The Z-drugs as carcinogens (zolpidem, zopiclone, indiplon)

[nuke]

Evidence That New Hypnotics Cause Cancer"
Department of Psychiatry, UCSD. University of California

Fifteen epidemiologic studies have associated hypnotic drugs with excess mortality, especially excess cancer deaths. Until recently, insufficient controlled trials were available to demonstrate whether hypnotics actually cause cancer. The U.S. Food and Drug Administration (FDA) Approval History and Documents were accessed for zaleplon, eszopiclone, and ramelteon. Since zolpidem was used as a comparison drug in zaleplon trials, some zolpidem data were also available. Incident cancers occurring during randomized hypnotics administration or placebo administration were tabulated. Combining controlled trials for the 4 drugs, there were 6190 participants given hypnotics and 2535 given placebo in parallel. Restudy of on-line FDA files led to somewhat altered counts of incident cancers, which are currently being checked against an FDA case review. FDA files revealed that all 4 of the new hypnotics were associated with cancers in rodents. Three had been shown to be clastogenic. Combining these new randomizing trials provided equivocally- significant data that new hypnotics cause cancer. Together with the epidemiologic data and laboratory studies, the available evidence signals that new hypnotics may increase cancer risk. Due to limitations in available data, further review of case files for these trials and confirmatory research is needed.

http://repositories.cdlib.org/cgi/viewcontent.cgi?article=1002&context=ucsdpsych (full text, 2008)

Any guesses for the source of this activity (IE, is it more likely to be a result of the drug's structures rather than their specific GABA agonism)?

 

[Hammilton]

seems pretty unlikely it's the GABA agonism. ramelteon is pretty unrelated though structurally and functionally.

 

[nuke]

Yeah, I have a feeling whatever results from that is different from zolpidem et cetera.

 

[nabollocks]

Maybe people who have trouble sleeping have a higher risk of cancer? Maybe mice that sleep too much get cancer more readily?

Make what you want of this, but the evidence shown here seems to be very much aimed at getting a grant to study the drugs further. What better way to get funding than to tell people they will get cancer if the researchers don't get more money?

 

[nuke]

Make what you want of this, but the evidence shown here seems to be very much aimed at getting a grant to study the drugs further.

Well, yeah, that's the entire point of the paper. They want to investigate this further because it demonstrates carcinogenicity in smaller order mammals. I fail to see any ethical misgrounding in wanting funding to research this (quite the opposite).

 

[Pteropod]

I showed this to an acquaintance who is very familiar with the safety data for ramelteon, and he said that the assertion that that drug was carcinogenic was very dubious. When the safety data were compiled, an open-label study was lumped in with the placebo-controlled studies, and I got the impression that that study was conducted in a population with elevated cancer risk (namely elderly people). He couldn't speak to the safety of the other three drugs.

 

[nabollocks]

Here is a bit of background info on the drugs in question...

Drug Metab Dispos. 1999 Sep;27(9):1068-73.

Becquemont L, Mouajjah S, Escaffre O, Beaune P, Funck-Brentano C, Jaillon P.

Zopiclone is a widely prescribed, nonbenzodiazepine hypnotic that is extensively metabolized by the liver in humans. The aim of the present study was to identify the human cytochrome P-450 (CYP) isoforms involved in zopiclone metabolism in vitro. Zopiclone metabolism was studied with different human liver microsomes and a panel of heterologously expressed human CYPs (CYP1A2, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4). In human liver microsomes, zopiclone was metabolized into N-desmethyl-zopiclone (ND-Z) and N-oxide-zopiclone (NO-Z) with the following K(m) and V(m) of 78 +/- 5 and 84 +/- 19 microM, 45 +/- 1 and 54 +/- 5 pmol/min/mg for ND-Z and NO-Z generation, respectively. Ketoconazole (CYP3A inhibitor) inhibited approximately 40% of the generation of both metabolites, sulfaphenazole (CYP2C inhibitor) inhibited the formation of ND-Z, whereas alpha-naphtoflavone (CYP1A), quinidine (CYP2D6), and chlorzoxazone (CYP2E1) did not affect zopiclone metabolism. The generation of ND-Z and NO-Z were highly correlated to testosterone 6beta-hydroxylation (CYP3A activity, r = 0.95 and 0.92, respectively; p =.0001), and ND-Z was highly correlated to CYP2C8 activity (paclitaxel 6alpha-hydroxylase; r = 0.76, p =.004). Recombinant CYP2C8 had the highest enzymatic activity toward zopiclone metabolism into both its metabolites, followed by CYP2C9 and 3A4. CYP3A4 is the major enzyme involved in zopiclone metabolism in vitro, and CYP2C8 contributes significantly to ND-Z formation.

Full text here


Another Possibility
...
These data confirm that SEP-174559 has benzodiazepine-like actions at gamma2-bearing subtypes of the GABA(A) receptor and suggest additional actions of benzodiazepine-site ligands at nACh and NMDA receptors.
Full text here

 

[vecktor]

the author wrote a book and runs a website,

http://www.darksideofsleepingpills.com/

there has long been animal evidence that some of the Z drugs cause specific cancers but only at very high doses, correcting to humans something like 30 times the normal doses.

the suspicion has always been that somehow they cause immune suppression, as quite a few benzos are linked to increased incidence of infection as well.

As the author accepts the meta study in the OP is not solid evidence on its own but it does suggest that there is something that should be looked into given the prevalence of these drugs.

 

[Hammilton]

And I find it hard to disagree with that- but any researcher who runs such a biased site has to fight an uphill battle with credibility- even if he turns out to be correct.

 

[vecktor]

And I find it hard to disagree with that- but any researcher who runs such a biased site has to fight an uphill battle with credibility- even if he turns out to be correct.

I actually thought his site to be pretty fair, he qualifies his claims carefully, a biased site would be much more forthright in its views.

this is in contrast with the sites promoted by the big pharmaceutical companies, an industry which has a reputation for various skullduggery including withholding negative results and judging by the amount of money big pharma shells out in compensation this bad reputation is fully deserved.

 

[fastandbulbous]

Well people who have disruped sleep patterns have reduced/impaired immune function - probably due to the release of cortisol (which has immunosupressant activity like all of the glucocorticoids), which is released in response to stress (like being unable to sleep) and reduced immune function increases the risk of cancer cells going undetected & subsequently dealt with by the immune system.


Of course they have to investigate in case the drugs are the primary cause, but with what they're proposing (trials with small mammals), shouldn't that have been picked up before the phase III trials of the drugs? (since thalidomide I thought pharmaceutical firms were hypervigilant regarding mutagenic drugs)

 

[nuke]

The carcinogenicity issue in rats is limited to the middle to high dose rats apparently, only in chronic doses. This is generally enough to pass through the FDA (there are carcinogenic benzodiazepines and antipsychotics that get by for this reason). Even diphenhydramine is a carcinogen in high enough dosages in rats (gliomas in male rats and some other tumour in female rats). It's hard to say how large the risk might actually be -- but when you have hundreds of thousands of people taking the drug on a regular basis, it's certainly curious.

The skin cancer in the one group is very curious, as it can often be difficult to tell the danger of drugs that enhance the toxicity of skin lesions caused by UV radiation -- they may only become apparently when the animals are exposed to UV radiation on a regular basis (which they aren't when they're inside a lab building).

 

[swilow]

Well, thats settled it for me. I'll not take these drugs again (as I puff away on a hand rolled smoke ).

 

[fastandbulbous]

^ Well if you do, it'd be best if you took on a vampire persona and avoided daylight like the plague... (couldn't bring myself to put a smiley at the end as it's too fuckin' serious)

 

[Pteropod]

I actually thought his site to be pretty fair, he qualifies his claims carefully, a biased site would be much more forthright in its views.

I haven't read his site particularly extensively, but he mentions the increase in suicide risk associated with sleeping pills without seeming to consider a really obvious explanation for this (namely, that insomnia is a symptom of clinical depression). That doesn't exactly incline me to respect his opinion.

 

[Limpet_Chicken]

I'l be fine with the Z drugs then eh FB, sunlight? I rarely ever go out in daylight, its awful stuff

 

[Hammilton]

I actually thought his site to be pretty fair, he qualifies his claims carefully, a biased site would be much more forthright in its views.

I read the site a bit closer; I changed me mind, I guess; he doesn't seem as biased as I first thought, or biased at all really, though I suspect he is.

 

[nabollocks]

Seriously, those who don't sleep well seem to have higher risks of cancer, as Fast&B said, Cortisol is an evil steriod that likes to break down alot of cells in the body, and if one is taking a sleep med, maybe you are not going into the correct phase of sleep that natural sleep provides, and one is still releasing cortisol as a stress response when "artificial sleep" is how a person sleeps, via Z-drug.

maybe.

Mainly phase 2 for Z-drugs.

Where you should be spending roughly 50% of your sleep time in phases 3 and 4.

I am not sure that this theory explains everything though as most benzos exhibit the same action on sleep as the Z-drugs.

I believe that Phenibut is the only drug related to this class of chemicals that allows proper sleep? That is beside the point anyway.

 

[mad_scientist]

That doctors website is...interesting. He has certainly done a lot of research but the impression I came away with was that he first decided "sleeping pills are bad" and then did extensive research with the specific aim of supporting this conclusion. The research does look valid, but he seems to have only cited studies that support his view. To be fair the pharmaceutical companies tend to do the exact opposite and only publish the research that portrays their products in a favourable light so I guess he has every right to be an advocate for the other side!

If these drugs are carcinogens then that certainly is a cause for concern, but my feeling is that if increased cancers are seen with all of these drugs despite their widely differing structures and mechanisms of activity then this is just as likely to reflect a relationship between insomnia and cancer as between sleeping pills and cancer - I'd like to see some data showing the cancer rates for chronic insomniacs who have never taken sleeping pills compared to people who have never suffered from insomnia before I make the conclusion that its the drugs that are the problem.

 

[Morissey]

Even if the Z-drugs are particularly carcinogenic, having only ever used them at medicinal doses for 3 consecutive days would be completely insignificant right?
ie. To what extent are these substances carcinogenic?