Talk:Zolpidem

Direct quotation from a meta-analysis about Zolpidem and cancer reverted, I disagree

I have put in, using two different phrasings, a direct quotation from a 2018 meta-analysis on this topic. Both times Zefr has reverted the change. The removed text is:

The study also states that "With regards to the type of hypnotics, zolpidem use showed the strongest risk of cancer"

Zefr's reason for reverting it was:

"Unnecessary and misleading; these were weak clinical studies -- don't overinterpret the results."

I disagree with this for several reasons. First, a meta-analysis's specific finding on zolpidem use and cancer is something I think is important to have on the zolpidem page's "adverse effects" page. I am not "interpreting" the study at all, I am quoting it.

Second, my edit itself cannot possibly be misleading. All I said is "the study also states" and then quoted the study.

Third, I likewise think Zefr's statement that the underlying studies are "weak" is OR and should not be the basis for an edit.

Fourth, as long as we are giving opinions of the underlying studies, I disagree with him that they are "weak." The authors of the meta-analysis, on page 212-215, address the quality of the underlying studies, grading them using the established Newcastle-Ottawa Scale procedure, and label four of the six studies to be "high quality studies." The remaining two included studies only fell 1 point short of high quality.

I invite Zefr, if he still disagrees with my edit, to address these points.

I also want to note my agreement with CanisLupisArctus above, who states:

"But more importantly I am a little bit disturbed, to say the least, that there is no discussion whatsoever about the real, perceived, or potential, carcinogeneticy of this compound. What is going on here? "

There appear to be quite a few other studies that conclude there is an association between zolpidem use and cancer. For instance, not included in the meta-analysis, but consistent with its results, is this article:

http://www.jmedscindmc.com/article.asp?issn=1011-4564;year=2016;volume=36;issue=2;spage=68;epage=74;aulast=Lin

That article's conclusion:

After adjustments for gender, age, comorbidities, and other medications, patients using zolpidem had a 1.75 times (95% confidence interval [CI], 1.02–3) greater risk of cancer events than those not using zolpidem during the 3-year follow-up. Greater mean daily dose and longer use were associated with increased risk. Among patients with sleep disorder, mean daily dose >10 mg and length of drug use >2 months was associated with 3.74 times greater risk (95% CI, 1.42–9.83; P = 0.008) of incident cancer events. Conclusions: In this study, zolpidem use increased cancer events risk in sleep disorder patients. Risks and benefits of chronic zolpidem usage should be explained to sleep disorder patients, and long-term use should be monitored.

Declanscottp (talk) 23:47, 17 August 2018 (UTC)

Leaning towards supporting you on this Declan but waiting for Zefr’s comments.--Literaturegeek | T@1k? 01:21, 18 August 2018 (UTC)

As editors, we have to interpret the quality of the source, which in this case, is established on observational studies. Described in WP:MEDASSESS, and shown in the middle of the left pyramid, observational studies are primary research, which disqualifies the source from use at all, in my opinion. I left part of the description in this edit, granting that it was a meta-analysis, but rethinking the issue leads me to conclude that the study is only preliminary research and is misleading for the encyclopedia (which should be based on high-quality reviews or meta-analysis of randomized controlled trials). It should be completely removed. Further, Declanscottp, please learn how to format a repeat reference, shown here. --Zefr (talk) 02:09, 18 August 2018 (UTC)

Zefr, I do not think your description of the pyramid is correct. Both "observational" and "randomized controlled trial" studies are grouped in the middle of the pyramid as "primary studies." Meta-analysis is placed above them as "Secondary, pre-appraised, or filtered." Do you have a source to support that a meta-analysis involving more than 1.8 million data points is "preliminary research?" Moreover, when it comes to long-term cancer risk from use of a drug, as opposed to drug efficacy, there simply are not going to be clinical trials. Demanding them, as you seem to do, is demanding that information on how drugs increase long-term cancer risks never appear in wikipedia. Indeed, in many cases, when there is strong evidence, as there is here, that a drug increases cancer, doing a clinical trial to prove it would be unethical. "Only clinical trials" would also mean that Wikipedia could not state smoking cigarettes cause cancer, since no randomized clinical trials of cigarettes exist. Declanscottp (talk) 02:41, 18 August 2018 (UTC)

I interpret the pyramid representing that one RCT would be an insufficient WP:MEDRS source, and a meta-analysis of observational studies - a lower quality type of clinical study than a RCT - is a meta-analysis of low-quality studies. Bottom line: this is weak, unusable evidence to make a statement that taking Zolpidem increases the risk of some cancers. Stronger evidence - reviews or meta-analyses of several RCTs - is needed for such an exceptional statement to appear in an encyclopedia. --Zefr (talk) 03:12, 18 August 2018 (UTC)

Of course nobody is going to get ethical approval and funding to perform randomised controlled trials to see who will and won’t get cancer, unless Adolf Hitler and his regime gets reincarnated. Your interpretation of MEDASSESS guideline, Zefr, is overly strict IMHO and in fact incorrect. MEDASSESS is about preventing newbie and POV pushers using primary sources such as individual observation studies to debunk secondary review and meta-analysis - it is to encourage editors to use the best quality sources available and that is what Declan has done. If Declan was trying to push a primary observational study then yes we could be having this discussion about MEDASSESS. I can’t imagine why withholding this information from the public or the sum of all human knowledge is a good idea. We are talking about people’s lives here. Cancer is serious.--Literaturegeek | T@1k? 03:19, 18 August 2018 (UTC)

Zefr, if we apply your interpretation of MEDASSESS to other subject matters then the existence of Wernicke–Korsakoff syndrome is unproven, weak and the whole article should be deleted from Wikipedia since no randomised controlled trials have administered alcohol at alcoholic levels and created thiamine deficiency, etc against a control group. Same goes for fetal alcohol syndrome. Drugs are withdrawn from the market because of case reports which the FDA and such like systematically review and we then report these review findings in our articles. Declan gave the example of cigarettes causing cancer being the result of observation but yet we report it as fact and nobody would argue the smoking cancer connection to be “weak”.--Literaturegeek | T@1k? 03:42, 18 August 2018 (UTC)

I also think Zefr's interpretation of MEDASSESS is too strict. In addition to the meta-analysis PMID 29973038, there is also the review PMID 27303633 that concludes The available clastogenicity data, animal data, randomized placebo-controlled clinical trials, and human epidemiology studies consistently, if not always conclusively, suggested that hypnotics likely cause human cancers and cancer deaths. (note zolpidem itself is apparently not clastogenic but as reviewed in this paper, there is animal, RCT, and epidemiology data demonstrating an association between zolpidem use and cancer). Boghog (talk) 05:06, 18 August 2018 (UTC)

These last two comments clearly show this is an area of Zolpidem research, so the following statements and sources should be moved from the Adverse effects section to Research: A 2009 meta-analysis found a 44% higher rate of mild infections, such as pharyngitis or sinusitis, in people taking zolpidem or other hypnotic drugs compared to those taking a placebo.[20] A 2018 meta-analysis of observational studies found that use of hypnotics, including Zolpidem, was "significantly associated with an increased risk" of some types of cancer.[21] To report Zolpidem as a cancer-risk drug is misleading and unencyclopedic, as this is not a fact. If it were, regulatory authorities would ban it from the market. --Zefr (talk) 15:37, 18 August 2018 (UTC)

The research has progressed well beyond preliminary primary research, so I think it would be a misrepresentation of the sources to label it as research as if to downplay the evidence to mere research opinions. Reporting zolpidem as a cancer risk is actually correct because that is what the sources say. We follow what the sources and available evidence says. Benzodiazepines and Z-drugs have been reported as cancer causing drugs for decades, it is quite well established. You are wrong to claim that regulatory bodies would ban this drug for cancer risk because there are actually no good alternatives (bromides and barbiturates are incredibly dangerous in overdose, for example) and often these drugs are licensed and used for the short-term treatment severe intolerable insomnia, at least that is the licensing conditions in the U.K. and most of the EU. Antipsychotics, including atypical antipsychotics, cause permanent tardive dyskinesia, a horrific disability caused by brain damage, but regulatory bodies don’t ban them because there is no safer alternative for certain serious psychiatric disorders. I am sure you will have heard of the benefit-risk ratio. What might happen is regulatory hypnotics carry stronger warnings and licensing conditions to further encourage short-term or very occasional use (for severe insomnia only) prescribing practices, I suspect. But anyway, we don’t know for sure what if any action regulatory bodies will take in response to that meta-analysis as it is not long published.--Literaturegeek | T@1k? 15:57, 18 August 2018 (UTC)

To make a blanket statement that research is unencyclopedic is patently absurd. As already stated by Literaturegeek, we will never have absolute proof that zolpidem causes cancer in humans because running the required clinical trials would be unethical. The best available scientific evidence as reviewed by reliable secondary sources suggests that zolpidem is a cancer risk and therefore I think we have a obligation to state this. Zolpidem cancer causation is not an established fact, but the association is. Boghog (talk) 16:38, 18 August 2018 (UTC)

All that is POV bluster. Fact: there is no mention of cancer risk in general public information from NIH or in FDA prescribing information. This topic is only preliminary research and should be stated as such in the Research section. --Zefr (talk) 17:42, 18 August 2018 (UTC)

I am sorry, but nobody agrees with you and policy and guidelines do not support your position. In fact, a clear sign of POV pushing is arguing for the exclusion or downplaying of meta-analysis and systematic reviews. It is commonly done by Alt-Med advocates, not so common when dealing with general pharmacology and medicine article but alas Zephyr you are doing it. Please stop, per WP:STICK, because it is time wasting.--Literaturegeek | T@1k? 18:01, 18 August 2018 (UTC)

Zefr - You appear to claim that all observational studies are of 'low-quality', on the basis that they are a lower quality form of research than the RCT. Being lower quality than the gold standard isn't the same as being low quality in absolute terms. But this is all completely irrelevant, anyway. There is no reason why it cannot be mentioned on the Zolpidem page, at the very least with some re-wording. Outright omission is unjustifiable. One can, and ought to, simply state that "X publication suggests there may be a link between Y and Z....The authors highlight methodological shortcomings and suggest more research is needed to reach more reliable conclusions". This is absolutely factual, not misleading, not a misinterpretation of the literature, or anything else like it.CanisLupisArctus (talk) 03:23, 28 September 2018 (UTC)

I agree with everything Boghog has said, by the way. They have put it better than I ever could have. Cheers.CanisLupisArctus (talk) 03:26, 28 September 2018 (UTC)

-

• couple of comments. I went to find the impact factor for the Korean Journal of Family Medicine and it is not even listed in JCI. That is a bad sign. That given, the conclusion is worth reading closely. It says "In conclusion, meta-analysis of observational epidemiological studies showed that hypnotics use was associated with an increased risk of cancer. However, this association should be cautiously interpreted because substantial heterogeneity was present as high value of I square (I square value was 93.9%, high above 50% in a main meta-analysis.). Larger prospective cohort studies or randomized controlled studies providing a higher level of evidence are required to confirm the present findings." The penultimate paragraph is also very important - the first and last lines are "Our meta-analysis has several limitations. First, we only included observational epidemiological studies because there have been few published randomized controlled trials on this topic. ...Thus, we were unable to exclude the confounding efficacy of important factors such as smoking or alcohol drinking on the association between hypnotics use and the risk of cancer." So hm. There are only three reviews that a pubmed search even finds on "zolpidem cancer". Is there even biological plausibility that might lead one to think that the correlation (with very clear confounders named) might be causation? (I note that the F1000 paper (the most recent version of which is here) is by Kripke, who acknowledges that he is "a frequent critic of hypnotics risks and benefits, especially through his non-profit internet web site, www.DarkSideOfSleepingPills.com"... so hm on that as well. If - and it is a big if - we generate content from the Korean journal, it needs to be much more couched that it was; correlation is not causation and there are very clear confounders. I've removed the bit of content for now, pending agreement on using the source and what kind of content is appropriate. Jytdog (talk) 19:34, 18 August 2018 (UTC)

Jytdog, I have a few responses to your comment.

1. The Korean Journal of Family Medicine is "the official journal of the Korean Academy of Family Medicine." It is in its 30th year, and does not charge authors either "submission" or "processing" fees. https://www.kjfm.or.kr/authors/processing_charge.php "No page charge or article processing charge applies. There is also no submission fee."

2. In terms of biologic plausability of zolpidem and cancer. Here is what the study I posted above says on this (the one not included in the meta-analysis, but coming to the same conclusion).

The exact relationship between zolpidem and infection events remains unknown although several mechanisms are plausible. Benzodiazepines have been found to affect polymorphonuclear cell chemotaxis and phagocytosis. Benzodiazepines in general suppress the immune response through peripheral and central benzodiazepine receptors. The impairment of macrophage spreading could be attributed to the anti‑inflammatory effect of the peripheral benzodiazepine receptor on blood cells through inhibition of the release of pro‑inflammatory cytokines such as interleukin‑6 and interleukin‑13.

An uncontrolled small case series described carcinogenicity following the prescription of zopiclone or eszopiclone to HIV Type 1 infected individuals. Eszopiclone and zolpidem use have been reported associated with increased risk of infection, raising the speculation that hypnotics impair immune surveillance.

A suppression of immune function may partly explain the increased risk of incident cancers. Sparse data on the new hypnotics (eszopiclone, zaleplon, zolpidem, and ramelteon) suggest an increased risk of cancer, which is supported by studies demonstrating a carcinogenic effect in rodents.

Furthermore, hypnotics such as zolpidem can increase the incidence of sleep apnea and may suppress the respiratory drive. Zolpidem increased the apnea index and provoked greater oxygen desaturation than flurazepam and placebo in a controlled, double–blind, cross‑over study. [...] Sleep apnea induced by medication may in turn induce early apoptosis of large granular lymphocytes which further compromises immunity and reduces immune surveillance.

A greater incidence of depression with zolpidem use has been reported. A decrease in the number of natural killer T‑cells has also been reported in patients with major depressive disorder. Depressed immunity to varicella zoster in older adults with major depressive disorder has been observed.

Compromised immunity may contribute to tumor formation. Benzodiazepines can decrease lower esophageal sphincter tone, independently of the awareness or drowsiness of patients. Zolpidem reduced the arousal response to nocturnal acid exposure and increased the duration of each esophageal acid reflux event. Gastroesophageal reflux can lead to chronic sinusitis, recurrent croup, and laryngitis. A recent meta‑analysis reported an increased risk of infection with zolpidem use. Infection may result from increased gastroesophageal regurgitation or from zolpidem usage and subsequent increased cancer development.

3. Kripke is/was a full professor of psychiatry at a top 20 American medical school who specializes in sleep medicine. He pretty clearly thinks zolpidem increases cancer risk. I spent a while following your links and links from there. Interestingly, it appears he published exactly what we agree would be good: a meta-analysis of data from controlled zolpidem trials, from way back in 2008. Here is the 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 any cancers. The US 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 four drugs, there were 6190 participants given hypnotics and 2535 given placebo in parallel. There were eight mentions of incident non‐melanoma skin cancers among participants receiving hypnotics but no comparable mentions of cancers among those receiving placebo (P = 0.064, one‐tailed). There were also four mentions of incident tumors of uncertain malignancy among those receiving hypnotics but none among those receiving placebo, so combining uncertain and definite malignancies yielded a more significant contrast (P = 0.016). FDA files revealed that all four of the new hypnotics were associated with cancers in rodents. Three had been shown to be clastogenic. 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, confirmatory research is needed.

Here is the link: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2869.2008.00685.x

Kripke also published a literature review that included this topic in 2017. It was peer-reviewed by two people. One is professor of medicine at a top-10 US medical school, the other was Barbara Phillips, whose webpage states:

"I am a past-chairman of the National Sleep Foundation and the American Board of Sleep Medicine. I have served on the boards of the American Lung Association, the American Academy of Sleep Medicine, the Medical Advisory Board of the Federal Motor Carrier Safety Administration, and the Advisory Board to the National Center on Sleep Disorders Research."

https://ukhealthcare.uky.edu/doctors/barbara-phillips

In other words, this seems like a very credible literature review to me. The conclusion of the section on cancer and hypnotics states:

"To summarize the cancer epidemiology, the available clastogenicity data, animal data, randomized placebo-controlled clinical trials, and human epidemiology studies consistently, if not always conclusively, suggested that hypnotics likely cause human cancers and cancer deaths."

Having read all this now, I am even more firmly in agreement with the very first Talk Page comment on cancer and zolpidem, from back in June:

"But more importantly I am a little bit disturbed, to say the least, that there is no discussion whatsoever about the real, perceived, or potential, carcinogeneticy of this compound. What is going on here? CanisLupisArctus (talk) 00:43, 10 June 2018 (UTC)"

Based on this, I think the way forward would be to quote the Kripke 2017 review article, then mention the meta-analysis, but with some emphasis on the qualifications/limitations of the study that authors state. Declanscottp (talk) 20:53, 18 August 2018 (UTC)

Please read WP:WEIGHT. Jytdog (talk) 21:09, 18 August 2018 (UTC)

I just did. WP:WEIGHT begins by saying:

Neutrality requires that each article or other page in the mainspace fairly represent all significant viewpoints that have been published by reliable sources, in proportion to the prominence of each viewpoint in the published, reliable sources.

From what I can tell, as I described above, on the question of whether zolpidem and similar z-drugs are associated with more cancer, every secondary source that has examined the subject has concluded there is an association between zolpidem use and cancer. So have two meta-analyses and one literature review article. Is there even once secondary source that has examined the question and stated the evidence is against an association between zolpidem (or other z-drugs used as hypnotics) and cancer? Declanscottp (talk) 22:37, 18 August 2018 (UTC)

Correct. So you have to look at all the literature; as Zefr has pointed out; mainstream refs do not discuss this. We have a very tentative finding published in a low quality journal, and an F1000 review by a person self-disclosed as an advocate against this class of drugs. So that means little to no WEIGHT. Right? Jytdog (talk) 23:54, 18 August 2018 (UTC)

He advocates against the drugs because of research he did and because he believes the risk-benefit ratio is generally against their use. In other words, Kripke is motivated by the evidence, not say money or an organisation. Don't forget, the National Institute of Clinical Excellence and official guidelines in the British National Formulary advocate against long-term use of these meds and restrict them to 2-4 weeks use only. Throughout the EU and Australia it is pretty mainstream to advocate against benzodiazepines and Z-drugs, maybe not for cancer, but for other issues such as tolerance, withdrawal, abuse, falls and hip fractures in the elderly, etc. I do not know why the specific issue of cancer has not received more mainstream research and comment, it clearly should. But it has not received any real criticism. No secondary sources exist dimissing the cancer link. If the research was flawed, surely it would have been shot down long ago.--Literaturegeek | T@1k? 00:37, 19 August 2018 (UTC)

What matters is what other sources say, not his motivation or what we think other refs should say. Also "recommend use as a second line treatment, short term =/= "advocate against". Does it? Jytdog (talk) 01:48, 19 August 2018 (UTC) (strike stray single quotemark. Jytdog (talk) 12:52, 19 August 2018 (UTC))

I can’t find your quoted text in the document. Read the first paragraph, in section 1.1 of the NICE guidance.--Literaturegeek | T@1k? 12:30, 19 August 2018 (UTC)

It is not a quote, obviously (I do assume that you are capable of clicking links and reading). That was summarizing paragraph 1.1. I will not respond to further time-wasting comments. Jytdog (talk) 12:45, 19 August 2018 (UTC)

Geeze, don’t be a weirdo getting aggressive over nothing. You put the text in double quotes, so I searched the whole reference looking for it, which took me unnecessary time. Please learn the difference between double and single quotes. You further missed the fact that in my previous comment I said to you NICE recommend/restrict to short-term use and recommend against long-term use. This is why your comment confused me.--Literaturegeek | T@1k? 13:33, 19 August 2018 (UTC)

• Regarding the impact factor, or lack thereof, of the Korean Journal of Family Medicine, could this be explained, jytdog, by the distance and language barrier in the sense that papers in western journals tend not to quote or read journals in foreign languages on the other side of the world? I am certainly no expert on how impact actors are calculated which is why I ask.--Literaturegeek | T@1k? 23:27, 18 August 2018 (UTC)
  • Nope there are several Korean journals in JCI. Jytdog (talk) 23:52, 18 August 2018 (UTC)
  • Here is a listing of journals in the "Family Medicine" catagory. The article in question appears in the jounal ranked ranked 12 out of 36 in the catagory, and it is also the highest rated journal of the 13 listed journals outside of the "Anglosphere." https://www.scimagojr.com/journalrank.php?category=2714 Declanscottp (talk) 01:44, 19 August 2018 (UTC)
    • yep scimago likes OA Jytdog (talk) 01:49, 19 August 2018 (UTC)

Is this a grown up, civil, discussion, or a phallus measuring contest? Genuine question. But more importantly - how does the author disclosing his authorship of publications, which have found negative effects associated with Z drugs, make the peer-reviewed publication lack credibility? If I have published a few articles on the link between cigarette smoking and lung cancer, does that mean that I now have a conflict of interest? Does that mean all consecutive publications authored by me lack credibility and should be entirely dismissed from discourse? That sounds beyond crazy to me...Surely if this line of logic were true, no researcher on the planet could ever publish on the same topic twice without either a) reaching different/opposite conclusions, or b) being dismissed as lacking credibility. I have never once seen this kind of argument used by any scientist, in my lifetime, to attack the credibility of an author, a publication, or its conclusions. Where does this line of thought come from?CanisLupisArctus (talk) 03:23, 28 September 2018 (UTC)

Also - Why has the credibility of the peer-reviewers, of the 2017 publication, been entirely ignored? I do believe there is bias present here...Whether the two sides have some kind of wikipedia rivalry, whether one has a friend that works for the manufacturer, I don't know. But it doesn't look good reading over this talk page. Sound arguments are being hand waved away or completely ignored altogether, and weak counter arguments appear to be taking precedence. I personally have no conflict of interest whatsoever - actually I even take this drug myself from time to time, and have no intention of stopping that. My only interest is open and transparent dissemination of science to healthcare consumers, myself being one of them. I struggle to accept that those arguing against the edit are doing so simply because they believe the above sources to lack credibility - if this is true, the credibility of the 2017 peer-reviewers would not have been outright ignored when brought up earlier. If your arguments are sound, why avoid addressing that? It makes no sense.CanisLupisArctus (talk) 03:23, 28 September 2018 (UTC)

Now can we have the article mentioned in a way that is worded so we can all agree, and put this to rest? There is a lot of more important work to be done and this is a fruitless waste of precious time, for all involved. CanisLupisArctus (talk) 03:23, 28 September 2018 (UTC)

Consensus building

Boghog has pointed out that data from both observational and randomised clinical trial data found evidence of a link to cancer.[1] I think the total number of patients studied is 1.8 million. I think we have to say something. Good counter points have been made that the research is not conclusive and otherwise has limitations and has not yet received more mainstream attention and publication in high impact journals. Surely the best solution is to summarise the evidence concisely but include the core limitations of the evidence/conclusions to avoid POV pushing or any misrepresentation. Thoughts?--Literaturegeek | T@1k? 14:00, 19 August 2018 (UTC)

Looking at all the refs, it would be UNDUE to include the risk of cancer as an actual adverse effect up in the medical section. It would be reasonable to discuss this in a research section, and to give the state of the art there, with all of its tentativeness. Jytdog (talk) 14:14, 19 August 2018 (UTC)

A research section that includes all the caveats definitely sounds like a good solution. Boghog (talk) 16:18, 19 August 2018 (UTC)

done, here. thoughts? Jytdog (talk) 18:33, 19 August 2018 (UTC)

Thanks for adding that. Some of the studies were controlled for confounding factors so I made a small change in the text to reflect that fact. Boghog (talk) 19:50, 19 August 2018 (UTC)

I think "some studies found, some studies didn't find" is wishy-washy and potentially misleading phrasing. 7 of the 8 studies in the meta-analysis found a correlation at the 95% level. (the remaining one looks like it just barely missed it, and it would be 8 for 8 at the 90% level). Why not just say that?

Same with with the "many of the studies failed to control for confounders like cigarette smoking and alcohol use." The meta-anlysis says "five studies adjusted tobacco smoking as a confounding factor, and four studies adjusted alcohol drinking as a confounding factor." Just say "3 of the 8 studies in the meta-analysis failed to adjust for tobacco smoking, which could bias the results either upward or downward depending on whether the hypnotic users smoked tobacco at a higher or lower rate than the control group."

I also think it is important to highlight the zolpidem-specific finding: "With regards to the type of hypnotics, zolpidem use showed the strongest risk of cancer..."

Finally, to the extent this isn't put in the adverse effect section (where I think it belongs, perhaps under a sub-header that identifies it as an area of ongoing research), there should be a internal link to it in that section. There is a lot of concern about the article not stating "Zolpidem causes cancer," but having an adverse effect section with no mention that large numbers of studies find an association between zolpidem and cancer, and a meta-analysis of them also finds a significant association, to me implies, incorrectly, this is not an area of significant concern many scientists are researching.

Do you all really think someone interested in the adverse effects of zolpidem would be more interested in the "diarrhea (1%)," in the second line of the section, but not be interested in a meta-analysis that links it with cancer? By all means, have a balanced presentation of the study, caveated as needed, but when I see in the adverse effects section "the most common side effects of long-term use included dry mouth (3%), allergy (4%), back pain (3%), flu-like symptoms (1%), chest pain (1%)" that says to me "The issue has been carefully studied and adverse effects quantified, and these are the only adverse effects out there." Declanscottp (talk) 03:56, 20 August 2018 (UTC)

Declan, does this edit address one of your main concerns?--Literaturegeek | T@1k? 13:57, 20 August 2018 (UTC)

It is an improvement, but doesn't really get to the central problem: there appear to be in excess of 100 published studies on the adverse effects of zolpidem, including many meta-analyses of them and at least one review article. People looking at "adverse effects" would have no way of knowing this. I think the article overall needs a lot of work, not just on the adverse effects section, and perhaps in a week or two after people have a chance to respond to my longer proposals, I can put in a more extensive revision that further changes can be based off of. Declanscottp (talk) 22:04, 20 August 2018 (UTC)

Declan, this drug actually causes diarrhea (to use the example you gave). We know this is true. Can you really not see the different between that, and a correlation with a bunch of confounders? The first is accepted knowledge; the second is a subject of research. Jytdog (talk) 20:07, 20 August 2018 (UTC)

I disagree the evidence that zolpidem causes diarrhea is stronger than it is for higher rates of falls in the elderly, higher all-cause mortality, higher rates of certain infections and cancers, and higher rate of overdose death. Declanscottp (talk) 22:57, 20 August 2018 (UTC)

Your stance is not supported by the breadth of high quality MEDRS refs. It is not OK to cherry pick refs, especially ones by self-acknowledged advocates, as you did here. That is not how we edit Wikipedia anywhere. Jytdog (talk) 23:13, 20 August 2018 (UTC)

You keep saying that, but then you don't respond to my detailed talk page comments. I am not cherry picking anything, I am citing the only meta-analyses in existence on these topics, as well a high quality review article from 2017. That seems to be as good as it gets on MEDRS.Declanscottp (talk) 23:32, 20 August 2018 (UTC)

If you mean the long section above where you cite a bunch of primary sources, those sources are irrelevant. We rely on MEDRS refs, and we listen to a bunch of them; not just the ones that we like. What MEDRS refs support the overall mortality cancer content? Jytdog (talk) 00:07, 21 August 2018 (UTC) (gah, un-distract Jytdog (talk) 01:45, 21 August 2018 (UTC))

In "that long section above" I argued in favor of including a secondary source, specifically "Zolpidem use and risk of fractures: a systematic review and meta-analysis Park, S.M., Ryu, J., Lee, D.R. et al. Osteoporos Int (2016) 27: 2935." I also described some primary sources to provide additional context and background to the secondary source. Declanscottp (talk) 00:38, 21 August 2018 (UTC)

This discussion is about what to say about cancer. It grew directly out of the section higher in the page, Talk:Zolpidem#Direct_quotation_from_a_meta-analysis_about_Zolpidem_and_cancer_reverted,_I_disagree. Everyone else in this section, is talking about cancer. You stayed on point in your first comment there, although you started to stray at the end; your next comment was completely off topic from cancer, and just above you were completely derailed. PMID 27105645 (the Ryu meta-analysis) says nothing about cancer or mortality; it says that it appears that zolpidem roughly doubles the risk of fracture; generally "139 cases of fracture occur for every 100,000 person-years not receiving zolpidem, and if we assume a 1.92-fold increased risk of fracture due to zolpidem, as determined in this study, an additional 127 cases of fracture can be expected for every 100,000 recipients of these drugs annually (the 1-year number needed to harm = 747)." To address this point. Sure we can add that. To put that in similar proportions to the percentages in the adverse effects section, the percentage of people taking the drug who can expect to have this sequella of impaired coordination is 3%. ((139+127)/100,000). Jytdog (talk) 01:25, 21 August 2018 (UTC)

If you want to talk about side effects generally, please open a new section on that, so we can focus on that. Jytdog (talk) 01:26, 21 August 2018 (UTC)

done Jytdog (talk) 01:29, 21 August 2018 (UTC)

Mortality

• I think we as editors would be negligent and doing a disservice and could cause real life harm to our readers if we were to withhold potentially lethal side effects from this article. I do not support the vague summary of the source as ‘zolpidem can cause death’ that Declan supports. Instead, I think we should summarise the Kripke source as follows: Zolpidem can increase the risk of depression, infection, poor driving, suppressed respiration which can be serious and potentially lethal side effects.[ref Kripke 2016]
• This will have the effect that our readers will have information of life threatening side effects that they can identify and discuss with their family physician. Depression, infection in immune compromised people, poor driving are serious shit side effects, which nobody disputes can result in death. Of course most people do not experience such problems and take the medication without incident but there will always be that small sensitive percentage.
• I don’t care that he has a website warning the public of certain side effects, all that says to me is he has a conscience, compassion, empathy and basically wants to be a doctor - improve people’s well-being. Our articles are full of references to papers written by people receiving financial rewards from pharmaceutical companies, which is a real COI issue but if we were to ban such papers we would lose valuable information.--Literaturegeek | T@1k? 00:45, 21 August 2018 (UTC)

Literaturegeek, I agree with your comment completely. To clarify, I don't think my initial edits adding several secondary sources to the "Adverse" section are the only/best way to mention these articles. I do think they are better than no mention of the articles, which is why I reverted their complete deletion. But your proposal is even better! Declanscottp (talk) 00:50, 21 August 2018 (UTC)

• • Literaturegeek, I care -- and I believe you do as well -- about the integrity of our content. When I select sources, I do so carefully, and try to find ones aiming to provide "accepted knowledge", and I rely primarily on those. I will read obviously conflicted or advocacy-driven ones to keep them in mind and see what they say, and I weight them against mainstream ones. I do this always, but I do that especially on topics where there is strong advocacy (and we very clearly have advocacy here, to add yet more WEIGHT to the adverse effects section, which is already unusually large). Per WP:Controversial articles we should raise source quality and be careful about advocacy-driven sources. As I noted here, it is clear already that there are several increased risks with this drug; the overdose section already makes clear that overdose can lead to death as does the section on interaction with opioids. We will need a much better source that Kripke to tie sequellae of other adverse effects to mortality per se. What other sources support that? Jytdog (talk) 00:56, 21 August 2018 (UTC)
    • There is a scientific consensus that depression, infections, impaired driving can result in death. But I guess you are asking me: do I have a specific high quality source at hand, other than Kripke, that attributes increased mortality specifically to zolpidem, well I am not sure I do and herein lies the problem. I will do some searching. Yes, I know you are a competent editor who does invaluable work here and yes we both care about content and our readers, as does Declan. Yes, I agree Kripke has advocated against the routine use of these drugs.--Literaturegeek | T@1k? 01:15, 21 August 2018 (UTC)
      • That's a kind and reasonable reply. Thanks.Jytdog (talk) 01:34, 21 August 2018 (UTC)
• I've found another review article on zolpidem and mortality. Common Drug Side Effects and Drug-Drug Interactions in Elderly Adults in Primary Care. J Am Geriatr Soc. 2017 Jul;65(7):1578-1585. doi: 10.1111/jgs.14870. Epub 2017 Mar 21.
• Notice the statements 1. Beers criteria states the elderly should not use zolpidem/z-drugs even on a short term basis 2. the harms are "well known" 3. "These agents increase the risk of delirium, falls, fractures, and motor vehicle crashes" 4. "There is relatively strong evidence from multiple studies over the past 30 years suggesting excess mortality with hypnotics"
• The relevant portion is:

Zolpidem

The risks of hypnotics, including benzodiazepine receptor agonists such as zolpidem, in elderly adults are well known, and the Beers criteria recommendation on this class of agents was strengthened in 2015 to recommend avoiding them even for short-term use. These agents increase the risk of delirium, falls, fractures, and motor vehicle crashes and have only a minimal effect on sleep latency and duration.1 New studies have raised concern about risks of dementia and mortality in individuals taking zolpidem, but the evidence is not conclusive. There is relatively strong evidence from multiple studies over the past 30 years suggesting excess mortality with hypnotics, but most of these studies included benzodiazepine receptor agonists and benzodiazepines. 31 Two recent retrospective cohort studies examined the association between benzodiazepine receptor antagonists and mortality, with conflicting results; one study showed greater risk of mortality, and the other showed a potentially dose-responsive protective effect.32,33 A retrospective case–control study of older adults in Taiwan found an association between zolpidem use and two ICD-9 codes for dementia (aOR = 1.33, 95% CI = 1.24–1.41), but the association between zolpidem use and neurologist diagnosed Alzheimer’s disease only held for doses between 170 and 819 mg/yr and not for higher or lower doses.34 The authors do not consider the potential association between zolpidem and dementia to be relevant to clinical decision-making. Nevertheless, given strong evidence of harm, benzodiazepine receptor agonists and benzodiazepines should be avoided in elderly adults. No pharmacological agents are recommended for treatment of insomnia in elderly adults; nonpharmacological treatments such as cognitive behavioral therapy are recommended instead.35

• In my view, I think LG's suggestion of how to cite Kripke is the way to go, and this study should be an additional citation. The reason for this is that Kripke's two review articles are longer and more detailed, and he is a specialist on this exact topic. Declanscottp (talk) 20:52, 21 August 2018 (UTC)
  • This is a powerful statement: "There is relatively strong evidence from multiple studies over the past 30 years suggesting excess mortality with hypnotics".--Literaturegeek | T@1k? 20:57, 21 August 2018 (UTC)
  • That review, PMID 28326532, is focused on older people, and it just repeats what our article already says in the contraindications section about use in older people. We can add it there as another ref. Jytdog (talk) 22:57, 21 August 2018 (UTC)
    • Yes the article as a whole is focused on older people; but the statement I quoted of their opinion of hypnotics causing increased mortality was not a statement focusing on the elderly. You asked if any other author had reached the same conclusion as Kripke in a reliable source and it seems that author agrees with his conclusion. Although, admittedly I do not have the full text and it is possible I am missing something? Have you read the full text Declan?--Literaturegeek | T@1k? 21:25, 22 August 2018 (UTC)
      • I can send it to you if you like -- you can email me at jytdogwiki at gmail (one cannot send attachments through the WP email system); ref 31 is.. Kripke. The key thing here is two studies in older people, which had opposite effects. Because of all that, I did not add increased risk of death when I added this as a ref. Jytdog (talk) 05:00, 23 August 2018 (UTC)
      • I pasted almost everything about zolpidem in the article above. It was just a single long paragraph under a header "Zolpidem". Unfortunately there is no open-access link. Declanscottp (talk) 18:36, 23 August 2018 (UTC)
        • If we cannot find consensus for inclusion of increased mortality in adverse effects, perhaps consensus can be found to include it in the research section?--Literaturegeek | T@1k? 16:57, 23 August 2018 (UTC)
          • I am OK with a single sentence in the Adverse Effects section that links downward to a longer discussion under research. I do not agree that is the best way to present, but as a compromise, sure. This would still not address the fact that several high-quality sources support an association between death, cancer, etc, but just about the first thing you see on the Adverse Effects section is a misleading list of mostly minor side effects, some of which lack biologic plausibility, and which were drawn from a study population that does not even come close to matching the actual population taking the drugs. (mostly young non-co-comorbid volunteers v mostly elderly and long term users). Declanscottp (talk) 18:36, 23 August 2018 (UTC)
            • This thread is about mortality. With regard to this comment -- Please answer this directly and simply -- please cite here the "several high-quality sources" that "support an association between death" and Zolpidem. Jytdog (talk) 19:14, 23 August 2018 (UTC)
              • Kripke's 2017 literature review found "Of 40 epidemiologic studies that provided comparable risk ratios for mortality associated with hypnotics, 39 found that hypnotics were associated with excess mortality." Looking at the titles, all or nearly all deal with benzo-agonists.

   1) Sun, Y., Lin, C. C., Lu, C. J., Hsu, C. Y., and Kao, C. H. Association Between Zolpidem and Suicide: A Nationwide Population-Based Case-Control Study. Mayo Clin Proc. 2016;91(3):308-315.

   2) Lan, T. Y., Zeng, Y. F., Tang, G. J., Kao, H. C., Chiu, H. J., Lan, T. H., and Ho, H. F. The use of hypnotics and mortality - A population-based retrospective cohort study. PLoS One. 10(12), e0145271. 2015.

   3) Palmaro A, Dupouy J, Lapeyre-Mestre M. Benzodiazepines and risk of death: Results from two large cohort studies in France and UK. Eur Neuropsychopharmacol 2015;25(10), 1566-1577.

   4) Chung, W. S., Lai, C. Y., Lin, C. L., and Kao, C. H. Adverse respiratory events associated with hypnotics use in patients of chronic obstructive pulmonary disease: A population-based case-control Study. Medicine (Baltimore) 94(27), e1110. 2015.

   5) Kriegbaum, M., Hendriksen, C. Vass, M., Mortensen, E. L., Osler, M. Hypnotics and mortality—partial confounding by disease, substance abuse and socioeconomic factors? Pharmacoepidemiol Drug Saf 2015;24(7):779-783.

   6) Pinot J, Herr M, Robine JM, Aegerter P, Arvieu JJ, Ankri J. Does the Prescription of Anxiolytic and Hypnotic Drugs Increase Mortality in Older Adults? J Am Geriatr Soc 2015;63(6):1263-5.

   7) Weisberg DF, Gordon KS, Barry DT, Becker WC, Crystal S, Edelman EJ, Gaither J, Gordon AJ, Goulet J, Kerns RD, Moore BA, Tate J, Justice AC, Fiellin DA. Long-term Prescription of Opioids and/or Benzodiazepines and Mortality Among HIV-Infected and Uninfected Patients. J Acquir Immune Defic Syndr 2015;69(2):223-33.

   8) Nakafero G, Sanders RD, Nguyen-Van-Tam JS, Myles PR. Association between benzodiazepine use and exacerbations and mortality in patients with asthma: a matched case-control and survival analysis using the United Kingdom Clinical Practice Research Datalink. Pharmacoepidemiol Drug Saf 2015;24(8):793-802.

   9) Neutel CI, Johansen HL. Association between hypnotics use and increased mortality: causation or confounding? Eur J Clin Pharmacol 2015;71(5):637-42.

   10) Frandsen R, Baandrup L, Kjellberg J, Ibsen R, Jennum P. Increased all-cause mortality with psychotropic medication in Parkinson’s disease and controls: a national register-based study. Parkinsonism Relat Disord 2014;20(11):1124-8.

   11) Weich S, Pearce HL, Croft P, Singh S, Crome I, Bashford J, Frisher M. Effect of anxiolytic and hypnotic drug prescriptions on mortality hazards: retrospective cohort study. BMJ 2014;348:g1996.

   12) Chen H-C, Su T-P, Chou P. A 9-year Follow-up Study of Sleep Patterns and Mortality in Community-Dwelling Older Adults in Taiwan. Sleep 2013;36(8):1187-98.

   13) Gunnell D, Chang SS, Tsai MK, Tsao CK, Wen CP. Sleep and suicide: an analysis of a cohort of 394,000 Taiwanese adults. Soc Psychiatry Psychiatr Epidemiol. 2013 Apr 2;48:1457-65.

   14) Jaussent I, Ancelin ML, Berr C, Peres K, Scali J, Besset A, Ritchie K, Dauvilliers Y. Hypnotics and mortality in an elderly general population: a 12-year prospective study. BMC Med 2013;11(1):212.

   15) Obiora E, Hubbard R, Sanders RD, Myles PR. The impact of benzodiazepines on occurrence of pneumonia and mortality from pneumonia: a nested case-control and survival analysis in a population-based cohort. Thorax 2012;68(2):163-70.

   16) Hartz A, Ross JJ. Cohort study of the association of hypnotic use with mortality in postmenopausal women. BMJ Open 2012;2:pii: e001413. doi: 10.1136/bmjopen-2012-001413.

   17) Kripke DF, Langer RD, Kline LE. Hypnotics’ association with mortality or cancer: a matched cohort study. BMJ Open 2012;2(1):e000850.

   18) Gisev N, Hartikainen S, Chen TF, Korhonen M, Bell JS. Mortality associated with benzodiazepines and benzodiazepine-related drugs among community-dwelling older people in Finland: a population-based retrospective cohort study. Can J Psychiatry 2011;56(6):377-81.

   19) Rod NH, Vahtera J, Westerlund H, Kivimaki M, Zins M, Goldberg M, Lange T. Sleep Disturbances and Cause-Specific Mortality: Results From the GAZEL Cohort Study. Am J Epidemiol 2010;173(3):300-9.

   20) Belleville G. Mortality hazard associated with anxiolytic and hypnotic drug use in the national population health survey. Can J Psychiatry 2010;55(9):558-67.

   21) Mallon L, Broman JE, Hetta J. Is usage of hypnotics associated with mortality? Sleep Med 2009;10(3):279-86.

   22) Winkelmayer WC, Mehta J, Wang PS. Benzodiazepine use and mortality of incident dialysis patients in the United States. Kidney Int 2007;72(11):1388-93.

   23) Hublin C, Partinen M, Koskenvuo M, Kaprio J. Sleep and mortality: a population-based 22-year follow-up study. Sleep 2007;30(10):1245-53.

   24) Hoffmann VP, Dossenbach M, West TM, Lowry AJ. Mortality in a cohort of outpatients with schizophrenia: 3-year outcomes from the Intercontinental Outpatient Health Outcomes Study (IC-SOHO). Biol Psychiatry 61(8S):163S-164S. Accessed 2007.

   25) Hausken AM, Skurtveit S, Tverdal A. Use of anxiolytic or hypnotic drugs and total mortality in a general middle-aged population. Pharmacoepidemiol Drug Saf 2007;16(8):913-8.

   26) Fukuhara S, Green J, Albert J, Mihara H, Pisoni R, Yamazaki S, Akiba T, Akizawa T, Asano Y, Saito A, Port F, Held P, Kurokawa K. Symptoms of depression, prescription of benzodiazepines, and the risk of death in hemodialysis patients in Japan. Kidney Int 2006;70(10):1866-72.

   27) Lack LC, Prior K, Luszcz M. 708. Does insomnia kill the elderly? Sleep 29[Abstract Supplement], A240. Accessed 2006.

   28) Phillips B, Mannino DM. Does insomnia kill? Sleep 2005;28(8):965-71.

   29) Ahmad R, Bath PA. Identification of risk factors for 15-year mortality among community-dwelling older people using Cox regression and a genetic algorithm. J Gerontol A Biol Sci Med Sci 2005;60A:1052-8.

   30) Mallon L, Broman J-E, Hetta J. Sleep complaints predict coronary artery disease mortality in males: a 12-year follow-up study of a middle-aged Swedish population. J Int Med 2002;251:207-16.

   31) Hedner J, Caidahl K, Sjoland H, Karlsson T, Herlitz J. Sleep habits and their association with mortality during 5-year follow-up after coronary artery bypass surgery. Acta Cardiol 2002;57(5):341-8.

   32) Kripke DF, Garfinkel L, Wingard DL, Klauber MR, Marler MR. Mortality associated with sleep duration and insomnia. Arch Gen Psychiatry 2002;59(2):131-6.

   33) Kripke DF, Klauber MR, Wingard DL, Fell RL, Assmus JD, Garfinkel L. Mortality hazard associated with prescription hypnotics. Biol Psychiatry 1998;43(9):687-93.

   34) Merlo J, Ostergren PO, Mansson NO, Hanson BS, Ranstam J, Blennow G, Isacsson SO, Melander A. Mortality in elderly men with low psychosocial coping resources using anxiolytic-hypnotic drugs. Scand J Public Health 2000;28(4):294-7.

   35) Sundquist J, Ekedahl A, Johansson S-E. Sales of tranquillizers, hypnotics/sedatives and antidepressants and their relationship with underprivileged area score and mortality and suicide rates. Eur J Clin Pharmacol 1996;51:105-9.

   36) Hays JC, Blazer DG, Foley DJ. Risk of napping: excessive daytime sleepiness and mortality in an older community population. J Am Geriatr Soc 1996;44:693-8.

   37) Merlo J, Hedblad B, Ogren M, Ranstam J, Ostergren PO, Ekedahl A, Hanson BS, Isacsson SO, Liedholm H, Melander A. Increased risk of ischaemic heart disease mortality in elderly men using anxiolytics-hypnotics and analgesics. Eur J Clin Pharmacol 1996;49:261-5.

   38) Brabbins CJ, Dewey ME, Copeland RM, Davidson IA, McWilliam C, Saunders P, Sharma VK, Sullivan C. Insomnia in the elderly: Prevalence, gender differences and relationships with morbidity and mortality. Int J Ger Psych 1993;8:473-80.

   39) Thorogood M, Cowen P, Mann J, Murphy M, Vessey M. Fatal myocardial infarction and use of psychotropic drugs in young women. Lancet 1992;340:1067-8.

   40) Isacson D, Carsjo K, Bergman U, Blackburn JL. Long-term use of benzodiazepines in a Swedish community: an eight-year follow-up. J Clin Epidemiol 1992 Apr;45(4):429-36.

   41) Rumble R, Morgan K. Hypnotics, sleep, and mortality in elderly people. J Am Geriatr Soc 1992;40:787-91.

   42) Kripke DF, Simons RN, Garfinkel L, Hammond EC. Short and long sleep and sleeping pills: Is increased mortality associated? Arch Gen Psychiatry 1979;36(1):103-16.  — Preceding unsigned comment added by Declanscottp (talk • contribs) 19:40, 28 August 2018 (UTC) 

Yes, this subject matter has received substantial research attention with the large majority of the studies finding benzodiazepines and Z-drugs cause increased mortality. Therefore, we definitely need to summarise a review and include it. We do not as of yet have consensus to include it in the adverse effects section, unless jytdog has reconsidered. What we could find consensus for, perhaps, is adding text summarised from a secondary source and adding it to the research section with a downward link or no downward link. I favour inclusion of a downward link. Jytdog?--Literaturegeek | T@1k? 00:52, 29 August 2018 (UTC)

A pile of primary sources has no value in WP. None. Zero. The fact remains that we have nothing but Kripke approaching a MEDRS ref on this (one, precisely one), and Kripke is Kripke. Jytdog (talk) 01:03, 29 August 2018 (UTC)

I think the point is that Kripke is not misrepresenting the weight of the available scientific evidence contained in primary research in his review. I accept that causation is not proven, but is strongly suggestive which is why I favour including it in the research section for now.--Literaturegeek | T@1k? 21:45, 29 August 2018 (UTC)

LG, I concur with both of your points and your suggestion of research section with a downward link, though as a compromise, not as what I think is best. "Kripke is Kripke"=unwarranted and unsupported ad hominem. Declanscottp (talk) 22:37, 29 August 2018 (UTC)

so the question is, given that a) we have precisely one MEDRS-like source about increased mortality; b) that piece is authored by self-disclosed activist against these drugs, how much WEIGHT do we give his paper? Note his other main headers (after he deals with mortality): "Hypnotics can cause serious and potentially lethal infections", "Hypnotics are associated with increased cancer", "Hypnotics increase incidence of clinical depression", "Automobile crashes, falls, and other accidents are associated with hypnotics", "Safe doses of hypnotics for target populations are unknown", "Contributory factors combined with hypnotics could cause covert deaths" (note the discussion of Scalia'a death, omg), "Hypnotics cause withdrawal insomnia, anxiety, panic, and epilepsy". This is so far out there compared to the rest of literature, and the drug labels (despite his claims about what "the FDA" says.) The journal is a ... dicey as well - see Faculty_of_1000#F1000Research. I am very hesitant here. Jytdog (talk) 02:26, 30 August 2018 (UTC)

A classic WP:REDFLAG case. Weight given should be zero or very little. Alexbrn (talk) 06:06, 30 August 2018 (UTC)

I agree that weight given should be little, which is why I am leaning towards placing the text in the research section.--Literaturegeek | T@1k? 19:57, 30 August 2018 (UTC)

I didn't put "little", but "zero or very little". That would be achieved by omitting it entirely, or maybe just having a link under further reading at most. Any sort of body text would probably be a bit much I think. Alexbrn (talk) 20:18, 30 August 2018 (UTC)

Ok fair enough. I don’t agree with zero body text because multiple mainstream sources have studied this area and almost all of this primary research by multiple experts agrees that this group of drugs increase mortality. Therefore, there is no evidence that Kripke is misrepresenting the scientific evidence in primary sources in his MEDRS secondary source. REDFLAG is more for POV pushing secondary sources that make wild FRINGE and/or pseudoscientific claims that have little underlying support primary or otherwise.--Literaturegeek | T@1k? 20:30, 30 August 2018 (UTC)

FRINGE includes exaggerated claims of efficacy or harm. Again there is one MEDRSish source that makes this global mortality claim. One. Not "multiple". It is not our place to evaluate the primary literature. (I will say, that you seem impressed by the big long list. I encourage you to actually review them, if you are, since this seems to be getting important to you on some level outside the boundaries of what we do here. #40, PMID 1569439, doesn't even mention this drug. I have no idea how many of the others do, nor what they actually say about mortality. Not my job here, and most importantly, not my place here.) Jytdog (talk) 23:34, 30 August 2018 (UTC)

It is a valid point that we do not know for sure - without another MEDRS source(s) by different authors becoming available - whether Kripke has allowed bias to creep into his review. I have reviewed the long list of sources and my thoughts are: yes, some of the sources are not specific to zolpidem but rather GABAergic hypnotics in general and a couple of the sources find no link to hypnotics increasing mortality. Certainly the evidence is not suffice to include the single MEDRS source in the adverse effects section and I now am opposed to including a downward link to the research section because this mortality issue is an important area of ‘active research’, it is not ‘settled science’ so has no business in the adverse effects section of the article. I should say I have never taken the drug zolpidem and I don’t know anyone in my personal life or otherwise who has had their life shortened by zolpidem, so I do not have an axe to grind on this mortality issue. If we can’t find consensus I will just let the subject drop and move onto other articles. I feel this conversation is coming to an end soon as everybody has heard each other’s points of view. And I feel valid points have been made by everybody which is why finding consensus has been and is difficult for this issue. Is there any carefully worded and WEIGHTed text that you could agree to for the research section, jytdog?--Literaturegeek | T@1k? 01:52, 31 August 2018 (UTC)

that is not what i meant, but thanks for the disclosure. i just meant intellectually interested. (fwiw a friend of mine -- a therapist with a PhD - started having emotional trouble and had trouble sleeping as part of that, and her $#@ psychiatrist gave her ambien for a long time, increasing the dose to the max, and now she is all addicted (even drug seeking behavior) and in worse shape. grrr)

I wonder if we should have something about Kripke's public advocacy in the society and culture section. I was looking for sources and found this and this. Wow. Am looking for high quality plain old RS about this. In a brief section on that, we could perhaps mention his claims. Need to think about that...Jytdog (talk) 02:38, 31 August 2018 (UTC)

This?

Daniel F. Kripke, a sleep doctor at University of California San Diego, began studying adverse effects of sleeping pills in 1975, and included zolpidem in those studies after it entered the market. He became known as somewhat of an alarmist with regard to the risks of hypnotics by 2004, and ran a website called "The Dark Side of Sleeping Pills". By 2012 he had become an emiritus professor at UCSD and had published 18 studies, specifically focused on the risks of death. By that time, doctors were prescribing the pills more carefully but his advocacy had not gained wide acceptance.

References

-- something like that? That was quickly done and is walking a fine line there with BLP and MEDRS and all... I will look for yet more and better sources. Jytdog (talk) 03:03, 31 August 2018 (UTC)

Yeah, but why not tag in the findings of his MEDRS review? Since your proposed block of text suggests he is a bit of an alarmist that means our readers can see that he might have a degree of bias in his research and look at it in context.--Literaturegeek | T@1k? 08:53, 31 August 2018 (UTC)

The reason is, that in the context of the proposed content above, his review paper becomes a primary source, and I avoid using them.Jytdog (talk) 19:56, 9 September 2018 (UTC)

Nah, because you can’t use a source dated to 2004 and another to 2012 to debunk a more recent 2016 review article. That would be poor editing. Also, you have not summarised the 2004 source fairly, the New York Times clearly states the person stating that ‘Kripke is about the only person to hold these views’ is a consultant for the pharmaceutical company who manufactures the drugs, but like I say it is too old of a source to discredit a 2016 review paper. The 2012 article, an expert is quoted as saying that Kripke’s research ‘certainly raises a red flag (about possible increased mortality) but it does not prove sleeping pills are the cause,’ but your summary of the source paints Kripke to be a crank with no mainstream support. The reality of course is that many experts have published primary research and the majority reach similar findings as Kripke (that hypnotics are associated with increased mortality, cancer, etc). Really I can’t see consensus forming on this Kripke and mortality issue and wonder should we all just leave this as ‘no concensus’ and wait for another MEDRS source to be published?--Literaturegeek | T@1k? 20:24, 9 September 2018 (UTC)

Racism as a side effect

In 2018, comedian Roseanne Barr faced controversy for tweets that were criticized as being racist. Barr defended her actions by saying that she had made her statement under the influence of Zolpidem. Zolpidem responded by claiming that racism is not a known side effect of this medication. Is this claim notable enough to be included in this article, and if so, is it a medical claim that requires further research? To my knowledge, there is not a clinical study disproving a link between Zolpidem and racism. The FDA approved label of Zolpidem states that patients may suffer "impaired inhibition" (page 3). --Xwedodah (talk) 04:32, 9 November 2021 (UTC)