Psycho-Babble Medication Thread 837647

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Are the 'Z-drugs' really carcinogenic?

Posted by Quintal on July 2, 2008, at 11:30:14

I've been coming across these sinister articles for a while. They seem to suggest that 'z-drugs' are associated with higher rates of cancer mortality. The FDA has expessed skepticism over the validity of these studies because of the short time lag between exposure and diagnosis (as little as fourteen days in one case, and all within six months). Also, the authors found that ramelton (Rozerem) carried a significant risk of cancer mortality despite having a completely different mechanism. I'm wondering why hypnotics as a class were singled out for investigation, rather than a chemical class i.e. benzodiazepines? This obviously raises questions as to whether the older benzos carry similar risks. As it is I'm not too concerned, but I am considering switching my zopiclone to lormetazepam (pdoc permitting), or even a nightly dose of diazepam.
__________________________________________________

Evidence That New Hypnotics Cause Cancer
Daniel F. Kripke, University of California, San Diego
March 17, 2008

ABSTRACT:
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.

SUGGESTED CITATION:
Daniel F. Kripke, "Evidence That New Hypnotics Cause Cancer" (March 17, 2008). Department of Psychiatry, UCSD. Paper 3.
http://repositories.cdlib.org/ucsdpsych/3

Full article (PDF document):
http://repositories.cdlib.org/cgi/viewcontent.cgi?article=1002&context=ucsdpsych
__________________________________________________

__________________________________________________

Zopiclone may be carcinogenic and mutagenic according to rat, mice and hamster studies. It should be noted that, at 100 mg per kg of bodyweight per day, the dosage was considerably higher than the therapeutic dose for humans. The authors of an uncontrolled study of Zopiclone said that it may take decades in immunocompetent people before carcinogenic effects from past zopiclone use develops. It was suggested that further research and monitoring was required into the potential for zopiclone to cause cancer in immunocompetant patients.[1]

A recent analysis of FDA and clinical trial data shows that nonbenzodiazepine Z-drugs at prescribed doses cause cancer in humans. The data shows that trial subjects receiving hypnotic drugs had an increased the risk of developing cancer and malignancies. There have been 15 epidemiologic studies which have shown that hypnotic drugs cause increased mortality, mainly due to increased cancer deaths. The cancers included, cancer of the brain, lung, bowel, breast, and bladder, and neoplasms. Initially FDA reviewers did not want to approve the drugs due to concerns of cancer but ultimately changed their mind and approved the drugs despite the concerns. FDA data has shown that zolpidem, zaleplon and eszopiclone are clastogenic and cause cancer in rodents. Benzodiazepine agonists are associated with an increased risk of ovarian cancer in humans. Zopiclone was reportedly refused a product license by the FDA in the USA due to indications that zopiclone caused cancer. Development of a malignant neoplasm has been associated with zolpidem usage but the rate of incidence of neoplasm in zolpidem users is as yet unknown. The rates, in clinical trials for the nonbenzodiazepine Z drugs, of malignancies and neoplasms are significantly higher in hypnotic groups than in placebo groups. Also the analysis of clinical trials and FDA data showed that eszopiclone, zaleplon, and zolpidem appeared to have an adverse effect on the immune system causing an increased rate of infections and colds in hypnotic users. Suppression of immune function might be the cause of the increased rate of cancer in nonbenzodiazepine hypnotic users. Indiplon has also shown an increased rate of cancers in clinical trials. The review author concluded saying; "the likelihood of cancer causation is sufficiently strong now that physicians and patients should be warned that hypnotics possibly place patients at higher risk for cancer".[2]
http://en.wikipedia.org/wiki/Zopiclone
__________________________________________________

The zopiclone study was carried out on a group of HIV positive men, and the cancers were mostly Kaposi's sarcoma - hardly unusual for that population. I sense a whiff of scaremongering among all this, but posibly a grain of truth. I can't help but wonder how many other psychiatric drugs would show a similar relationship with cancer mortality if studied in the same way though.

Q

 

Re: Are the 'Z-drugs' really carcinogenic?

Posted by dbc on July 2, 2008, at 12:05:27

In reply to Are the 'Z-drugs' really carcinogenic?, posted by Quintal on July 2, 2008, at 11:30:14

As to your question of why benzos in general werent researched its probably because any research possible has been done on benzodiazepines. They and amphetamines are probably the two most studied class of chemicals of the last 100 years. We just have nothing to say about them anymore.

Z-drugs are sketchy to me to begin with and i havent messed with them at all. The casual cancer connection is weird to say the least and not in a biased sense...its just plain weird. I dont know about cancer or carcinogens so i really cant comment on how this is even possible.

Its to bad people had to die to find out this link but possibly this will allow older drugs to come into the mainstream again. Halcion wasnt a bad drug in its day despite its reputation.

 

Re: Are the 'Z-drugs' really carcinogenic?

Posted by Phillipa on July 2, 2008, at 12:40:38

In reply to Re: Are the 'Z-drugs' really carcinogenic?, posted by dbc on July 2, 2008, at 12:05:27

Confused as to a z drug as isn't it lunesta here and there is no z. So only generic names ? Hence the reason I've used benzos for almost four decades now. Phillipa

 

Re: Are the 'Z-drugs' really carcinogenic?

Posted by Quintal on July 2, 2008, at 13:34:57

In reply to Re: Are the 'Z-drugs' really carcinogenic?, posted by Phillipa on July 2, 2008, at 12:40:38

The 'z-drugs' are the newer non-benzo sleeping tablets; zopiclone (Zimovane), eszopiclone (Lunesta), zolpidem (Ambien) and zaleplon (Sonata), most likely because they begin with a 'z'.

As for the older benzos, they are very widely used in research labs, but I'm not sure that they were ever tested to the same standards as newer drugs. They were introduced in the same era as thalidomide, and research is much more stringent now than it was back then. It's strange that all the z-drugs should cause cancer because they each belong to a different chemical class.

Q

 

Re: Are the 'Z-drugs' really carcinogenic? dbc

Posted by Phillipa on July 2, 2008, at 16:16:25

In reply to Re: Are the 'Z-drugs' really carcinogenic?, posted by dbc on July 2, 2008, at 12:05:27

Either was mephrobamate took it with valium and just stopped it when anxiety no longer there. No withdrawal just stopped. Doc was surprised but was only 25 and knew nothing about meds was into vitamins. Phillipa

 

Re: Are the 'Z-drugs' really carcinogenic?

Posted by linkadge on July 2, 2008, at 19:23:16

In reply to Re: Are the 'Z-drugs' really carcinogenic? dbc, posted by Phillipa on July 2, 2008, at 16:16:25

Strange, I hope my periodic zopiclone use hasn't caused a small mutation which will end up killing me down the road.

I certainly hope more research is done.

Linkadge

 

Re: Are the 'Z-drugs' really carcinogenic? Quintal

Posted by yxibow on July 2, 2008, at 23:43:20

In reply to Are the 'Z-drugs' really carcinogenic?, posted by Quintal on July 2, 2008, at 11:30:14

There is a lot of degree of skepticism that I have on this subject --- first of all the person who has "studied" these agents, Dr. Kripke, also claimed some years ago that the remaining napalm stored in Fallbrook could potentially bomb the entire Southern California basin with toxicity and there was hysteria to finally remove it all -- it has passed its sell date in military technology anyhow, but that's another story.


I wouldn't drink napalm (duh), but the awful mixture is just gasoline, styrene and benzene, all "known to the state of California" (Prop 65) to be carcinogens and unlikely to ever spread beyond their storage region.


> I've been coming across these sinister articles for a while. They seem to suggest that 'z-drugs' are associated with higher rates of cancer mortality. The FDA has expessed skepticism over the validity of these studies because of the short time lag between exposure and diagnosis (as little as fourteen days in one case, and all within six months).


That I would have skepticism over also -- unless you worked during the day in a highly concentrated uranium mine and at night in an asbestos mine for that period of time, not to make light of those who have passed on or have become ill because of that, the period of carcinogenicity and mutation takes decades and is still an unclear subject.

Also, the authors found that ramelton (Rozerem) carried a significant risk of cancer mortality despite having a completely different mechanism.

Ramelteon is basically a compound related to melatonin but 17 times as powerful, and yes, a completely different mechanism. Are we toxic to our own melatonin system ?

I'm wondering why hypnotics as a class were singled out for investigation, rather than a chemical class i.e. benzodiazepines? This obviously raises questions as to whether the older benzos carry similar risks. As it is I'm not too concerned, but I am considering switching my zopiclone to lormetazepam (pdoc permitting), or even a nightly dose of diazepam.

Its up to you to do that, but I really wouldnt -- first of all, neither are intended for long term use except the racemer of zopiclone (Lunesta).

Habituation will develop much more rapidly to a benzodiazepine than a pseudobenzodiazepine.

__________________________________________________
>
> Evidence That New Hypnotics Cause Cancer
> Daniel F. Kripke, University of California, San Diego
> March 17, 2008

If you go to his PDF, it mentions this:

"Competing Interests
Dr. Kripke has no competing interests, other than a desire to confirm and extend previous
work of his research group. He has been a long-time critic of hypnotic safety, e.g., in his nonprofit
web site, www.DarkSideOfSleepingPills.com."


Which if you start reading it, one gathers, at least in my opinion a rather scaremongering site for a health professional. Read at your pleasure, be a skeptic, disagree, I have no qualms.

> The zopiclone study was carried out on a group of HIV positive men, and the cancers were mostly Kaposi's sarcoma - hardly unusual for that population. I sense a whiff of scaremongering among all this, but posibly a grain of truth. I can't help but wonder how many other psychiatric drugs would show a similar relationship with cancer mortality if studied in the same way though.


I would say a very very small grain of sand of truth, and as noted the population tested -- remember even people "healthy" with HIV can have medication interactions that can cause neurological problems and all sorts of things.

Yes, we don't know the effects of medication in 50 years, but we do have more than 50 years of medical knowledge of psychiatric drugs.

Benzodiazepines, when taken as directed, are probably the most benign of agents at the moment. Now, habituation can occur. I mean Librium was in the lab around 1958.


I guess the point I'm trying to make is, there is no "safe agent", everything has side effects, including water -- drink too much and it can kill you too. Life isn't "safe" -- its messy, it has trauma, but it also has beauty, and if something is working for someone and not causing endless untolerable side effects, why stop it?

It becomes the esoteric debate of what is the value of the quality of life and what can improve it, drugwise, or not.

In the end, something gets us all. Its just the rules -- I don't like it any more than I think anybody else does.

Its what anything from atheism and agnosticism to religion tries to sooth us (and unfortunely I won't go on about it but certain belief systems can become cults, etc... that will be an endless debate and I'd rather be civil here)

But why not enjoy the vastness between this space?

-- tidings

Jay

 

Re: Are the 'Z-drugs' really carcinogenic? yxibow

Posted by Quintal on July 3, 2008, at 8:37:41

In reply to Re: Are the 'Z-drugs' really carcinogenic? Quintal, posted by yxibow on July 2, 2008, at 23:43:20

>Dr. Kripke has no competing interests, other than a desire to confirm and extend previous
work of his research group. He has been a long-time critic of hypnotic safety, e.g., in his nonprofit
web site, www.DarkSideOfSleepingPills.com."

I saw that website a few months ago but didn't realize they were the same person. I thought it was very poor quality. Seemed like he wanted to fashion himself as the American Heather Ashton, but I can't imagine Heather herself making such sweeping claims, or endorsing his website for that matter. This has swayed me very much towards thinking Dr. K is doing little more than trying to make regular users of sleeping tablets feel bad. It looks more like a personal vandetta than objective research.

Q

 

Re: Are the 'Z-drugs' really carcinogenic?

Posted by linkadge on July 4, 2008, at 7:46:25

In reply to Re: Are the 'Z-drugs' really carcinogenic? Quintal, posted by yxibow on July 2, 2008, at 23:43:20

I didn't know ramelton was related to melatonin at all. I knew it was a melatonin receptor agonist, but did not know that it was a hormone, or posessed any antioxidant activity.

If the drugs are associated with cancer, I'd suspect that poor quality of sleep is the underlying factor. There are a number of immune responces that occur during sleep. There is also the release of the potent antioxidant (and anticancer) hormone melatonin. Persistant insomnia is probably itself a risk factor for cancer, but treating it with benzos does not restore natural rhythems of brain chemicals and hormones. Prolonged usage of sedatives probably leaves the body more open to cancer on account a lack of restoration of natural disease fighting sleep.

Linkadge


 

Re: Are the 'Z-drugs' really carcinogenic?

Posted by undopaminergic on July 4, 2008, at 7:56:33

In reply to Re: Are the 'Z-drugs' really carcinogenic?, posted by linkadge on July 4, 2008, at 7:46:25

>
> Persistant insomnia is probably itself a risk factor for cancer, but treating it with benzos does not restore natural rhythems of brain chemicals and hormones.
>

Benzos also impair sleep quality - at least as determined by EEG. For comparison, antihistamines in general are neutral, while the antihistamine and serotonin 5-HT2A antagonist cyproheptadine seems to improve it.

 

Re: Are the 'Z-drugs' really carcinogenic? undopaminergic

Posted by Crotale on July 4, 2008, at 11:02:25

In reply to Re: Are the 'Z-drugs' really carcinogenic?, posted by undopaminergic on July 4, 2008, at 7:56:33

> Benzos also impair sleep quality - at least as determined by EEG.

One of my professors who is a sleep expert mentioned that benzos can screw up your EEG for months or even years. However...

> For comparison, antihistamines in general are neutral, while the antihistamine and serotonin 5-HT2A antagonist cyproheptadine seems to improve it.

My experience with antihistamines as sleep aids is that I build up tolerance to them within a few days. And when I tried cyproheptadine, it worsened my mood. Whereas Ambien still works and I've been taking it for years, practically every night.

I think this guy sounds like he's scaremongering too.

-Crotale

 

Re: Are the 'Z-drugs' really carcinogenic?

Posted by Quintal on July 4, 2008, at 12:52:55

In reply to Re: Are the 'Z-drugs' really carcinogenic? undopaminergic, posted by Crotale on July 4, 2008, at 11:02:25

I took some cyproheptadine last night to help 'augment' my zopiclone. I'm aware of the studies that show improved sleep quality on an EEG, but that hasn't translated into what I would call good quality refreshing sleep in real life. It makes me feel tired and drowsy for most of the next day, negating any beneficial effect on sleep architecture it might have. Benzos have always made me feel better.

Q

 

Re: Are the 'Z-drugs' really carcinogenic? undopaminergic

Posted by linkadge on July 5, 2008, at 8:38:53

In reply to Re: Are the 'Z-drugs' really carcinogenic?, posted by undopaminergic on July 4, 2008, at 7:56:33

Yeah, 5-ht2a antagonists enhance melatonin release if I am not mistaken.

Melatonin itself antagonizes 5-ht2a and potentiates 5-ht1a activity.

Linkadge

 

Re: Are the 'Z-drugs' really carcinogenic?

Posted by linkadge on July 5, 2008, at 8:45:13

In reply to Re: Are the 'Z-drugs' really carcinogenic? undopaminergic, posted by Crotale on July 4, 2008, at 11:02:25

> For comparison, antihistamines in general are >neutral, while the antihistamine and serotonin 5->HT2A antagonist cyproheptadine seems to improve >it.

>My experience with antihistamines as sleep aids >is that I build up tolerance to them within a >few days. And when I tried cyproheptadine, it >worsened my mood. Whereas Ambien still works and >I've been taking it for years, practically every >night.

There are no guarentees. I think tollerance builds more completely to antihistamine effects than 5-ht2a antagonist effects. Cyproheptadine can worsen mood. I find it very calming not depressing. The calcium chanel blockade and perhaps nonselective serotonin antagonism might worsen mood. I find it more of a mood stabilizer personally. Melatonergic drugs can sometimes cause depression (possably its anticonvulsant or serotonin modulating effects).

Just because ambien works well doesn't mean it isn't possably carcinogenic.

>I think this guy sounds like he's scaremongering >too.

Possably, but why? Sombody just randomly picks a drug to associate with cancer? Anyhow, I would personnally assume its true until proven false.

Linkadge

 

Re: Are the 'Z-drugs' really carcinogenic? Quintal

Posted by linkadge on July 5, 2008, at 9:03:27

In reply to Re: Are the 'Z-drugs' really carcinogenic?, posted by Quintal on July 4, 2008, at 12:52:55

I'm kind of the opposite. I'd rather take cyproheptadine than a benzo. I think the thing with cyproheptadine is that it is very potent. Generally 1/4mg (1/4mg not 1/4 tablet) is enough for myself. It is especially helpful if I feel particularly stressed.

I don't think it works well for an 'as needed' sleep aid because it does seem to affect more than sleep. I think that, like melatonin, it can have an almost antimanic or mood stabilizing effect. I think when people can't sleep it is sometimes during a 'ramping up' period. I feel that melatonin, cyproheptadine, or remeron can somtimes reset that, which initially leads to subjective dysphoria (I don't know if that makes any sense).

It feels like a balloon for me. Stress causes the balloon to inflate. The mealtonin cyprohelptadine / remeron deflates the balloon, benzo's do not. Initially this makes me feel worse the next day, but over a few days I feel much more normal and in control. If I use cyproheptadine for a few nights in a row, I almost always feel better a few days down the road then if I have used benzos.


Everbody is different though.


Linkadge


 

Re: Are the 'Z-drugs' really carcinogenic?

Posted by Quintal on July 5, 2008, at 10:14:24

In reply to Re: Are the 'Z-drugs' really carcinogenic?, posted by linkadge on July 5, 2008, at 8:45:13

For the record, Dr K also thinks taking melatonin and antihistamines for sleep is a bad idea, more because they are being used as sleep aids than any evidence that they are actually harmful. He seems to have developed some sort of fixation early in his career on the idea that anything that helps insomniacs sleep is inherently harmful. The website is poorly constructed, almost fanatically biased, and is littered with basic spelling mistakes and other obvious errors. One worries that the quality and motives of his research is on a par with his website.

Just a smaple quote:

"I am not insensitive to the idea that some dying people at the end of their lives should receive medications to ease their pain when they want them, even if it shortens their lives. Most people who take sleeping pills are a long way from being ready to die. I do not think that relief of distress justifies a drugs which may shorten life for most people who take sleeping pills. Regardless of whether or not you agree with assisted suicide, most patients who seek sleeping pills are not ready for this assistance."

I just the feeling he has a rather extreme calvanistic view on anything that brings sensations comfort or wellbeing to the patient. I think this is what colours and motivates his research.

Q

 

Re: Are the 'Z-drugs' really carcinogenic?

Posted by undopaminergic on July 6, 2008, at 3:33:32

In reply to Re: Are the 'Z-drugs' really carcinogenic?, posted by Quintal on July 5, 2008, at 10:14:24

> For the record, Dr K also thinks taking melatonin and antihistamines for sleep is a bad idea, more because they are being used as sleep aids than any evidence that they are actually harmful.
>

He does have the following to say specifically about melatonin:
* "there is evidence that melatonin interferes with gonadal functions in humans"
* "In some mammals, melatonin whitens the fur or promotes obesity"
* "Considerable evidence indicates that melatonin might cause depression."
* "Melatonin causes headache and nightmares."
* "In animals, melatonin constricts brain blood vessels and affects the arteries of the heart."
* "In humans, melatonin affects blood pressure."

I can't seem to find any comment of his on antihistamines, at least not as part of his book on sleeping pills.

 

Re: Are the 'Z-drugs' really carcinogenic?

Posted by Quintal on July 6, 2008, at 8:20:43

In reply to Re: Are the 'Z-drugs' really carcinogenic?, posted by undopaminergic on July 6, 2008, at 3:33:32

I thought there were some comments on Vistaril as a sleep aid in the same tone to the rest of the book, but I'll take your word for it.

Q

 

Re: Are the 'Z-drugs' really carcinogenic?

Posted by linkadge on July 6, 2008, at 12:11:55

In reply to Re: Are the 'Z-drugs' really carcinogenic?, posted by undopaminergic on July 6, 2008, at 3:33:32

> "there is evidence that melatonin interferes >with gonadal functions in humans"
>* "In some mammals, melatonin whitens the fur or >promotes obesity"
>* "Considerable evidence indicates that >melatonin might cause depression."
>* "Melatonin causes headache and nightmares."
>* "In animals, melatonin constricts brain blood >vessels and affects the arteries of the heart."
>* "In humans, melatonin affects blood pressure."

I don't know if I agree with all of these. A certain level of melatonin is of course physiological. Many of these effects are dose dependant. Melatonin has been shown to have depressogenic effects in some studies and antidepressant effects in others.

Some of the statements should not be absolute. Melatonin causes headaches and nighmares? I've also heard the opposite ie melatonin use for migrane - and its use to reduce nightime awakenings.


Linkadge

 

Re: Are the 'Z-drugs' really carcinogenic?

Posted by undopaminergic on July 6, 2008, at 13:49:10

In reply to Re: Are the 'Z-drugs' really carcinogenic?, posted by Quintal on July 6, 2008, at 8:20:43

> I thought there were some comments on Vistaril as a sleep aid in the same tone to the rest of the book, but I'll take your word for it.
>
> Q

Maybe it was elsewhere. The sleeping pills book isn't the only thing he has written.


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