  

Well, the fact that there may be other drugs that have a suspected link with cancer is not an argument for not investigating metronidazole's suspected link. All of them should be investigated.

So we have a tentative link and strong mechanistic evidence, doesn't that suggest that the link should be further investigated before the drug is prescribed en masse as we are in fact doing?

I actually don't think the study would be that difficult, this drug is widely prescribed, it wouldn't be hard to find subjects to enroll, even a massive number of them, and all you need to do is match them with controls and follow them over, yes, decades, but all that means is check ins every 5-10 years to see who got cancer. But let's set this aside, I want to focus the debate on whether it makes sense to prescribe this drug given the evidence for it causing cancer.

To your last paragraph, I think it's a matter of urgent concern because it has substantial (tho not conclusive) evidence for possibly causing cancer, yet we prescribe the drug widely. Is it the most urgent drug to investigate for such a link? I don't know, I make no claim with regards to that, my claim is simply that prescribing a drug with evidence for causing cancer without disproving a causal connection with an adequate study is insane.

On 7/12/2023 at 3:10 AM, CharonY said:

Helicobacter infections are associated with a potentially four to  eight fold increase in stomach cancer. For metronizadole there is no clear linkage, hence no numbers. That is where the designation comes from. It is plausible due to the animal studies, but so far no human cohorts have found a difference between users and non-users. If a linkage was found, the designation would shift.

But have the studies been done? Is there an adequately powered study with adequate followup that allows us to conclusively say there is no increase in cancer risk or that it is trivially small? Or is it simply that we haven't done the studies so we don't know how much we are potentially increasing people's risk of cancer?