Talk:Benzodiazepine

/Archive 1

Misuse?

I believe that using the word "misuse" in section 9 constitutes an example of bias in the article. Using the word "misuse" implies that the substance has a "proper" use and an "improper" use. However, people use substances for a variety of reasons, and in order to keep our neutral point of view, we must avoid making such inferences in the article. These are the edits I would like to see on this article, if consensus allows it.

• Renaming section "Benzodiazepine drug misuse" into "Recreational use". This gives no opinion on whether or not this use of benzodiazepines is "proper", which illustrates neutral point of view, and specifies what kind of use is being discussed, rather than a vague reference to a "misuse" of the drug.
• Replacing each use of the word "misuse" by "use", and "misuser" by "user", per above.
• Replacing "amphetamine abusers" by "amphetamine users". At which point do we judge one's use of amphetamines as abuse? This shows bias against recreational users of amphetamines, and that bias could be removed by simply stating "amphetamine users".
• Replacing "drug abusers" by "recreational drug users". What is being discussed here is people using drugs for recreational purposes. Patients with legitimate medical conditions may also abuse the drug by taking too much of it; there is therefore an ambiguity about who we are exactly talking about.
• Replacing "poly-drug misusers" by "poly drug users", per above. In fact, the title of the article in question is Poly drug use, and not "misuse".
• Specifying which "additional health consequences" are induced by using benzodiazepine intranasally rather than with another form of administration.

By fixing those problems of neutrality and ambiguity, I think this article should be one step closer to the BA status. Any comments? Zouavman Le Zouave 10:23, 4 May 2009 (UTC)

Renaming the section to recreational use would be improper because the section is not about recreation use but is about harmful use. The section is not discussing occasional use once or twice a month of few tablets without notable harm to the user or society.

These are a summary of the points made in the misuse section.

• mental health problems and social deterioration
• increased needle sharing
• greater levels of risk and psycho-social dysfunction
• Mortality is higher among poly-drug misusers that also use benzodiazepines
• severe withdrawal symptoms
• medical complications including abscesses, cellulitis, thrombophlebitis, arterial puncture, deep vein thrombosis, hepatitis B and *C, HIV or AIDS, overdose and gangrene
• Problem benzodiazepine use can be associated with drug related crime.

As far as neutrality goes I think misuse is the neutral term because it is what is used by most drug recovery and treatment organisations because many people take offense at the word abuse or else because they say they "didn't realise what they were getting themselves into" etc and other reasons. The word abuse does have bias in it but I disagree that misuse is biased especially when we are talking about a section which is discussing harmful use leading to increased rates of mental health and social problems, blood bourne diseases, gangrene, severe withdrawal symptoms increased rate of death etc. You are correct that many patients will misuse their medications or even lie to their doctors to get drugs. Even sometimes doctors will "misuse" medications to "keep their patients happy" or to "keep them quiet" or out of ignorance of correct use or rarely for personal gain. Infact the crime section actually mentions misuse of prescribed medications by patients. I have changed misuse section which talk about abuse to misuse for neutrality. So I guess my position is that harmful use is not generally the same as recreational use.--Literaturegeek | T@1k? 10:56, 4 May 2009 (UTC)

Let me take an example. Nicotine gum in comparison to cigarette smoking. Nicotine gum is the healthier way to go, yes, but is cigarette smoking a "misuse" of nicotine use? No. Because users are willing to go through the medical complications, including a high risk of cancer, to get the effects of recreational use of nicotine. Here, same deal. People who use benzodiazepine for non-medical purposes generally know it is not healthy, and are often willing to go through those medical complications. It's not a misuse, it's a use by people who estimate the value of the positive aspects of the substance to be more important than that of the negative effects, in the short run and the long run. And as editors of a neutral encyclopedia, we cannot make a judgment on that estimation. Zouavman Le Zouave 05:11, 5 May 2009 (UTC)

Nicotine is referred to as drug misuse/abuse.[1], [2] although here it is referred to as "use" [3]. Nicotine is not very intoxicating so it is not as commonly associated with the term misuse or abuse so it is not a good comparison. As explained above misuse is neutral and a term that people who have problematic drug use habits prefer. What you are wanting to do is to change it to a biased version. Wikipedia works via citations. The vast majority of the literature refers to it as abuse or misuse when talking about harmful or problematic drug use. Do you have a secondary source (eg review article or meta-analysis) which says that generally benzodiazepine misusers know what they are getting themselves into and are willing to accept the risks? From my knowledge on the subject and meeting people I would say with regard to benzos the vast majority didn't fully realise what they were getting themselves into, eg severity of the withdrawal syndrome, length of time to recover, effects on mental health etc.--Literaturegeek | T@1k? 07:10, 5 May 2009 (UTC)

I did a search of pubmed and found the following results.

• A search of pubmed using the term benzodiazepines "non-medical" use brings back only 20 results.
• A search of pubmed using the term benzodiazepines "misuse" brings back 203 results.
• A search of pubmed using the term benzodiazepines "abuse" brings back 1845 results.

The term that you want to use is rarely used in the literature. I think misuse is the neutral and compromising term. If anything it should be abuse based on how often it is used in the literature but for neutrality purposes misuse is prefered.--Literaturegeek | T@1k? 07:41, 5 May 2009 (UTC)

Questionable data from questionable sources

The following sentence in Benzodiazepine#Contraindications is questionable. "Benzodiazepines are also contraindicated in patients with severe liver insufficency, phobic or obsessional states, chronic psychosis, sleep apnoea syndrome.[72]" For example benzodiazepines are indicated for agoraphobia as a second line treatment. The source www.patient.co.uk is also questionable. The page is full of adverts. It is almost a mom-and-pop site. Patient UK is a joint venture between PiP and EMIS. PiP is a partnership between Dr Tim Kenny and Dr Beverley Kenny. EMIS develops, supplies and supports General Practice computing systems.

The following sentence in Benzodiazepine#Contraindications is questionable: "Benzodiazepines should be avoided in patients with depressive mood disorders such as major depression as benzodiazepines often worsen depression and thus may precipitating suicidal tendencies". For example, oxazepam sometimes is used in the first weeks of SSRI treatment to counteract akathisia. The source www.bjcbehavioralhealth.org is also questionable. It is simply a website for a psychiatric practice and not peer reviewed: "BJC Behavioral Health (BJC BH) is an affiliated member of BJC HealthCare offering comprehensive community-based behavioral health services". The Sceptical Chymist (talk) 23:07, 27 May 2009 (UTC)

Benzodiazepines are not indicated for phobic disorders (except for example one off doses eg before going to dentist). You may find a source where the opinion of a individual psychiatrist says benzos can be used second line but it is an opinion. There are probably some doctors who prescribe for agoraphobia as well. They are not licensed and it is not a prescribing indication. Benzodiazepines long term inhibit the learning of new skills. Thus benzos are generally inappropriate for conditions such as bereavement (unless given for the acute shock eg a couple of days or weeks).

Taking benzodiazepines to counteract SSRI side effects is not a licensed indication. The official recommendations that I am aware of eg manufacturer guidelines is to start off at a low dose and gradually titrate it up. You can find sources for use of benzos off label for almost any condition. Actually I remember reading a source of a doctor who believed benzos should be added to the water supply so that everyone could benefit from their effects.

I will try and find better sources anyway to replace those sources. I may have to resort to medical text books though as I think that any of these online sources are going to be challenged.--Literaturegeek | T@1k? 00:22, 28 May 2009 (UTC)

What about this ref?pubmed and full text here. It is a review article so a secondary source.--Literaturegeek | T@1k? 00:29, 28 May 2009 (UTC)

On reflection I agree with you that the sources are not as good as they could be but I disagree that the data is inaccurate.--Literaturegeek | T@1k? 00:30, 28 May 2009 (UTC)

For example, one of the references used in the article states: "In major depression, short-term management of anxiety with benzodiazepines in addition to an antidepressant is frequently used." "Panic disorder, with or without agoraphobia, has been shown to respond to benzodiazepines, but usually at higher doses than those recommended for generalised anxiety disorder." The Sceptical Chymist (talk) 01:31, 28 May 2009 (UTC)

I think that since there are contradictions in the literature that we should go with medical text books such as the British National Formulary and www.uptodate.com for official data. I will work on this tomorrow.--Literaturegeek | T@1k? 01:38, 28 May 2009 (UTC)

Please be careful using uptodate.com. Recently, it was bought by Walters Kluwer and is no longer independent. Their drug articles are mediocre at best. I fail to see any reason for the excitement it generated in medical circles. The Sceptical Chymist (talk) 02:29, 28 May 2009 (UTC)

My connection is slow at present, but I do recall guidelines recommending benzos for agitation in acute exacerbations of schizophrenia, and in manic episodes (which is how we use them), although not long term hopefully. Did we do this already? Casliber (talk · contribs) 04:02, 28 May 2009 (UTC)

Hi Sceptical. Thanks for your work on the article. I think that we are making good progress now. What is wrong with Walters Kluwer? I am not familar with Walters Kluwer. I have used the British National Formulary to replace the refs that were in dispute and also the committee on safety of medicines ref which I added yesterday.

Hi Casliber. Yes this article mentions the use of benzos in acute schizophrenia or mania. They can also be used in cautiously in people with depression who perhaps have severe agitation (eg agitated depression) as alternatives or add-ons to atypical antipsychotics or sedating antidepressants (eg tricyclic antidepressants), correct me if I am wrong though.--Literaturegeek | T@1k? 13:11, 28 May 2009 (UTC)

Looks like the problems with the article have now been resolved.--Literaturegeek | T@1k? 13:13, 28 May 2009 (UTC)

seizures

The section on seizures is inadequate. Individual seizures (what the article calls acute seizures, presumably to distinguish from epilepsy) are not generally treated ("managed" as the article puts it) with medication at all. It is only when a seizure is dangerously prolonged or there is a prolonged cluster of seizures that emergency medication is required. The role of BZ in both emergency and general epilepsy medication should be discussed. There is a role for some BZ's in epilepsy therapy though as you say, tolerance is generally a problem. For example, clobazam is sometimes used long term and is also used during short periods of increased seizure frequency such as in catamenial epilepsy. But mainly they are used for emergency medication. Some of the sources used here are old. Lorazepam is given intravenously and a first-line choice in a hospital setting. You should probably cite some clinical guidelines for this, rather than a meta-analysis, good though that may be. I'm not sure children are "more difficult" than adults here but more likely the issue with children is that parents are unable to give this drug to their children at home. Diazepam is given rectally and is commonly used at home and in hospital. It does not require trained medical personnel but this form of administration is socially embarrassing so there are limits on where it can be used. Buccal midazolam is becoming popular for use by parents and carers and involves a squirt of a tiny amount in the cheek - it is absorbed quickly through the lining of the mouth. Oral administration is simply not quick enough to deal with status epilepticus. You may find some sources for this in Epilepsia; many of their papers are free online. Colin°^Talk 20:36, 28 May 2009 (UTC)

I am not sure what word or term to use in the place of treated or managed. I have changed managed to treated for now. If you have any suggestions feel free to edit the article or suggest here on the talk page. I have added in about buccal midazolam. I have also added a ref about lorazepam being the benzodiazepine of first choice. Your suggestion of guidelines is a good idea. I will check out the National Institute for Clinical Excellence and see if they have produced any national guidelines. Clobazam is an interesting benzodiazepine because it is a 1,5 series benzodiazepine and it binds to selectively or with higher affinity to certain benzodiazepine receptor subtypes, so it may be more appropriate than say 1,4 series benzodiazepines which generally are unselective in their binding profile. Clorazepate (a prodrug) is metabolised into a partial agonist and tolerance is slower to develop. Anyway I am not an expert or particularly knowledgable about epilepsy so great to get some feedback and suggestions from someone more knowledgable than I in this area. Let me know what you think of my latest edits to the seizure section.--Literaturegeek | T@1k? 21:48, 28 May 2009 (UTC)

Literaturegeek, It is hard for me to find time for Wikipedia at the moment -- real life is taking over. I'm no (qualified) expert either and it takes me a while to get hold of good sources. So I'm saying you might be able to fix things quicker than me. I'll try but don't know when I'll get the chance to work on this. Colin°^Talk 13:33, 30 May 2009 (UTC)

I am feeling the same thing, real life taking over but I am determined to get this article to featured article status before I let real life take effect. :) I will see what else I can find, regarding guidelines. I think seizure section is largely finished anyway but perhaps some minor additions can enhance it.--Literaturegeek | T@1k? 19:28, 31 May 2009 (UTC)

I found some national guidelines. I filled in the missing gaps in the seizure section. I think that the seizure section is now complete. I am sure there is a lot more info but that is better covered in the epilepsy article I feel. I think the basics are summarised nowon benzos and seizures and epilepsy.--Literaturegeek | T@1k? 00:15, 1 June 2009 (UTC)

I've had a go a redoing the seizure section. I've based it on the clinical guidelines for England and Wales (NICE) and Scotland (SIGN) as well as an excellent, recent and freely available review on epilepsy drugs introduced during the last 50 years. These three sources cover the relevant facts for an article on benzodiazepines IMO. I've eliminated some details that I didn't consider particularly relevant nor significant. Colin°^Talk 23:00, 2 June 2009 (UTC)

You did a good job, I think that the section is much improved. Thank you for taking the time to redo the section, I can see what you mean about the improvements that were needed. I did make a small change which I felt contradicted the withdrawal section further on down the page (which wouldn't make sense as additional caution is required in epileptics). I think my change is in keeping with the ref.

Ref says for anticonvulsants (which aren't barbs or benzos),,,,, "When AED treatment is being discontinued in a individual who has been seizure free it should be carried out slowly (at least 2-3 months) and one drug should be withdrawn at a time.2

For benzos it says,,,, "Particular care should be taken when withdrawing benzodiazepines and barbiturates (may take up to 6 months or longer) because of the possibility of drug-related withdrawal symptoms and/or seizure recurrence." and barbiturates (may take up to 6 months or longer) because of the possibility of drug-related withdrawal symptoms and/or seizure recurrence."

I hope that this edit is ok.--Literaturegeek | T@1k? 00:52, 3 June 2009 (UTC)

Side effects - evidence needed

Evidence needed that the following side effects are of any significance for benzodiazepines or really happen at all: upset stomach, headache, changes in heart rate, hypotension, dissociation or depersonalisation, chest pain. MEDMOS directs us to avoid laundry lists of side effects. I would rather remove the side effects I listed above unless there is evidence of their significance. The Sceptical Chymist (talk) 19:16, 31 May 2009 (UTC)

The British National Formulary lists them as notable. The hypotension is not all that unusual, infact some doctors use benzos offlabel for certain cardiovascular disorders. All of the side effects are cited. The British National Formulary is a reliable source.--Literaturegeek | T@1k? 19:22, 31 May 2009 (UTC)

There are benzodiazepine receptors in the gut so that would explain benzo GI side effects, headache is a fairly frequent side effect of most drugs. Benzodiazepines effect calcium ion channels which is why they cause hypotension and changes in heart rate. Disociation, feeling spaced or detached is not unusual from sedative hypnotic drugs. They are reliably cited.--Literaturegeek | T@1k? 19:24, 31 May 2009 (UTC)

Meyer's side effects of drugs: "Hypotension follows the intravenous injection of benzodiazepines, but is usually mild and transient(SED-11,92) 56),except in neonates who are particularly sensitive to this effect(57)" - indicates that this side effect is of low significance. If you want to keep it, it has to be qualified as occurring with IV use. No heart rate changes or chest pain is mentioned so I suggest deleting it regardless. The Sceptical Chymist (talk) 20:16, 31 May 2009 (UTC)

The presence of BD receptors in the gut cannot explain the stomach upset :)). As for the gut, BDs do not cause any irritation, to the contrary, they are prescribed for irritable bowel syndrome. The Sceptical Chymist (talk) 20:22, 31 May 2009 (UTC)

Headache is a common side effect of all drugs because the rate of headache rate with placebo is 20-30%. What you need to prove is that for many benzodiazepines the rate of headache is significantly higher than for placebo. Again, Meyer's handbook does not mention it so I believe it is not notable. To the contrary, BDs are sometimes prescribed for tension headache. The Sceptical Chymist (talk) 20:30, 31 May 2009 (UTC)

I am sorry but it is the British National Formulary. Why exactly does the Meyer book trump the British National Formulary? I don't know why you are disputing it. I do agree that hypotension is usually not severe but hypotension is still hypotension. I have met people though who have had this side effect from oral use of benzodiazepines, one lady on a low dose of diazepam 6 mg where it was quite marked. The BNF does not say that it only occurs with IV use. Why do I need additional references to back up the British National Formulary? It is a high quality source. I am not familar with Meyers. The elderly can be quite sensitive to this side effect. Also pplease note that stomach upset can cover a range of symptoms, it can also include nausea for example. I have also met people who experienced nausea on benzodiazepines. Nausea is a common side effect from many drugs. Also please remember that "common" does not mean typical, perhaps you are thinking these side effects are typical and that is why you are disputing them? I am not trying to be annoying, I do appreciate the many good edits you have done over the past number of days to this article.--Literaturegeek | T@1k? 20:43, 31 May 2009 (UTC)

I do not believe that I need additional references to prove the British National Formulary correct as it is a high quality source.--Literaturegeek | T@1k? 20:43, 31 May 2009 (UTC)

Please provide the full citation proving that depersonalization is a notable side effect of BDs. What makes me suspicious in this side effect is that in the 80s there were psychiatrists who successfully treated depersonalization syndrome with BDs. The Sceptical Chymist (talk) 20:34, 31 May 2009 (UTC)

The depersonalisation/disociation side effect is listed as a less common (or occasional) side effect. Antipsychotics typically help agitation but sometimes they can cause agitation especially akasthesia. Antidepressants usually help depression or else don't work for the patient but occasionally they induce or worsen depression. Benzos typically calm a person down but sometimes they make a person agitated or more anxious. It is known as a paradoxical effect.--Literaturegeek | T@1k? 20:43, 31 May 2009 (UTC)

So my point is that the method you are using to try and prove a point is flawed.--Literaturegeek | T@1k? 20:44, 31 May 2009 (UTC)

I do not doubt the validity of British National Formulary. However the formulary presents us with a long and unreadable list of side effects. To make the article readable we have to chose the most notable side effects. WP:MEDMOS also recommends that. I am asking for the additional sources in order to ascertain that the purported side effects are indeed significant and notable. I use Meyer's as a rough guide because it is a comprehensive 5000-pages long handbook on side effects of drugs. It has 14 pages on the side effects of benzodiazepines as a class (in addition to the entries on individual BDs). So if it is not mentioned in Meyer's, in all probability, it is not notable. I am ready to be convinced otherwise with the appropriate citations. Unfortunately, in response you are referring to personal experiences. Please accept my assurances that I am not doubting your dedication and hard work you put into the writing of this article -- I am merely trying to make it palatable for an occasional reader. The Sceptical Chymist (talk) 21:30, 31 May 2009 (UTC)

ADVERSE REACTIONS SIGNIFICANT

>10%:

• Central nervous system: Sedation
• Respiratory: Respiratory depression

1% to 10%:

• Cardiovascular: Hypotension
• Central nervous system: Confusion, dizziness, akathisia, ataxia, headache, depression, disorientation, amnesia
• Dermatologic: Dermatitis, rash
• Gastrointestinal: Weight gain/loss, nausea, changes in appetite
• Neuromuscular & skeletal: Weakness
• Ocular: Visual disturbances
• Respiratory: Nasal congestion, hyperventilation, apnea

I have bolded side effects which are relevant. Amnesia, confusion, disorientation would describe disociation. All of the GI side effects cover stomach upset and there is hypotension as a significant side effect.

The source is uptodate.com which you dispute as a reliable source but I shall look for another source but they must be getting these side effects from a reliable source themselves, i.e., clinical trial data, manufacturer data etc.--Literaturegeek | T@1k? 23:20, 31 May 2009 (UTC)

They are getting their data from reliable sources because they cite their sources.--Literaturegeek | T@1k? 23:42, 31 May 2009 (UTC)

Drug companies are either honest or they minimise side effects, they don't exagerate or make side effects up. So if drug company clinical trial data says that hypotension, stomach upsets etc occur frequently then you can pretty much take it to the bank.--Literaturegeek | T@1k? 23:25, 31 May 2009 (UTC)

I understand that your intentions are noble and that you just want this article to be the best that it can be and I do appreciate the many improvements that you have brought to the article. I understand what WP:MEDMOS says but the side effect list here is not very long in my opinion. :)--Literaturegeek | T@1k? 23:37, 31 May 2009 (UTC)

Still a lot problems with the side effects list:

• Upset stomach. Nausea, weight loss/gain and changes in appetite do not equal upset stomach. In the case of BDs they are caused by their central effects not by upset stomach. Suggest keeping to the references.

• Headache. No proof presented.

• Changes in heart rate. No proof presented.

• Chest pain. No proof presented.

• Dissociation. It is jargon. "Amnesia, confusion, disorientation" are a good description, which lay people would understand. Why not keep to the reference?

In addition, the quotation you presented is from the article Lorazepam in Uptodate.com and some of the side effects may be specific for IV administration or only to lorazepam. I am looking for a description of the class side effects. Ideal source would be a review on BDs from a textbook or from a serious journal (written for specialists not for GPs). I have several textbooks on psychopharmacology in my possession and none of them mentions headache, changes in heart rate and chest pain. (I concede hypotension with IV use as a significant side effect). The Sceptical Chymist (talk) 10:43, 1 June 2009 (UTC)

British National Formulary uses the term upset stomach. I have added the uptodate ref so why not just change upset stomach to nausea and changes in appetite. You state proof needed. So a summary of drug company clinical trial data is not enough and the drug companies are conspiring to smear their own products? Regarding the chest pain and heart rate changes and "no proof". I do not need to "prove" the British National Formulary as being correct. The secondary source review article says disociation and is wiki linked.

Benzodiazepine side effects are largely class effects. Sure some potent benzos may have side effects occur more commonly or less commonly and high doses are more likely to cause side effects but they are the same side effects. My evidence for this is that the British National Formulary says for side effects of benzo anxiolytics "see under diazepam" or hypnotics "see under nitrazepam" without mentioning any drug specific side effects.

Books on psychopharmacology are not package inserts or prescribers books eg like the British National Formulary so may leave out side effects, I dunno man but I really don't feel that I have to "Prove" the British National Formulary" to be correct. I could start referencing dozens of sources but it seems to prove refs correct we will need about 100 refs for the side effect section, 5 refs per side effect.--Literaturegeek | T@1k? 00:01, 2 June 2009 (UTC)

Here is a ref for headache, [4] but I really don't want to get involved in debating and "proving" one word at a time. The talk page is starting to fill up now with disputes which result in little productivity.--Literaturegeek | T@1k? 00:16, 2 June 2009 (UTC)

Ok agree headache is not an important side effect but still disagree about hypotension.

The BNF citation has been deleted from use to cite hypotension and changed to say only with IV use. Roche Pharmaceuticals list this side effect for all of their benzos feeling it is noteworthy to give it its own subheading due to its serious problem in the elderly and those with pre-existing cardiac and cerebral problems.

Quoting from product information leaflet for bromazepam which is a benzo which is not available for intravenous use.

Hypotension

Although hypotension has occurred rarely, LEXOTAN should be administered with caution to patients in whom a drop in blood pressure might lead to cardiac or cerebral complications. This is particularly important in elderly patients. Bromazepam Product information

Even though I believe it is inaccurate I am not going to fight over it but just saying I feel currently it is inaccurate and feel a mention of the words saying "or rarely with oral administration". It is an important albeit rare serious side effect from oral administration.--Literaturegeek | T@1k? 02:11, 13 June 2009 (UTC)

URLs

The citation links should not have "URL=..." if the article is not freely available (see WP:MEDMOS). I've gone over the first third of the citations, checking the links and fixing them or removing them. I'm out of time tonight. Could someone else do the remaining two-thirds. If your PC automatically grants you access to subscribed journals (via cookies, for example) you may need to use a different browser or PC to find out which ones joe-public can read. Colin°^Talk 20:26, 31 May 2009 (UTC)

What WP:MEDMOS said was to add urls if the article is free. If the intention of WP:MEDMOS was to only include URLs if the article is free, I think the guideline should be changed. Providing a DOI or URL to an open access version is certainly preferable, but if an open access version of an article doesn't exist, a link to a version that requires a payment or subscription may still be useful to some people. First of all, in cases where article is not abstracted in PubMed, the links often provide free access to at least an abstract and reading the abstract may be enough to verify that the citation supports the corresponding text in the Wikipedia article. Please keep in mind that the primary purpose of these citations is to support statements made in the Wikipedia article, and second, to provide background information for readers looking for more detailed information. Finally, the link to a for fee site could be useful to students or company employees with institutional access to the journal or possibly even a private individual who is willing to pay the fee.

Of the citations where you have removed URLs, there was usually a DOI. Because both normally point to the same page, having both in the citation is usually redundant. Since DOIs are supposed to be "persistent" whereas URLs may become obsolete, DOI are preferable to URLs. So in these cases, I think the URLs should be deleted, but the DOIs retained. Cheers. Boghog2 (talk) 21:00, 31 May 2009 (UTC)

Lead problems

Please read WP:NOT PAPERS:

A Wikipedia article should not be presented on the assumption that the reader is well versed in the topic's field. Introductory language in the lead and initial sections of the article should be written in plain terms and concepts that can be understood by any literate reader of Wikipedia without any knowledge in the given field before advancing to more detailed explanations of the topic. While wikilinks should be provided for advanced terms and concepts in that field, articles should be written on the assumption that the reader will not follow these links, instead attempting to infer their meaning from the text.

The lay reader will have difficulty with the following terms in the lead: "drug accumulation"; "active metabolites"; "mediated via the modulation of GABA_A receptors"; "CNS". You may find that some subjects (mechanism of action) need to be particularly dumbed down in the lead so as not to put off the reader, and some subjects (perhaps drug accumulation?) might be too technical to be important for the lead.

• The stuff about controversy/major malformations/major teratogens seems too long for the lead and somewhat contradictory. (i.e., it claims there's a controversy but then falls down on one side of the debate).
• The text says "are considered to be" and "are not considered to be" when an encyclopaedia should just say "are" or "are not".
• I'm a bit concerned about the sourcing in the lead. A number of sources appear to be only used for the lead or for a very minor aspect of the body text. This is a warning sign since the lead is meant to summarise the body, which would normally have the same ref. In addition, since the lead is an overview (of what is already a major topic: a class of important drugs), there doesn't seem to be any excuse for citing primary research papers in the lead. Reviews are preferred (see WP:MEDRS) generally and for a subject like this, academic monographs might also provide a good source for much of the lead content. Colin°^Talk 20:51, 31 May 2009 (UTC)

Hmmm, I am not sure how much more simple I can make it. I have made a stab at it and made a few changes which should hopefully address your concerns. I agree that "CNS" and "active metabolites" in isolation may confuse lay people but I think that the way they are structured in sentences are generally self explainatory. However, have a look at my edits here and see if I have helped make it more self explainatory. I feel that the average lay person would know that the central nervous system refers to the brain. Perhaps I am over-enthusiastic of lay people's knowledge. If you have any suggestions pleae feel free to make them or edit the article. It is important that the article is understandable by lay people.

Regarding controversy, the sentence does not actually take a side. Major malformations are not high like say you would see with thalidomide or alcohol during pregnancy, so stating that there is controvery but yet which ever side of the controversy is correct it can be concluded that they are not major teratrogens is not taking sides. There is no controversy over whether benzos are major teratrogens. The controversy is over whether they occasionally cause major malformations or whether they are completely free of any malformations.

I removed the "considered to be" as being unencyclopedic.

I have changed CNS to "central nervous system".

One of the only primary source in the lead is citing a non-controversial factoid about benzos having sedative, hypnotic, amnesic, muscle relaxant etc effects. I couldn't find a secondary source stating this for some reason. I don't see a problem with this as essentially those properties are not a controversial or disputed fact. I could do a synthesis of 3 or 4 reviews I am sure to get all of the properties listed but I think that one primary source is preferable seeing as it is not disputed content.--Literaturegeek | T@1k? 21:27, 31 May 2009 (UTC)

The Lader paper is a review article, infact it is probably the largest and most indepth review of the literature I have ever read. It is pages upon pages long. I got or at least had the full text of that article and read it all. For some reason pubmed does not list it as a review but it is a secondary source, unless I am confused as to what a secondary source is. It is probably one of the most indepth citations cited in this article. The only other primary source is leo sternbach but I think that it is justfied to cite a paper by the creator of benzos as he is so notable but if it is going to get in the way of featured article status or if it is opposed, I can try and find a better citation to replace the leo sternbach citation.--Literaturegeek | T@1k? 21:40, 31 May 2009 (UTC)

On second thoughts, I have removed the reference to accumulation in the lead and active metabolites. It is not necessary to go that much indepth into the pharmacokinetics and I think you have a point that it might be offputting to a lay reader. So I have deleted it.--Literaturegeek | T@1k? 21:43, 31 May 2009 (UTC)

I'll try to find some time tomorrow. The Lader paper is classified as a review on PubMed and is fine, if a bit old and obviously focussing on the elderly, though puzzling why you don't use it in the body if the lead is summarising the body. Colin°^Talk 21:47, 31 May 2009 (UTC)

I was refering to this lader paper, which is very recent. I guess that I could also include it in the body of the article as well. I am not sure which parts you feel are not notable enough to be in the lead. If you mean the malformations, I guess we could delete that bit and just mention the neonatal withdrawal effects or we could replace it with the controversy regarding persisting neurodeficits in children born to mothers taking benzos? I dunno.--Literaturegeek | T@1k? 21:57, 31 May 2009 (UTC)

Oh! Pubmed now class that Lader paper as a review. They didn't used to. :)--Literaturegeek | T@1k? 22:01, 31 May 2009 (UTC)

I have included the lader elderly paper in the elderly section using ref name.--Literaturegeek | T@1k? 22:11, 31 May 2009 (UTC)

The article is I would say at least 95% secondary sources which (I believe) is acceptable for a featured article and the 5% which is not secondary sources is mostly non-controversial stuff.--Literaturegeek | T@1k? 22:51, 31 May 2009 (UTC)

Paradoxical reactions -- clarification needed

Clarification needed for three points:

• paradoxical reactions such as physical aggression, criminal acts, impulsivity, violence and suicide can occur but are considered rare occurring in less than 1% of the general population. No proof for this statement. Several reviews suggest that paradoxical reactions are on the level of 10%. The Sceptical Chymist (talk) 11:10, 1 June 2009 (UTC)

• "paradoxical worsening of EEG readings in patients with seizure disorders.[97]" The reference provided PMID 7403357 states: "In 29 patients (72.5 per cent) the peak potential activity showed a decrease". Explain how this is "worsening of EEG", not, for example, an improvement. The reference does not state "worsening". The paper itself is very old and marginal. The Sceptical Chymist (talk) 11:10, 1 June 2009 (UTC)

• "Paradoxical rage reactions due to benzodiazepines occur as a result of a partial deterioration from consciousness, which generates automatic behaviors, anterograde amnesia and uninhibited aggression. These aggressive reactions may be caused by a disinhibiting serotonergic mechanism.[98]" Looks to me like jargon and poor translation from French in the abstract text of PMID 7618826. What is "partial deterioration from consciousness"? "Automatic behaviors" is jargon. To blame anterograde amnesia for rage reactions is unorthodox and other references advancing the same point are desirable. The involvement of serotoninergic mechanism needs better foundation than speculations taken from a single short abstract.The Sceptical Chymist (talk) 11:10, 1 June 2009 (UTC)

Point 1, Why did you remove the word "severe" from the start of the sentence when quoting here? 10% of people don't get severe paradoxical reactions. If there are reviews stating 10% have paradoxical reactions, why not add on a sentence say up to 10 percent of patients may experience paradoxical reactions which are usually not severe.

Point 2, Why are you not quoting this statement, "and 4 patients (10 per cent) showed an increase." Most people get an anticonvulsant effect from clonazepam but for certain people or seizures it has a paradoxical effect.

Whether people misspelt a word when translating from french to english does not make the review useless. A partial deterioration from conciousness would be where someone is not comatose but they are not fully aware or conscious. Please see this wiki page for automatic behaviors. To be quite honest I am finding it increasingly stressful and time consuming to be debating every last reference and several terms and points in a secondary source especially when disputes are created by quoting out of context my edits or sources. If it is verifiable we don't need to debate and question the findings indepth unless there are serious problems. We will end up with a 1,000 kb talk page in a week's time if we keep doing this.

I have made an edit which I think you had a valid point on regarding the jargon, wiki linked a term and reworded the conciousness part to "altered conciousness level, easier for lay readers to understand now.--Literaturegeek | T@1k? 11:47, 1 June 2009 (UTC)

Tell ya what, seeing as you dispute the paradoxical EEG citation I have removed it and placed it in the paradoxical reactions page. I removed it because it was a primary source. It is better in the paradoxical reactions page as that article is only a stub article and this benzo article is headed for featured article status.--Literaturegeek | T@1k? 12:03, 1 June 2009 (UTC)

In response to "I am finding it increasingly stressful and time consuming to be debating every last reference and several terms and points in a secondary source especially when disputes are created by quoting out of context my edits or sources." - I am sorry that you are frustrated. We have not even gotten to the middle of the article. I decided that I should stop editing it. There have been so many problems in just first three chapters that I have to conclude that the article is nowhere close to the FA level. It is unreadable, has multiple stylistic problems, factual errors and suffers from poor sourcing. The Sceptical Chymist (talk) 23:16, 1 June 2009 (UTC)

That's right 95% secondary sources but it is poorly sourced and The British National Formulary can't be trusted either. I notice that you didn't answer why you cut up my edits here to dispute them and took refs out of context. If you recall we or at least I had problems with Mwalla doing similar things that you are doing,Wikipedia:Sockpuppet investigations/Mwalla/Archive cutting sentences up, taking sources out of context or distorting them and then starting up pointless debates and disputes like what you did above. Also I am involved in an arbcom with a user named scuro who did the same thing. This is why I got "tired and frustrated", because to me it came across that you were intentionally cutting out words of a sentence or misquoting refs in order to start a debate as well as being tired from other editors who did the same (although they had been causing problems for months or years on end). I do not mind productively going over the refs and wording and style. I just do not like playing time wasting games.--Literaturegeek | T@1k? 23:41, 1 June 2009 (UTC)

I have replied to your comments in this section as well.Talk:Benzodiazepine#Side_effects_-_evidence_needed--Literaturegeek | T@1k? 00:09, 2 June 2009 (UTC)

FWIW, I agree with the removal of the paradoxical...EEG bit. Pretty minor point and possibly debatable. Not seen it discussed elsewhere. There is some disagreement about frequency of disinhibition and paradoxical agitation and aggression among health professionals as is. This could be tricky to find a consensus figure on. Casliber (talk · contribs) 04:56, 2 June 2009 (UTC)

The French review article is interesting, but not anything I have seen discussed much elsewhere. FWIW, I am not sure why they looked for a separate pharmacological explanation above that of sedation and disinhibition as to why these events occur but there you go. If contested, I don't think the article loses anything by its removal, but would be interested to see what others think. i.e. although the article is a review, the serotonergic hypothesis is speculative. Casliber (talk · contribs) 05:00, 2 June 2009 (UTC)

Glad to hear you are happy with removal of EEG study. It was a small primary study as well albeit interesting findings. I have removed the French review to shorten the bloated section and placed it in the paradoxical reactions article. I have seen serotonin mentioned before in articles regarding benzodiazepines and adverse effects but agree that it is not widely discussed in relation to benzos. Here are a couple of refs for serotonin and violence.[5], [6] I was contesting the quoting of refs or article edits out of context and then having to engage in frustrating unproductive discussions on the talk page. I don't mind discussing whether their relevance and inclusion or removal is benefitial to the article or not. FWIW, I agree that serotonin and violence/rage from benzos is not proven.--Literaturegeek | T@1k? 10:37, 2 June 2009 (UTC)

Eliminated par from mechanism section

I have eliminated the following par. I leave it here since it could be of use in the future: Some compounds lie somewhere between being full agonists and neutral antagonists and are termed either partial agonists or partial antagonists. There has been interest in partial agonists for the BzR, with evidence that complete tolerance may not occur during chronic use, with continued anxiolytic properties, reduced sedation, dependence and withdrawal problems. My rationale is that the mechanism explanation of the article applies only for full agonists; which according to the ref of the eliminated section are those benzos that are clinically used. For this par to fit the mechanism section would have to be expanded to include mechanism of antagonists benzodiazepines (and then it would probably be too large and specific to reamain in the main article). Bests regards.--Garrondo (talk) 17:28, 9 June 2009 (UTC)

Although I was not bold enough to do it I think that the following par could also be eliminated: As mentioned above, different benzodiazepines can have different affinities for BzRs made up of different collection of subunits. For instance, those with high activity at the α1 (temazepam, triazolam, nitrazepam, etc) are associated with stronger hypnotic effects, whereas those with higher affinity for GABAA receptors containing α2 and/or α3 subunits (diazepam, clonazepam, bromazepam, etc) have good anti-anxiety activity. The first part as it says has already been said; while the second sentence (for instance...) is an example which is problably too specific for the article. Comments?--Garrondo (talk) 17:28, 9 June 2009 (UTC)

I would remove only the phrase "as mentioned above", since what is "mentioned above" is specificity of binding (all or nothing) whereas the paragraph in question concerns moderate binding selectivity. The passage in question is only two sentences long and gives important insight into the subtle variations in pharmacological activity that currently prescribed benzodiazepines may possess. Therefore I think these two sentences should be kept. Boghog2 (talk) 18:17, 9 June 2009 (UTC)

Comments, quite a few benzos are pro drugs or else metabolised into partial agonists. Diazepam, ketazolam, chlordiazepoxide, clorazepate, and many others are metabolized into the partial agonist desmethyldiazepam. There are other benzos which act as partial agonists. Those two sentences are also informative to the reader I feel in helping them to understand the mechanism of action of benzodiazepines. I think that the sentences should be kept.--Literaturegeek | T@1k? 22:57, 9 June 2009 (UTC)

Catalog of sources

After reading Colin's fine comment opposing FA status, I thought I'd try to help out a bit by cataloging all the sources, to try to a handle on Colin's primary criticism about sources. I compiled a catalog of all the sources cited in the current version of the Benzodiazepine article, along with some brief comments about each category of sources. Categories are listed (very roughly) most-reliable first. Within a category, sources are listed in time order, newest first; I listed them this way because more up-to-date sources are typically preferred.

Most of the sources are quite good, but there are some problems. Here's a brief summary of the possibly problematic areas in sources, pointed out in Colin's remarks:

• Many of the cited reviews are pretty old. However, this has been improved lately, and many aspects of benzos are no longer actively researched, so perhaps this is OK.
• 1 primary study is cited, Loxley 2007. However, it's fairly new and in a lightly-reviewed area (criminal behavior), and is briefly and carefully summarized, so this looks OK.

Eubulides (talk) 02:16, 10 June 2009 (UTC) updated 08:53, 11 June 2009 (UTC); 09:52, 12 June 2009 (UTC); 07:36, 14 June 2009 (UTC); 09:46, 15 June 2009 (UTC) 06:33, 18 June 2009 (UTC)

Catalog

• Consensus recommendations and guidelines. These are high-quality consensus documents put out by respectable organizations.

• ACOG 2008 (PMID 18378767)
• Lal et al. 2007
• NICE 2004
• Stokes et al. 2004
• Stokes et al. 2004 (Appendix B)
• Allgulander et al. 2003 (PMID 14767398)
• Scottish Intercollegiate Guidelines Network 2003
• AAP Committee on Drugs 1998 (PMID 9614425)
• Fruchtengarten 1998
• Moss 1998 (doi:10.1351/pac199870010143)
• Committee on Safety of Medicines 1988

• Systematic reviews. These high-quality sources attempt to cover a topic by systematic discovery and summarization of sources. The 1980 review is pretty old, though.

• Orriols et al. 2009 (PMID 19418468)
• Gillies et al. 2005 (PMID 16235313)
• Okoromah & Lesi 2004 (PMID 14974046)
• Committee on the Review of Medicines 1980 (PMID 7388368)

• Meta-analyses. These attempt to answer specific questions by combining results from several reliable sources.

• Rapoport et al. 2009 (PMID 19389334)
• Curtin & Schulz 2004 (PMID 15013244)
• Dolovich et al. 1998 (PMID 9748174)

• Narrative reviews in biomedical or psychiatric journals. These are summaries of a topic by experts in the field, using the best available sources at the time. Older reviews may be somewhat dated. 19 of these reviews are more than a decade old; can some of these be trimmed?

• Charlson et al. 2009 (PMID 19125401)
• Cloos & Ferreira 2009 (PMID 19122540)
• Lader et al. 2009 (PMID 19062773)
• Lader 2008 (PMID 18671662)
• Olkkola & Ahonen 2008 (PMID 18175099)
• Zimbroff 2008 (PMID 18278976)
• ElDesoky 2007 (PMID 17890940)
• Jufe 2007 (PMID 18265473)
• Kintz 2007 (PMID 17340077)
• Lemmer 2007 (PMID 17049955)
• Perugi et al. 2007 (PMID 17696574)
• Bain 2006 (PMID 16860264)
• Ebell 2006 (PMID 16623205)
• Espay & Chen 2006 (PMID 16969837)
• Nardi & Perna 2006 (PMID 16528135)
• Narimatsu et al. 2006 (PMID 16780077) [in Japanese]
• Rudolph & Möhler 2006 (PMID 16376150)
• Wang et al. 2006 (PMID 17074284)
• Allain et al. 2005 (PMID 16156679)
• Ashton 2005 (PMID 16639148)
• Hulse et al. 2005 (PMID 16240487)
• Stevens & Pollack 2005 (PMID 15762816)
• Stewart 2005 (PMID 15762814)
• Verdoux et al. 2005 (PMID 15841867)
• Bogunovic & Greenfield 2004 (PMID 15001721)
• DTB 2004 (PMID 15587763)
• Faught 2004 (PMID 16400293)
• Murinson 2004 (PMID 15140273)
• Seger 2004 (PMID 15214628)
• Wafford et al. 2004 (PMID 15157182)
• Ashton & Young 2003 (PMID 12870563)
• Snowden et al. 2003 (PMID 12919245)
• Arvat et al. 2002 (PMID 12240908)
• Iqbal et al. 2002 (PMID 11773648)
• Paton 2002 (doi:10.1192/pb.26.12.460)
• Longo & Johnson 2000 (PMID 10779253)
• Lader 1999 (PMID 10622686)
• Kraemer et al. 1999 (PMID 10408740)
• Noble et al. 1999 (PMID 10581329)
• Prater et al. 1999 (PMID 10507746)
• White & Irvine 1999 (PMID 10707430)
• Bond 1998 doi:10.2165/00023210-199809010-00005
• Fraser 1998 (PMID 9780123)
• Hevers & Lüddens 1998 (PMID 9824848)
• Gerada & Ashworth 1997 (PMID 9274553)
• Norman et al. 1997 (PMID 9397065)
• Zavala 1997 (PMID 9504140)
• Zisterer & Williams 1997 (PMID 9378234)
• Johnston 1996 (PMID 8783370)
• Peppers 1996 (PMID 8700792)
• Podell 1996 (PMID 8813750)
• Pétursson 1994 (PMID 7841856)
• King 1992 (PMID 1389432)
• Spivey 1992 (PMID 1611650)
• Ashton 1991 (PMID 1675688)
• Gaudreault et al. 1991 (PMID 1888441)
• Klein-Schwartz & Oderda 1991 (PMID 1794007)
• Miller & Gold 1990 (PMID 1971487)
• Tesar 1990 (PMID 1970816)
• Frey 1989 (PMID 2520134)

• Narrative reviews published in other journals. This looks reliable.

• Drummer 2002

• Biomedical textbooks. All quite-good sources, though reviews might be a bit better if a more-recent one is on the same point. Two of them (marked below) are older editions of books where newer editions have been published.

• BNF 2009 (ISBN 978-0853698456)
• Dikeos et al. 2008 (ISBN 0-415-43818-7)
• Harrison et al. 2006 (ISBN 0-19-856667-0)
• Lieberman & Tasman 2006 (ISBN 0-470-02821-1)
• Meyler & Aronson JK (eds.) 2006 (ISBN 0-444-50998-4)
• Olsen & Betz 2006 (ISBN 0-12-088397-X)
• Roach & Ford 2006 (ISBN 978-0-7817-7595-3)
• McIntosh et al. 2005 (ISBN 0-19-852783-7) (a newer edition is available, and should be used if possible)
• Merck Vet Manual 2005
• Shorter 2005 (ISBN 0-19-517668-5)
• Wyatt et al. 2005 (ISBN 978-0198526230)
• Chouinard 2004 (PMID 15078112)
• Mozayani & Raymon 2004 (ISBN 1-58829-211-8)
• Longmore et al. 2003 (ISBN 0-19-852518-4) (a newer edition is available, and should be used if possible)
• Ashton 2002 and Ashton 2007
• Goldfrank 2002 (ISBN 0-07-136001-8)
• Page et al. 2002 (ISBN 978-0723432210)
• Gross 2001 (ISBN 0-8138-1743-9)
• Kaplan & Sadock 2000 (ISBN 0-683-30128-4)

• Biomedical websites. Looks OK.

• Green et al. 2008
• Benzodiazepines – oral 2005

• Government-maintained websites. Authoritative for their points. However, the 2nd source is all that is needed to support the claim that midazolam and temazepam are Schedule III in the UK, so the 1st source can be removed.

• Randall 2009
• List of Drugs Currently Controlled Under The Misuse of Drugs Legislation 2009-01-28

• History articles. These look good.

• Shorvon 2009 (PMID 19298435)
• Sternbach 1979 (PMID 34039)

• Summary websites. These look fine too.

• The complete story of the benzodiazepines 2005
• Benzodiazepines advanced consumer information 2005-02-24

• Primary studies. Primary studies are problematic, as per WP:MEDRS. Any primary study older than about five years old is particularly dubious: if it's that old, and its point can't be supported by a reliable review instead, then something is amiss. However, this study is newer, and in a lightly reviewed area, and is carefully summarized.

• Loxley 2007

• Testimony. This one is fine, for the legal point it supports.

• Peart 1999-06-01

Hope this helps. Eubulides (talk) 02:16, 10 June 2009 (UTC) updated 08:53, 11 June 2009 (UTC); 09:52, 12 June 2009 (UTC); 07:36, 14 June 2009 (UTC); 09:46, 15 June 2009 (UTC) 06:33, 18 June 2009 (UTC)

Catalog comments

Great job, thanks for going through the refs. My only comment and disagreement is that you seem to class meta-analysis's as primary studies. For example Curtin & Schulz 2004 (PMID 15013244) you have listed as a primary source. Meta-analysis's are secondary sources. Perhaps you didn't read the abstract and didn't realise that it was a meta-analysis.

I have removed several primary sources and will continue to do so. As discussed on FA review pages there may be certain aspects where newer or even old secondary sources are not available for certain content but shall try my (our) best. Thank you so much for taking your time to do this list. It is immensely helpful to further improving the article.--Literaturegeek | T@1k? 11:49, 10 June 2009 (UTC)

Another example, you have listed Dolovich et al. 1998 (PMID 9748174) which is a meta-analysis as a primary source. A meta-analysis is a secondary source.--Literaturegeek | T@1k? 11:56, 10 June 2009 (UTC)

Ok, I have went through all of the primary sources that you listed and deleted about half of them. Many were not necessary. The remaining ones I cannot find secondary sources. Some aspects of benzos do not undergo reviews or meta-analysis. In most cases the content is not contenscious but are merely factoids eg molecular structure of benzos or something like that which is not something which is going to be disputed in the foreseeable future if ever, so don't see a problem with such references being used. Again thank you so much for doing this list. It has enabled myself to go over critically all of the primary sources and do a good pruning of them.--Literaturegeek | T@1k? 12:31, 10 June 2009 (UTC)

Thanks for doing that. I revised the list above to take into account the recent changes to the article, and to correct the two miscategorizations you noted above. The two remaining problematic areas are the 7 citations of primary studies, and the 30 citations to reviews more than a decade old. Some of these citations no doubt should be kept, but it'd be nice to trim in this area. To help things get started, I looked at the 1st two some of the primary studies listed above; please see #Loxley 2007 and #Buckley et al. 1995 below. Eubulides (talk) 08:53, 11 June 2009 (UTC)

I've trimmed it down to 1 primary study, which looks keepable. We still cite too many old, old reviews; can we get rid of some of those? 1981 is wayyy old in this field. Eubulides (talk) 09:52, 12 June 2009 (UTC)

Ok, most of the 1980's refs have been replaced by myself. I have also trimmed down the 1990's refs. I really think that we have a very uptodate article now and think that the remaining refs in the article are necessary baring in mind some aspects are not repeatedly reviewed or else are not subject to change and are not controversial eg for example molecular structure of benzos etc. I am hoping that you are able to "support" this article going to featured article status now. I feel that it is actually above the standard of many articles which have already been made FA status. :)--Literaturegeek | T@1k? 14:49, 14 June 2009 (UTC)

Thanks for trimming the references. From my point of view I am trying to address Colin's remarks. The primary-study part of it has been fixed. Most of the reviews are now from the last 10 years, which perhaps is good enough. Eubulides (talk) 09:46, 15 June 2009 (UTC)

Loxley 2007

Loxley 2007 is currently given a lot of weight in the article; nearly 260 words, and nearly an entire subsection to itself (Benzodiazepine #Drug-related crime). That's pretty heavy weight for one primary study, particularly for a 2007 study which Google Scholar says no scholarly source has cited. Surely this should be trimmed down, or perhaps even eliminated. Eubulides (talk) 08:53, 11 June 2009 (UTC)

This was fixed by trimming and by carefully summarizing the study.[7][8] The study is relatively recent and is in a lightly reviewed area, so I hope this is OK. Eubulides (talk) 09:52, 12 June 2009 (UTC)

Looks good to me. :)--Literaturegeek | T@1k? 14:59, 14 June 2009 (UTC)

Buckley et al. 1995

Buckley et al. 1995 (PMID 7866122) is used to support a claim that temazepam is the most toxic in overdose. But this primary study is obsolete, and was essentially refuted by Isbister et al. 2004 (PMID 15206998), who showed that alprazolam is the most toxic. (Buckley et al. did not look at alprazolam.) The article shouldn't be citing either of these primary sources; instead, it should cite a recent reliable review or textbook on the subject. Here's one possibility; it's not exactly the nicest source (the publisher's web site is messed up, and incorrectly claims that the article was published in The Journal of Family Practice!), but it is on point:

• Ramadan MI, Werder SF, Preskorn SH (2006). "Protect against drug–drug interactions with anxiolytics". Curr Psychiatr. 5 (5): 16–28.{{cite journal}}: CS1 maint: multiple names: authors list (link)

Another possibility, if you have ready access to it (I don't; all I see are tantalizing hints in Google Books), is:

• Dikeos D, Theleritis CG, Soldatos CR (2008). "Benzodiazepines: an overview". In Pandi-Perumal SR, Verster JC, Monti JM, Lader M, Langer SZ (eds.) (ed.). Sleep Disorders: Diagnosis and Therapeutics. Informa Healthcare. pp. 96–104. ISBN 0-415-43818-7. {{cite book}}: |editor= has generic name (help)CS1 maint: multiple names: authors list (link)

Eubulides (talk) 08:53, 11 June 2009 (UTC)

I fixed this by substituting Ramadan et al. and rewriting to match the new source.[9] Eubulides (talk) 09:52, 12 June 2009 (UTC)

I wouldn't say it was refuted because the buckley ref was assessing stats in the UK where alprazolam is not available on the National Health Service but anyway in Australia temazepam is available as is alprazolam so it does show that alprazolam is significantly more toxic in overdose than temazepam (probably because alprazolam is a high potency benzodiazepine). I think that your changes are a great improvement and accurate just pointing out alprazolam is not available in on NHS in the UK.--Literaturegeek | T@1k? 14:59, 14 June 2009 (UTC)

Other primary studies

I removed other primary sources, partly by replacing them with reviews,[10][11], and partly by removing duplicative sources.[12]. The only remaining primary source is #Loxley 2007, noted above. Is it time to trim some of the older reviews now? Eubulides (talk) 09:52, 12 June 2009 (UTC)

Good job, looks like good improvements to me. Thank you for all of you hard work. It is very much appreciated. I am wondering if you are ready to support the article going to FA status. I feel that the main problems raised by yourself and Colin and other editors and reviewers have been resolved satisfactorily. :)--Literaturegeek | T@1k? 14:59, 14 June 2009 (UTC)

I think we have addressed most of (and perhaps enough of) Colin's objection to citing. However, there is still Tony's (and Colin's) objections based on prose quality. I have been focusing on citations so far, but have not yet looked at prose. Has anyone else? I don't see followups about this under either Tony's or Colin's objections. Somebody needs to do a 1st-class copy-editing pass at some point, once the citing stuff has settled down; Colin and Tony are both better at that than I am. Eubulides (talk) 09:46, 15 June 2009 (UTC)

I made changes to prose like refs are now cited in the body as well as the lead which was Colin's main objection. FV also made a couple of suggestions for the lead which I made so I think and hope that I have resolved the problems raised with the lead.--Literaturegeek | T@1k? 12:45, 15 June 2009 (UTC)

Recent reviews that may be worth citing

There's a plethora of recent reviews on benzodiazepines, and as per WP:MEDRS it would be helpful to have the article cite them in preference to primary studies. To try to help with this, I did a search for benzodiazepine reviews that Benzodiazepine does not curretly cite, and found the following. This list focuses on relatively recent (5 years old or less) reviews, emphasizing reviews that are freely readable. It's not a complete list, but I hope it can be helpful anyway.

• Lonergan E, Luxenberg J, Areosa Sastre A, Wyller TB (2009). "Benzodiazepines for delirium". Cochrane Database Syst Rev (1): CD006379. doi:10.1002/14651858.CD006379.pub. PMID 19160280.{{cite journal}}: CS1 maint: multiple names: authors list (link)
• Parr JM, Kavanagh DJ, Cahill L, Mitchell G, McD Young R (2009). "Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis". Addiction. 104 (1): 13–24. doi:10.1111/j.1360-0443.2008.02364.x. PMID 18983627.{{cite journal}}: CS1 maint: multiple names: authors list (link)
• Watanabe N, Churchill R, Furukawa TA (2009). "Combined psychotherapy plus benzodiazepines for panic disorder". Cochrane Database Syst Rev (1): CD005335. doi:10.1002/14651858.CD005335.pub2. PMID 19160253.{{cite journal}}: CS1 maint: multiple names: authors list (link)
• Gibson RC, Walcott G (2008). "Benzodiazepines for catatonia in people with schizophrenia and other serious mental illnesses". Cochrane Database Syst Rev (4): CD006570. doi:10.1002/14651858.CD006570.pub2. PMID 18843722.
• Watanabe N, Churchill R, Furukawa TA (2007). "Combination of psychotherapy and benzodiazepines versus either therapy alone for panic disorder: a systematic review". BMC Psychiatry. 7: 18. doi:10.1186/1471-244X-7-18. PMC 1894782. PMID 17501985.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
• Rosenbaum JF (2005). "Attitudes toward benzodiazepines over the years" (PDF). J Clin Psychiatry. 66 (Suppl 2): 4–8. PMID 15762813.
• Stewart SA (2005). "The effects of benzodiazepines on cognition" (PDF). J Clin Psychiatry. 66 (Suppl 2): 9–13. PMID 15762814.
• Roy-Byrne PP (2005). "The GABA-benzodiazepine receptor complex: structure, function, and role in anxiety" (PDF). J Clin Psychiatry. 66 (Suppl 2): 14–20. PMID 15762815.
• Stevens JC, Pollack MH (2005). "Benzodiazepines in clinical practice: consideration of their long-term use and alternative agents" (PDF). J Clin Psychiatry. 66 (Suppl 2): 21–7. PMID 15762816.
• O'Brien CP (2005). "Benzodiazepine use, abuse, and dependence" (PDF). J Clin Psychiatry. 66 (Suppl 2): 28–33. PMID 15762817.
• Otto MW, Bruce SE, Deckersbach T (2005). "Benzodiazepine use, cognitive impairment, and cognitive-behavioral therapy for anxiety disorders: issues in the treatment of a patient in need" (PDF). J Clin Psychiatry. 66 (Suppl 2): 34–8. PMID 15762818.{{cite journal}}: CS1 maint: multiple names: authors list (link)
• Stewart SA, Rosenbaum JF, Pollack MH, Roy-Byrne PP, O'Brien CP, Otto MW (2005). "Discussion: using benzodiazepines in clinical practice" (PDF). J Clin Psychiatry. 66 (Suppl 2): 39–45. PMID 15762819.{{cite journal}}: CS1 maint: multiple names: authors list (link)
• Rosenbaum JF (2004). "The development of clonazepam as a psychotropic: the Massachusetts General Hospital experience" (PDF). J Clin Psychiatry. 65 (Suppl 5): 3–6. PMID 15078111.
• Chouinard G (2004). "Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound" (PDF). J Clin Psychiatry. 65 (Suppl 5): 7–12. PMID 15078112.
• Moroz G (2004). "High-potency benzodiazepines: recent clinical results" (PDF). J Clin Psychiatry. 65 (Suppl 5): 13–8. PMID 15078113.
• Davidson JR (2004). "Use of benzodiazepines in social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder" (PDF). J Clin Psychiatry. 65 (Suppl 5): 29–33. PMID 15078116.

The following reviews are not specific to benzodiazepines, but are recent and do discuss them, and may be helpful if we don't find a more on-point review:

• Tiwari AK, Souza RP, Müller DJ (2009). "Pharmacogenetics of anxiolytic drugs". J Neural Transm. doi:10.1007/s00702-009-0229-6. PMID 19434367.{{cite journal}}: CS1 maint: multiple names: authors list (link)
• Orriols L, Salmi LR, Philip P; et al. (2009). "The impact of medicinal drugs on traffic safety: a systematic review of epidemiological studies". Pharmacoepidemiol Drug Saf. doi:10.1002/pds.1763. PMID 19418468. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)

Eubulides (talk) 07:28, 10 June 2009 (UTC)

I do not think removing older reviews is necessary, and it actually may be harmful. They are mostly needed to represent older studies, while newer reviews concentrate on newer studies. The quality of double-blind trials have mostly stayed the same whether they were conducted in the 60-s or in the 00-s. To the contrary, it may be argued that nowadays their quality is worse because of the rampant conflict of interest and the advent of contract research organizations. Another problem is that a conclusion from the older review often gets mindlessly repeated in the later reviews and, eventually, becomes distorted. For example, "less than 1% and similar to placebo" frequency of paradoxical reactions from 1988 review becomes solid "1%" without comparison with placebo in the 2008 review. The Sceptical Chymist (talk) 10:13, 12 June 2009 (UTC)

Even if the research on benzos hasn't moved on, other drugs have arrived and health prescribing practices change. For example, the use of midazolam for community seizure control is relatively new and wouldn't be mentioned at all in an old review. If the article says "are used for" then any reader would have good reason to query a 30-year-old paper as the source, no matter how great that paper was. Sure, we can cite an old review to say "XYZ reduces anxiety by blah blah blah mechanism" but if we are making statements about current clinical usage then we need current sources. And we need to avoid the vague "can be used for" without indicating whether it actually is still used for ... or under what circumstances it is considered for ... . Colin°^Talk 15:16, 12 June 2009 (UTC)

Can't disagree with that. The Sceptical Chymist (talk) 10:30, 13 June 2009 (UTC)

Agree with Colin but also agree with Sceptical. Colin is totally right in his example of clinical uses of benzos needing to be reffed to recent sources. I think Sceptical is right in that we don't need to have almost every ref within the last 5 years especially if it leads to a deterioration in the quality of the article. Most of the reviews above are not useful or are too narrow in their review. For example many simply state there is not enough evidence to conclude that benzos are effective in this or that. I don't think that this article should cover lots of possible scenarios that benzos are not effective in or evidence is weak unless it is notable. Narrow focus for example one review discusses benzos in delirium. It says little evidence for benzos in delirium not caused by alcohol withdrawal. True but alcohol withdrawal is already covered in the article anyway. Delerium due to acute benzodiazepine withdrawal is also alleviated by recommensement of benzos typically. Also the review article is narrow in that it doesn't talk about benzos being a frequent cause of delirium in the elderly.

The reality. Benzos for alcohol withdrawal or benzo withdrawal are effective. Benzos for other forms of delirium, not effective and often cause or worsen other causes of delirium but this kind of info is really more relevant to the delirium wikipedia article.

I honestly think that this article is one of the best documents on benzodiazepines. It is more informative, comprehensive and diverse in subject matters than any review article that I have read. I think that the improvements made over the past number of weeks have been immense and it is time now to support FA status. :)--Literaturegeek | T@1k? 16:11, 14 June 2009 (UTC)

I think it's right up there as well. I'm trying to help to make it better, to overcome any objections. I agree that many of the reviews are too narrow. However, I'm not sure I agree as to negative results. Benzos have been prescribed for many situations for which there is insufficient scientific evidence to provide recommendations. Where these situations are significant enough so that someone has written a Cochrane review about them, isn't it reasonable to briefly say something about them? E.g., "There is insufficient evidence to recommend benzos for conditions A, B, and C." and cite the Cochrane review (or whatever) for each such condition? Or (preferably) perhaps there's some overall summary of negative results that we could cite. Negative results are often notable results, after all. Eubulides (talk) 09:46, 15 June 2009 (UTC)

I think that it is an issue of notability so depends on notability. I just want to avoid article deteriorating with a long list of benzos don't work for xyz or evidence is weak.--Literaturegeek | T@1k? 12:44, 15 June 2009 (UTC)

Misuse revisited

I have been taking a look at the misuse section. As already commented in the FAC there is a very long par with only a primary source (a survey) for it as a reference. (In a survey of police detainees carried out by the Australian Government (...) The main problems highlighted in this survey were concerns of dependence, the potential for overdose of benzodiazepines in combination with opiates and the health problems associated with injection of benzodiazepines) Per WP:Weight unless a secondary source is found I feel that all this paragraph should be reduced to a single small sentence: too much importance is given to a single study. My proposal would be to simply add the ref for the first sentence (Problem benzodiazepine use can be associated with drug-related crime) and eliminate all the other sentences of the par. Additionally these could lead the reorganize the misuse section since it would leave two very small subsections that could be combined eliminating third level subsections. Bests.--Garrondo (talk) 10:35, 11 June 2009 (UTC)

Go for it. The Sceptical Chymist (talk) 10:39, 11 June 2009 (UTC)

Alrighty I have been convinced, it needs shortening. :) I reduced to two sentences. I have an article here with other reports on drug related crime, reduced violence when benzo prescribing was banned in prison populations etc etc but unfortunately from what I can tell they are primary sources. I wish someone would do a review on this aspect of benzos. Let me know what you think of my edits to the crime section (which I have now merged with the drug misuse section).--Literaturegeek | T@1k? 11:40, 11 June 2009 (UTC)

This is hard work getting an article to featured article status but worth it I am sure. :)--Literaturegeek | T@1k? 11:42, 11 June 2009 (UTC)

I read that primary study and (with a copy-editing assist from Garrondo) modified the two sentences to summarize the source with more details and accuracy. It's now down to one sentence. Eubulides (talk) 10:01, 12 June 2009 (UTC)

Looks good to me. :)--Literaturegeek | T@1k? 23:17, 12 June 2009 (UTC)

Body should cite every source that the lead does

I just now edited the lead so as to move the contents of its citations to the body, leaving only the ref name= stuff in the lead. This is to start to fix a problem noted by Colin in the FAC, namely that the lead cites sources that the body does not. As per WP:LEAD, the lead should summarize the body; but if the lead cites sources that the body does not cite, this suggests that the lead is not faithfully summarizing the body, and is relying on independent sources. It's good style to use only <ref name=FOO/> in the lead, with the definition of reference FOO in the body, where the body cites the same source; this serves as a useful reminder to editors that the lead shouldn't cite sources that the body doesn't. Eubulides (talk) 03:45, 13 June 2009 (UTC)

Fully agree with this and the suggested practice. But just to be clear: there isn't a policy/guideline on WP that I'm aware of that says the lead must cite the same sources as the body. Indeed, some quality articles have few or no citations in the lead and there it is assumed that the lead is an exact summary of the body text (effectively, the body is the source for the lead). IMO that style makes it harder to verify the lead and may cause potential newbie contributors to think that unsourced additions are OK (most newbies try to add their "vital" facts to the lead). Colin°^Talk 10:57, 13 June 2009 (UTC)

Agree with Colin here. I see different preferences with regards to refs in the lead, and each of those preferences is defensible. For a mature article like this, I think it's a good idea to only include the most general refs in the lead, the sort which will be cited several times during the article. It makes the lead a handy place to find them and it means they appear at the top of the reference list at the end of the article. Looking at the lead now, I don't think it would hurt to lose a few references, especially where there are multiple refs for the same fact: such long lists of superscript numbers are often necessary in the article text, but they seem a bit much for the first view of the page. The article needs a copy-check to ensure that the superscript numbers appear in the right order: I'd do it myself (I've spotted one case), but there's a minor point about the chemistry I'd like to fix as well! Physchim62 (talk) 15:27, 13 June 2009 (UTC)

I have resolved this issue. The citations used in the lead are also used in the body of the article now.--Literaturegeek | T@1k? 00:06, 14 June 2009 (UTC)

Lead questions

Benzodiazepines are often taken in overdoses, but because they are much less toxic than their predecessors the barbiturates, overdoses rarely are fatal.^[16] When they are combined with other central nervous system depressants such as alcohol or opiates, however, the potential for overdose greatly increases. This is particularly problematic in the drug misusing community.^[17][18]

a) The improved safety profile of benzodiazepines is already mentioned in the second paragraph of the lead. Should we imply causality here—benzo overdose is rarely fatal because they are less toxic than barbiturates? b) Strictly speaking, the "potential for overdose" doesn't increase with concomitant use of central nervous system depressants (unless you're considering that, e.g, someone is more likely to take a toxic dose when they're drunk, which is original research territory). What increases is the toxicity—the potential for morbidity and mortality. Fvasconcellos (t·c) 16:27, 13 June 2009 (UTC)

It's not infrequent for people to attempt suicide by taking a massive overdose of sleeping pills, not realizing that it is almost impossible to kill yourself by OD'ing on benzodiazepines. A notable case is Bud McFarlane, one of Ronald Reagan's advisors, who after the Iran-Contra affair tried to kill himself by taking a huge quantity of Valium, and only ended up sleeping for a couple of days. Another route to overdose is for people to take a sleeping pill, forget that they've done so, and then take another, and maybe even another. With barbiturates the effective dose is close enough to the fatal dose that this can be very dangerous, but with benzo's it won't usually have a serious effect. In these cases at least, causality seems clear. Regarding point (b), I agree -- that bothered me too when I was copy-editing, but I left it alone. — Preceding unsigned comment added by Looie496 (talk • contribs) 16:57, 13 June 2009 (UTC)

Can we be careful here when talking about suicide methods. See this article for details. I note that the Benzodiazepine overdose contradicts the "virtually impossible to kill yourself" statement. Looking at its source (PMID 12850977), in the elderly, a benzodiazepine was implicated in 39% of the drug poisoning suicides and of these, a benzodiazepine was the sole agent in 72% (with flunitrazepam or nitrazepam accounting for 90% of those sole agent cases). So, in the elderly at least, benzo OD is dangerous. The fact that 3.9% climbs to 39% in the elderly (WP:OR here, I admit) seems to show that we may need to qualify that 3.9% stat without indulging in WP:OR. Does the source for the 3.9% say anything about the elderly or other higher risk groups?

While we are on the subject, can someone with access to that paper fix the Benzodiazepine overdose article. It gets the bathtub stats wrong. The abstract could be clearer, but my interpretation is that the cases of drowning in one's bathtub are 3/4 of "a drug contributed to death (but not poisoning)" (not specifically benzos, though they "predominate"). The WP article implies drowning is the method by which 3/4 of all benzo-related suicides occur (including poisoning).

Once we've looked into these issues in the article text, I'd be quite happy for some/all of this talk-page-section to be erased. Colin°^Talk 18:50, 13 June 2009 (UTC)

FV, benzos and opiates and alcohol do synergistically enhance the toxicity of one another due to effects on respiratory sysstem and also cardio system. I also did some small changes to the sentence you are talking about so hopefully I resolved your issues. Looie is right in that many people can take extremely large doses of benzos and survive. This may in some cases be explained by tolerance or quick admission to hospital but also is indicative of benzodiazepines relative safety in overdose. However, I share the same concerns with Colin regarding overdose potential of benzodiazepines. I think the statement that benzodiazepines taken alone rarely cause death is inaccurate or at least misleading. Equally I wouldn't say they frequently cause death either. I think a better term would be "usually" don't cause death when taken alone or "only occasionally cause death" but it comes down to sources and verifiability and secondary sources etc. I have read conflicting sources myself. We can't use primary sources either to debunk secondary sources so I am happy to leave it as it is though and if or when a secondary source comes to my attention which disputes the rare statement I will bring it up on talk page for discussion. I would for now go with verifiabilty and then if another secondary source is found somewhere down the line we can seek consensus for which one to use.--Literaturegeek | T@1k? 00:17, 14 June 2009 (UTC)

I have fixed I think the misinterpretation of the ref in the benzodiazepine overdose article.--Literaturegeek | T@1k? 00:36, 14 June 2009 (UTC)

Excellent. But now the sentence in the lead is truncated: "Benzodiazepines are often taken in overdoses, but because they are much less toxic than their predecessors the barbiturates." I'm sure that's not what you meant :) I'd still rather see something along the lines of "When they are combined with other central nervous system depressants such as alcohol or opiates [...] the potential for toxicity greatly increases", as in the article body. Fvasconcellos (t·c) 00:38, 14 June 2009 (UTC)

How did you know? :) I have fixed this issue FV.--Literaturegeek | T@1k? 00:47, 14 June 2009 (UTC)

Fixed other issue as well. :)--Literaturegeek | T@1k? 00:49, 14 June 2009 (UTC)

Paton 2002

A recent edit (with edit summary "reverted misleading. the review provides evidence both for 1% and 20% frequency of disinhibition") removed this text:

"The frequency of paradoxical reactions to benzodiazepines is uncertain. Although large studies and systematic reviews have generally found paradoxical reactions to be rare in the general population, with incidence rates below 1% and similar to placebo, some small studies have reported high incidence rates in well-defined groups such as individuals with borderline personality disorder. Most reports of disinhibition involve high doses of high-potency benzodiazepines such as alprazolam, clonazepam or triazolam."

and restored the following text, which contains some information that is incorrect, and some that is misleading or obsolescent:

"A review of 45 controlled trials found no difference in their incidence between patients given triazolam, flurazepam and placebo. Another review estimated that the incidence of aggressive reactions to the administration of benzodiazepines is similar to placebo and below 1%. On the other hand, in controlled trials and case series for alprazolam, paradoxical reactions were observed in 10–20% of the cases. In several trials oxazepam demonstrated a lower rate of disinhibition reactions than other benzodiazepines."

There are several problems with this edit:

• The first two sentences of the restored text simply lists results from earlier studies, with no summary or analysis from the cited source, Paton 2002. But a review like Paton 2002 should not be cited merely to give individual summaries of the underyling sources (the original sources should be cited for that). Reviews should be cited for the synthesis work that they do.
• The edit restored the claim that "in controlled trials and case series for alprazolam, paradoxical reactions were observed in 10–20% of the cases". This is incorrect, as the Paton gives the 10–20% figure only for case series, not for controlled trials.
• The edit removed the topic sentence "The frequency of paradoxical reactions to benzodiazepines is uncertain". This sentence summarizes the rest of the passage, and is well-supported by the cited source, Paton 2002, which says "Although the first reports of paradoxical reactions to benzodiazepines date back over 40 years (Boyle & Tobin, 1961), the incidence of this adverse effect remains uncertain."
• The edit removed the important point that smaller studies in well-defined groups have found paradoxical reactions to be more common, whereas large studies and systematic reviews over the general population have generally found paradoxical reactions to be rare. This is also well-supported by Paton, who writes "Some small studies in well-defined homogeneous patient groups report high rates of paradoxical reactions.... While these studies, numerous case reports and published case series suggest that paradoxical reactions are common, large studies and systematic reviews have generally found them to be rare."
• The edit summary said "review provides evidence both for 1% and 20% frequency of disinhibition". The removed text mentioned the 1% figure, so presumably that is not at issue. The 10–20% figure is mentioned by the review for case series, but this number is of much lower quality, as it is just for a case series. The review also mentions other high figures, such as 13.7% and 58%. None of these figures are randomized controlled trials for the general population, however. It does not seem wise to mention the 10–20% figure (which is not scientific data), while at the same time not mentioning the 13.7% and 58% figures (which are from double-blind, placebo-controlled randomized trials). As all of these figures are poorly supported, it is better not to mention any of them, and simply to say "high incidence rates".
• The edit replaced the more-informative:

"Most reports of disinhibition involve high doses of high-potency benzodiazepines such as alprazolam, clonazepam or triazolam." (supported by Paton 2002)

with the less-informative:

"In several trials oxazepam demonstrated a lower rate of disinhibition reactions than other benzodiazepines." (supported by a 1981 review that must predate alprazolam).

Given all these problems, I have reinstalled the new text, adding the phrase "published case series suggest that they [paradoxical reactions] are common" in order to allay any concerns of POV here. Eubulides (talk) 07:36, 14 June 2009 (UTC)

Point-by-point answer:

• a review like Paton 2002 should not be cited merely to give individual summaries of the underyling sources... First, a review like Paton 2002 CAN BE cited merely to give individual summaries of the underlying sources. That is what the reviews are for. They give authoritative summaries of the sources, so I can avoid OR. Secondly, it is necessary to state for which benzodiazepines (triazolam, flurazepam) the paradoxical side reactions are similar to placebo. It is a misinterpretation to generalize that result to other benzodiazepines.

• the Paton gives the 10–20% figure only for case series, not for controlled trials. Wrong, see Paton "In a placebo-controlled study of alprazolam in the treatment of panic disorder, 13.7% of patients randomised to alprazolam experienced paradoxical reactions compared with none given placebo." It is a controlled study. 13.7% is in the middle of 10-20% range. Panic disorder is a primary indication for alprazolam, and so panic disorder patents are fairly representative of the "general population" of those treated with alprazolam.

• The frequency of paradoxical reactions to benzodiazepines is uncertain. It is a good introductory sentence. I agree that I should have not removed that.

• Some small studies in well-defined homogeneous patient groups report high rates of paradoxical reactions.... While these studies, numerous case reports and published case series suggest that paradoxical reactions are common, large studies and systematic reviews have generally found them to be rare. Paton does say that. However she states that only in the context of a) meta-analysis was conducted only for triazolam and flurazepam. b) controlled study of alprazolam indicating 14% paradoxical reactions. If we are to include the controversial statements, we should not remove the context.

• The edit summary said... Let's not discuss the edit summary which is, by necessity, a stripped down justification for changes.

• The edit replaced the more-informative:... These two sentences do not contradict each other. Suggest including both.

The Sceptical Chymist (talk) 12:14, 14 June 2009 (UTC)

Additional information.

• A review by Bond (1998) doubts the conclusions of the old Greenblatt (1984) metaanalysis of 45 studies: "In a review of 45 double-blind, controlled trials, Greenblatt et

al.[40] could find no difference in the incidence of disinhibition between triazolam, flurazepam and placebo. However, the fact that no unusual or excessive adverse reactions were reported may mean that such events were not witnessed or recorded, rather than they did not occur." The Sceptical Chymist (talk) 12:31, 14 June 2009 (UTC)

• In the light of paucity of newer controlled studies on paradoxical reactions, the conclusion from Hall (1981) remains appropriate: "Thus, the question of frequency, severity, quality and significance of benzodiazepine-induced hostility remains unsettled." That is why we should be cautious of the over-generalizing the results of few trials of few benzodiazepines to the whole group. That is why we should mention which BDs showed what in controlled trials. The Sceptical Chymist (talk) 12:53, 14 June 2009 (UTC)

• It is somewhat of an accepted wisdom among the professionals that oxazepam has a more benign profile of side effects than other BDs. It is a very old drug so it is difficult to come up with newer review references than already mentioned in the article. Another review supporting this is PMID 367058: "Next, the controversy regarding benzodiazepines and aggression is examined. Oxazepam appears exceptional here in that it is not associated with paradoxical release of aggression in patients." Later studies seem to further support this conclusion. See PMID 762032: "A double-blind, controlled clinical trial of chlordiazepoxide, oxazepam and placebo was conducted in 65 outpatients with past histories of temper outbursts, assaultive behaviour and impulsiveness associated with anxiety, irritability and hostility. Of those tests showing statistically significant results, there was a tendency for oxazepam to be somewhat more effective in the reduction of anxiety than chlordiazepoxide. Oxazepam was also superior to the latter on 1 subscale of tests used to measure hostility." Also see PMID 3137624 "Oxazepam and lorazepam had very similar subjective effects, but the higher dose of lorazepam increased aggressive responding on the task more than any other treatment." The Sceptical Chymist (talk) 13:21, 14 June 2009 (UTC)

Regarding oxazepam, oxazepam still behaves like other benzodiazepines. The reeason that it has a better side effect profile is because simply it is less potent. If one was to compare 8 mg of codeine to 5 mg of diamorphine (heroin) or fentanyl one would find that diamorphine and fentanyl would have a higher incidence of side effects such as euphoria, hallucinations confusion etc because they are more potent. As oxazepam at standard doses has less severe side effects it is also a relatively weak anxiolytic, has weak hypnotic effects and weak anticonvulsant properties. There is nothing different about oxazepam from other benzodiazepines other than the dose form that it is marketed in is "low potency" and it crosses the blood brain barrier slowly. If one was to take maybe 4 - 5 times say the therapeutic dose of oxazepam you probably would find that it has the same incidence of side effects as many other benzodiazepines and is as potent.--Literaturegeek | T@1k? 13:49, 14 June 2009 (UTC)

I think that other at risk groups such as elderly, children and those with neurological or learning impairments should also be noted in the article as these are all sizable population groups and thus ommiting these groups from the articles with just an example of one group borderline personality disorder does a diservice to the reader. Sometimes just giving one example and trying to shorten a sentence adversely effects article quality in my opinion.

This is the conclusion of Paton, "The overall incidence of disinhibitory reactions is small, but those with impulse control problems, neurological disorders, learning disabilities, the under 18s and the over 65s are at significant risk."--Literaturegeek | T@1k? 16:52, 14 June 2009 (UTC)

• "a review like Paton 2002 CAN BE cited merely to give individual summaries of the underlying sources." I'm afraid we'll have to continue to disagree here. This is not good style, unless the review is providing perspective on those sources, which was not the case here.
• "it is necessary to state for which benzodiazepines (triazolam, flurazepam) the paradoxical side reactions are similar to placebo. It is a misinterpretation to generalize that result to other benzodiazepines." The current text is not generalizing that result. It is relying on the cited source, Paton 2002 (doi:10.1192/pb.26.12.460), which says "The majority of case reports of behavioural disinhibition are in patients treated with high doses of high-potency benzodiazepines ...".
• "Wrong, see Paton "In a placebo-controlled study of alprazolam in the treatment of panic disorder, 13.7% of patients randomised to alprazolam experienced paradoxical reactions compared with none given placebo." It is a controlled study. 13.7% is in the middle of 10-20% range." This sort of calculation is original research, and we can't rely on it. Paton mentions the 10–20% figure for a different context, one that has nothing to do with controlled studies. The article can't silently combine that with the 13.7% figure for one controlled study, and then omit the 58% figures for another controlled study, and then just say "10–20%": that would be misleading.
• "Panic disorder is a primary indication for alprazolam, and so panic disorder patents are fairly representative of the "general population" of those treated with alprazolam." As I understand it, "general population" does not mean "those treated with alprazolam"; it means everybody in general.
• "Paton does say that. However she states that only in the context of ..." Paton is summarizing existing research. I see no evidence that her summary is controversial, or that there's any need to list each and every study that Paton refers to. Encyclopedias are supposed to summarize what reliable sources say, rather than flood the reader with unnecessary detail.
• "These two sentences do not contradict each other. Suggest including both." I'm leery of citing a 1981 (!) review that (obviously) does not cover newer benzos. Also, the average reader does not need this much detail, and it'd be better to remove all mention of specific benzos, resulting in simply "Most reports of disinhibition involve high doses of high-potency benzodiazepines." I did that in my edit (noted below).
• "Additional information" Those comments cite Hall 1981, Ladler 1978, Liohn 1979, and Bond & Lader 1988. These are old sources and they don't disagree with the newer review. I don't see a need to go into so much (ancient) detail in the article.
• "I think that other at risk groups such as elderly, children and those with neurological or learning impairments should also be noted" Good point. This is noted in Paton's abstract. I added "In these groups, impulse control problems are perhaps the most important risk factor for disinhibition; learning disabilities, neurological disorders, and ages under 18 or over 65 are also significant risks". This edit also removes the unnecessary detail noted above.

Eubulides (talk) 09:46, 15 June 2009 (UTC)

Most of Eubulides objections are centered around the age of the reviews. This issue cannot be helped because most of these drugs are ancient. Most of the research in pharmaceuticals is driven by pharma companies and often stops when the drug goes off patent. Another problem with newer reviews is that they tend to parrot the conclusions of the older reviews. The telling example is the "1% of the general population" bit. It is repeated over and over again in different "new" reviews. But you cannot tell what the authors of the original 1988 review meant under this without reading the old original review and citing it. Was it general population of those who were prescribed BDs, that is mostly people with anxiety disorders? Was it general population, that is mostly healthy people? Although, why would you prescribe BDs to healthy people? The Sceptical Chymist (talk) 11:47, 15 June 2009 (UTC)

Please see #Current Paton-related problems below. Eubulides (talk) 08:31, 17 June 2009 (UTC)

I personally think that the Paton review (perhaps unintentionally) plays down the paradoxical adverse effects. Conflict of Interest in clinical trials and selective publishing are a problem. However, as wikipedia works via reliable sources unless we find a different secondary source then we should just go with this citation and what it says. I have no doubt that severe paradoxical reactions are relatively rare but I am not convinced that mild and moderate paradoxical effects are also rare and "similar to placebo" as Paton seems to suggest.--Literaturegeek | T@1k? 12:11, 15 June 2009 (UTC)

Conflict of interest cuts both ways. Big pharma would rather have physicians prescribe newer, more-expensive, patented drugs, instead of the older, cheaper, out-of-patent benzodiazepines. Big pharma is therefore happy to see studies emphasizing the adverse effects of benzodiazepines, as exemplified by Paton's review. But all this is not supposed to matter. We have to follow what reliable sources say, even if big pharma is influencing mainstream opinion. Unfortunately, the article is currently significantly distorting Paton's review in a negative way. For more, please see #Current Paton-related problems below. Eubulides (talk) 08:31, 17 June 2009 (UTC)

Depends, I have read a couple of interesting points by people who would be classed as "antipsychiatry" but I don't cite those individuals because their research is biased. I actually think there were some issues with how the Paton paper was cited and summarised. I have made some changes which I really hope will resolve the dispute and will satisfy yourself as well as Sceptical. It is difficult sometimes to satisfy opposing views amongst editors so hope you both are happy with the changes. See subsection below.--Literaturegeek | T@1k? 16:12, 17 June 2009 (UTC)

I guess my point is I try to seek out the best sources and avoid sources which I believe after reading them severely distort evidence such as antipsychiatry or pharmaceutical company based publications peer reviewed secondary sources or not. I am not categorising Paton as this, Paton paper is fine and am happy with it. I am just clarifying my editing beliefs is all. I still do cite pharmaceutical company driven papers as they can have high quality data in them, I am just more cautious I guess.--Literaturegeek | T@1k? 16:18, 17 June 2009 (UTC)

Current Paton-related problems

A recent edit reintroduced some of the problems noted above. That's one too many reverts for my taste. Rather than edit war over this, I am tagging the relevant section with {{POV-section}} and {{Summarize section}} and noting the problems below. My edit is also introducing citations to studies that the disputed section discussed without citing.

Here are some problems with the edit:

• It removed the point that large studies and systematic reviews have generally found paradoxical reactions to be rare in the general population.
• It removed the point that disagreement comes from published case series and some small studies.
• It removed the point that the disagreement comes from studies of well-defined groups, notably of people with impulse control problems.

More generally, the edit has reintroduced problems that Colin objected to in the FA review:

• "There are areas where the important facts are lost among the lesser." That's definitely a problem with this edit.
• "There are far too many cases where three, four and even five citations are strung together, sometimes just to source a single sentence." Also a problem.
• "primary research papers cited without good reason" As mentioned above, the edit discusses several sources without citing them. I have fixed this, but this means the section is citing ancient primary sources and very old reviews, which is a negative we've been trying to fix.

Worse, this edit has made the section POV. The overall effects of the edit is to emphasize this adverse effect of benzodiazepines, far out of proportion to what the source says.

In response to some of the comments above:

• "Most of the research in pharmaceuticals is driven by pharma companies" It is not our job to filter out parts of reviews that we don't like, simply because research is driven by pharma companies. We are here to summarize the mainstream opinion, not the opinion that we think would be mainstream if big pharma didn't exist.
• 'Another problem with newer reviews is that they tend to parrot the conclusions of the older reviews. The telling example is the "1% of the general population" bit.' This is backwards. If several reviews mention the 1% figure, this article can (and should) too.
• "Was it general population" That's what Paton said, yes. If it's important to define what "general population" is, then we should define it in the text. However, it's clearly not that important (the term is well-understood by the general reader); so we needn't define the term in the text or cite the ancient study it's derived from.
• "Most of Eubulides objections are centered around the age of the reviews." Not so. Most of my objections are based on two things:

• The text about paradoxical reactions in Benzodiazepines significantly mischaracterizes what is is said by the review (Paton 2002, (doi:10.1192/pb.26.12.460).

• Paton starts off by saying that in most cases benzos have a calming effect, whereas paradoxical reactions of increased anxiety etc. happen only in a minority of cases. In contrast, the text starts off by making it sound that paradoxical reactions are common, with strong language talking about "numerous cases" of "aggression ... and suicidal behavior", giving the naive reader a misimpression of how common the problem is. Only buried later in the paragraph do we discover that this happens only in a minority of cases (whether <1% or higher we don't know).
• Paton makes a primary point that large studies and systematic reviews have generally found paradoxical reactions to be rare in the general population, whereas smaller studies and case report series have found it to be relatively common in well-defined subgroups. This important point is absent in the text: instead, it simply lists studies or reviews, and their numbers. The naive reader cannot be expected to understand this point without its being said.

• The text swamps the reader with way too much detail about old studies, without presenting the big picture that an encyclopedia should.

• There is no need to present the results of any single primary study here, regardless of whether that study is cited or not. This area is well reviewed.
• There is no need to give overly exact percentages like 14% (in a study with only 70 patients!) or 10–20% (not from any controlled study at all!). Not only are these percentages unnecessary detail, they are misleading: they give the naive reader the mistaken impression that there's general agreement that 10–20% of people experience paradoxical reactions with alprazolam, whereas in reality there is no such agreement. Paton cites Gardner & Cowdrey 1985 as a controlled study reporting 58% of patients with paradoxical reactions to alprazolam, for example.

Eubulides (talk) 08:31, 17 June 2009 (UTC)

Is what E. doing -- WP:POINT? Or maybe WP:PUSH? And for sure, it is WP:TLDR big time! Whatever I was able to read from E.'s long-winded answer was mostly incorrect. For example, E. called old reviews - primary sources. He found POV in the text, which states that frequency of the side effects is unclear and illustrates both points of view.

I am reverting to his version. Let him have his way. IMHO, this way of handling issues is inexcusable for an experienced editor. E. should be ashamed. The Sceptical Chymist (talk) 10:45, 17 June 2009 (UTC)

That is unfair. Please stick to discussing the article and the sources, and bear in mind that a talk page isn't as easy a communication forum as if we were talking in a room.

We are trying to make our text faithful to the sources, and this includes giving appropriate weight to aspects of the topic. For each section, we should ask ourselves: "What are the main points to get across" and ensure those come across loud and clear. It is really tempting when reading about fascinating research studies to think the reader shares our fascination. They don't; it just clouds things.

I note that currently the text still doesn't satisfy some of Eubulides issues: particularly that it opens with "Numerous cases" when we later claim the rate may be "below 1% and similar to placebo". Currently, the main point the reader gets is that paradoxical reactions are "numerous" and include "aggression, violence, impulsivity, irritability and suicidal behavior". Colin°^Talk 12:55, 17 June 2009 (UTC)

Numerous is fine because it is true, it has been widely reported in the peer reviewed literature. Wikipedia primarily concerns itself with reporting facts. In this case it is not misleading as it is clarified in the paragraph. Please note that the less than 1% statistic is for "healthy patients" in clinical trials. The paton paper states that in certain groups, elderly (which make up a sizable number of the general population), the young, high doses or high potency benzos, recreational users, learning impaired etc are at significant risk of paradoxical reactions. My personal opinion is that everyone here is taking the Paton and other reviews out of context.--Literaturegeek | T@1k? 14:15, 17 June 2009 (UTC)

I am going to do afew changes to try and improve that section.--Literaturegeek | T@1k? 14:17, 17 June 2009 (UTC)

FWIW, I can add from clinical practice that paradoxical reactions as such are pretty rare really. They also don't much rate a mention when one is prescribing benzos except as a footnote that we're all aware of but rarely see. Casliber (talk · contribs) 14:24, 17 June 2009 (UTC)

I don't dispute your clinical experience Casliber. What I am saying is that the elderly [particularly 75 and over] for example it is not rare (think of delerium, confusion resulting in agitation, anxiety etc) or children becoming hyperactive or aggressive or learning impaired and also borderline personality disorder it is not similar to placebo. I have done a rewrite of the section, removed redunancy/repeating and I have also removed the "numerous reports" to try and resolve dispute.--Literaturegeek | T@1k? 16:04, 17 June 2009 (UTC)

The main problems with benzodiazepines are tolerance and withdrawal (including the protracted nature of withdrawal) and the adverse effects of long term use in my opinion. Acute side effects upon commensing benzodiazepines are not a significant concern for the general population except certain groups which we have acknowledged now.--Literaturegeek | T@1k? 16:08, 17 June 2009 (UTC)

Thanks, Literaturegeek, I think your changes have helped. I've tweaked it a little to remove all trace of references to literature or studies. The paragraph now concentrates on the facts, as well as we can determine them, which is what an encyclopaedia should focus on. I think that resolves this issue for me. Colin°^Talk 16:27, 17 June 2009 (UTC)

You are welcome Colin. Glad this issue iss resolved. Your tweaks looked good to me. I spoke to a geriatrician who said in his experience about 10 percent of patients 75 years or older would have a paradoxical reaction to benzodiazepines such as anxiety, agitation usually as a result of benzo induced confusion etc. He said in the case of opiates eg morphine it would be more like 30 percent who would become anxious or agitated as a result of confusion so benzos ain't as bad as the opiates for these acute side effects in the elderly. I also read in a ref today somewhere that clinical trials of benzos in the elderly are rare so I really don't think we will get good statistical data on this from say a systematic review or meta-analysis for the elderly but at least we have it reffed that it is rare in general population but more common in certain groups of people. I am happy with that as accurate as we are gonna get. Anyway as this issue I believe is resolved we should move on to other contructive criticisms or suggestions or else vote to support FA. :)--Literaturegeek | T@1k? 02:14, 18 June 2009 (UTC)

Thanks to both of you for a masterful rewrite of the paragraph. Eubulides (talk) 06:51, 18 June 2009 (UTC)

Characterisation of benzodiazepine structure

Wouldn't it be more accurate to mention the phenyl group somewhere in the Chemistry section? As is, it makes it sounds as if merely a benzodiazepine base is necessary, but AFAICT the overwhelming majority (though not quite all) of comemrcial benzodiazepines are in phenylbenzodiazepines. (specifically 5-phenylbenzodiazepines in the case of 1,X-benzodiazepines). I hope I'm not messing up with the chemical nomenclature and this makes sense. Circeus (talk) 18:53, 15 June 2009 (UTC)

I agree. The phenyl group was included in a previous version, but was overwritten by this edit. I have tried to combine elements of the original version which IMHO are more relevant to medicinal chemistry (and therefore by definition the specific subject matter of this article) and organic nomenclature (which is relevant to the more general subject of the benzodiazepine ring system). Boghog2 (talk) 20:24, 15 June 2009 (UTC)

No, in that particular section, it would be inaccurate to include a phenyl group. Physchim62 (talk) 20:50, 15 June 2009 (UTC)

Both the entire article and that particular section within this article pertain to pharmacologically active benzodiazepines which possess a phenyl or a bioisosteric equivalent at position-5. In the new version of the graphic I have attempted to find a compromise which depicts both the core benzodiazepine ring system which is the basis for the benzodiazepine name as well as the minimum pharmacologically active core. As discussed here, perhaps I should also add an R group to position-1 and a X group to position-7 (done). Boghog2 (talk) 21:29, 15 June 2009 (UTC)

The problem is that the structure you want to include is (1) a substituted benzodiazepine, rather than a simple benzodiazepine in the chemical sense, and (2) almost identical to the structure shown in the top right-hand corner of the article, next to the lead. I'm very sorry for wanting to tell people where the name comes from, and to illustrate the basic structural similarity. The small image is in the "technical" part of the article – improve it if you wish, I'm having trouble with my new version of ChemSketch. Physchim62 (talk) 23:25, 15 June 2009 (UTC)

I'm very sorry for wanting to tell people where the name comes from. What are you apologizing for? A completely agree with you and that is why I merged our two figures. At the same time, it is important to note that this article and the chemistry section within this article concern pharmacologically active benzodiazepines and not the benzodiazepine heterocyclic ring system. I agree that it is important to make clear where the name came from (the left hand side of the graphic) but it is equally important to make clear what is pharmacologically active (the right hand side of the figure). In addition, the right hand figure also includes the ring numbering and make reference to diazepam. Furthermore, I don't see the problem with a little repetition, especially considering the two figures in question are far removed from each other. Boghog2 (talk) 23:45, 15 June 2009 (UTC)

I removed the following statement from the article: "Benzodiazepines are structurally similar to several groups of drugs, some of which share similar pharmacological properties, including the quinazolinones, hydantoins, succinimides, oxazolidinediones, barbiturates and glutarimides.[86]" First of all, it is nonsense. If you look at the structures, benzodiazepines look nothing like hydantoins, oxazolidinediones etc. Second, the statement misrepresents the article, which only points at a single common structural feature "a carboxamide group as a constituent part of a five-, six- or seven-membered heterocyclic ring structure". Third, the presence of such a common structural feature in benzodiazepines is not notable because benzodiazepines share it with hundreds of thousand other compounds.The Sceptical Chymist (talk) 01:51, 16 June 2009 (UTC)

Thanks for pointing out the problem. I agree that the statements that you deleted do not make any sense. Perhaps what should be included instead is a statement that:

• Nonbenzodiazepines also bind to the benzodiazepine binding site on the GABA_A receptor and share similar pharmacological properties. While the nonbenzodiazepines are by definition structurally unrelated to the benzodiazepines, both classes of drugs share a common pharmacophore which explains their binding to a common receptor site. (Madsen U, Bräuner-Osborne H, Greenwood JR, Johansen TN, Krogsgaard-Larsen P, Liljefors T, Nielsen M, Frølund B (2005). "GABA and Glutamate receptor ligands and their therapeutic potential in CNS disorders". In Gad SC (ed.). Drug Discovery Handbook. Hoboken, N.J: Wiley-Interscience/J. Wiley. pp. 797–907. ISBN 0-471-21384-5.{{cite book}}: CS1 maint: multiple names: authors list (link)).

A graphic of the pharmacophore (similar to Figure 18.14 on page 822 of the cited book) could also be inserted. Boghog2 (talk) 06:00, 16 June 2009 (UTC)

I do not have the cited book but a picture would be useful because common pharmacophore is not evident (at least to me). The Sceptical Chymist (talk) 10:26, 16 June 2009 (UTC)

OK, I will generate a new public domain figure which will take a sometime since I am busy with other things at the moment. In the meantime, you can get an idea of what the pharmacophore looks like by downloading the following pdf:

• $ ftp ftp.wiley.com
• ftp> cd /public/sci_tech_med/drug_discovery/Chapter18/
• ftp> get drug_discovery_Chap18.zip
• in the above zip file, Fig14.pdf contains an overlay of diazepam with CGS 9896 where both ligands interact with receptor sites H1, H2/A3, L1 and L2. This model is compatible with most of the known ligands which bind to the benzodiazepine site on the GABA_A receptor. Boghog2 (talk) 17:53, 16 June 2009 (UTC)

Access to the Cochrane Library

Colin recently reverted my removal of the url for this Cochrane paper saying that it's freely-available. It's certainly not freely-available to me in the United States, as I noted with a poorly autogenerated reference a while ago [13] (PMID 18238981). As the Cochrane Library page states, many countries have free access to Cochrane, but significant other ones don't. I don't think the URL should be included. II | (t - c) 22:39, 15 June 2009 (UTC)

I wasn't aware that Cochrane restricted access based on the client PC's country. I guess you'll need to move to Wyoming or the UK :-). I'll leave it up to someone else to decide if this is freely available enough to justify a URL link. How about removing the standard url link and adding a suffix: "Text freely available here in some countries." Colin°^Talk 20:27, 16 June 2009 (UTC)

In other articles when this issue (access to Cochrane0 has come up, I have omitted the URL. A source that is "freely readable" only (say) on the campus of Johns Hopkins is clearly not free; on the other hand a source that is freely readable everywhere except (say) inside the Great Firewall of China is clearly free. In this case it's more of a gray area, but when most typical Wikipedia readers can't read a source, I'd say it's not free, so I removed the URL. Eubulides (talk) 22:35, 16 June 2009 (UTC)

More sourcing comments

Lead

The third paragraph in the lead has four points:

1. Benzodiazepines are generally safe and effective in the short term
2. Cognitive impairments or paradoxical effects such as aggression or behavioral disinhibition occasionally occur.
3. Their use in the longer term is not recommended due to their propensity to cause tolerance, physical dependence, addiction and a withdrawal syndrome upon cessation of use.
4. They are also major drugs of abuse.

These are all sourced to three papers at the end. I'd prefer really that each major point had its own citation(s). One (PMID 18671662) is a comment on a review of their effectiveness/efficacy for GAD, which concludes they aren't effective. One (PMID 15460178) is possibly focussing only on sedation and it deals with "paradoxical reactions" rather than all side effects. I don't see anything on them being "major drugs of abuse" but I don't have access to the full papers.

Therapeutic uses, Anxiety, panic and agitation

What are the main points we are trying to get across here? There are three aspects that our sources testify to:

1. Clinical guidelines, hopefully based on evidence (... are recommended (indicated) for the treatment of ...)
2. The results of studies and the analysis of those studies (... have been found to be efficacious in treating ...)
3. Actual clinical practice, whether supported by guidelines and evidence or not (... are used for the treatment of ...)

The article mostly cites aspects 2 and 3. The article often says "can be useful for", which to me implies there is evidence of usefulness, but only sometimes. IMO the "can" is too vague and allows us to mention usage that is not even first or second-line recommended. I would argue that the section title "therapeutic uses" implies "usage that has been proven to have a therapeutic effect in clinical practice". Usage that goes against the evidence and advice isn't "therapeutic", even if it is widespread.

I've discovered recently, there is a difference between "efficacy" and "effectiveness" (see this article). One paper you cite (PMID 18671662) is actually just a comment on a single systematic review paper (PMID 17881433) that concludes "This systematic review did not find convincing evidence of the short-term effectiveness of the benzodiazepines in the treatment of GAD. On the other hand, for the outcome of efficacy, this review found robust evidence in favour of benzodiazepines." We need to be careful in our choice of words.

Looking at the prescribing guidelines I see:

• BNF: Benzodiazepines are indicated for the short-term relief of severe anxiety; long-term use should be avoided
• BNF: In panic disorders (with or without agoraphobia) resistant to antidepressant therapy

• a benzodiazepine (lorazepam 3–5 mg daily or clonazepam 1–2 mg daily [both unlicensed]) may be used
• alternatively, a benzodiazepine may be used as short-term adjunctive therapy at the start of antidepressant treatment to prevent the initial worsening of symptoms.

• BNF: Diazepam or lorazepam are very occasionally administered intravenously for the control of panic attacks. This route is the most rapid but the procedure is not without risk (facilities for reversing respiratory depression with mechanical ventilation must be at hand) and should be used only when alternative measures have failed.
• BNF: Benzodiazepines may be helpful in the initial stages of treatment for mania until lithium achieves its full effect; they should not be used for long periods because of the risk of dependence.
• CSM: Benzodiazepines are indicated for the short-term relief (two to four weeks only) of anxiety that is severe, disabling, or subjecting the individual to unacceptable distress, occurring alone or in association with insomnia or short-term psychosomatic, organic, or psychotic illness.
• CSM: The use of benzodiazepines to treat short-term ‘mild’ anxiety is inappropriate and unsuitable.
• NICE (CG22): Benzodiazepines are associated with a less good outcome in the long term and should not be prescribed for the treatment of individuals with panic disorder. (compare this with the BNF)
• NICE (CG22): In Generalised Anxiety Disorder, benzodiazepines may be considered if immediate management is required, but should not usually be used beyond 2–4 weeks.

Some of this agrees with the article text but the emphasis isn't always right. For example, the main indications get a brief sentence but lesser ones get several sentences. Sometimes the article text describes clinical practice that is at odds with prescribing guidelines. The biggest examples here would be long term use and use for panic disorder, both of which appear to be absolutely forbidden by the guidelines yet routinely ignored. Perhaps such usages should appear in the "Drug misuse" section?

The final paragraph says benzos "can be very useful" for acute mania. This indication is noted in the BNF (though much reduced to "may be helpful") but the Cochrane review cited is decidedly lukewarm on the evidence. If we're going to cite Cochrane, shouldn't our text agree with it to some degree?

Broken text

I think some edits have broken some sentences:

• "Although their effectiveness is not recommended as a..."
• "Some benzodiazepines are prescribed for the short-term management of severe or debilitating insomnia. They have strong hypnotic effects, are typically the most rapid-acting and have strong receptor affinity."

Colin°^Talk 22:57, 15 June 2009 (UTC)

I made a stab at fixing the main problems that you raised. Forbidden is not the right word but unlicensed and not recommended or evidence based. breaking the guidelines means if something goes wrong eg dependence adverse long term effects severe withdrawal symptoms and the ppatient sues the doctor has to be able defend his "clinical judgement or lack of" but other than that a clinician is free to prescribe outside via exercising his clinical judgement.--Literaturegeek | T@1k? 12:00, 16 June 2009 (UTC)

Ultimately, benzo use is a vexed issue in amny cases and I think it depends alot on the views of the prescribing authority on addiction potential, which is responsible for the variation in views on their use in anxiety. Clonazepam was often used in mania a decade or more ago but you don't see it used now and I think most of in psychiatry accept that the benefit was non-specific. Anyway, there is a question on how much detail and how well cited this could be. I haven't looked at the page for a bit. Casliber (talk · contribs) 02:21, 16 June 2009 (UTC)

The article says lorazepam is most commonly prescribed but clonazepam is sometimes prescribed, so it was changed but perhaps you think that it should be deleted (clonazepam) from the article or is sometimes an appropriate enough word? I believe clonazepam is more often used in the USA than in other Western countries.--Literaturegeek | T@1k? 12:00, 16 June 2009 (UTC)

Thanks, Casliber. I'm an outsider with no expertise in this field, so I'm rather reluctant to propose alternative text or choose quality sources. I do feel this section blurs the three aspects I mentioned above, making it hard to for the reader to know what the main indications are, what is rare due to rarity, what is rare due to it being a last resort, and what is sadly common but not at all recommended. I think the foundation of an "indications" section in WP should be evidence-based clinical guidelines. I don't know where to look for US or Australian versions (a professional body?), but the UK ones are freely available. Notable deviance from those guidelines (such as routine long term use, or use in unsuitable populations groups) should be noted and discussed (and the are plenty first-class articles on that subject). Primary sources have been largely eliminated from the article, which is good. But it looks like one can find a review to support almost any opinion wrt usage in this field. And fashions change, so old papers may now be irrelevant. This is where I think the clinical guidelines from a professional body, insurance group or government body can help to establish the current consensus opinion of experts.

Look at what we say about panic disorder: "and occasionally prescribed for panic disorder." and "Limited data from longitudinal studies have suggested benefit from long term use in panic disorder.". Should we be noting research that merely "suggests" benefit? Surely it only gets encyclopaedic when this becomes a formal, widely respected or practised indication. We say they are "occasionally prescribed" but that fact is partly sourced to a 19-year-old US paper. Nowhere do we say that such usage is unlicensed (in the UK) and goes against NICE guidelines. Nor do we say that this is short-term use for panic disorder.

I will try to revisit the FAC later. Got bogged down in this section last night. Colin°^Talk 08:17, 16 June 2009 (UTC)

I have added a NICE citation Colin for the anxiety section. I agree that national prescribing guidelines are the best sources for the indications sections. I actually think in this situation we should be adding a review for the evidence base of prescribing in panic disorder of benzos (mainly in the USA) but also in other countries is significant enough to warrant it and it explains to the reader the "controversy" in the literature for this offlabel indication. I have added that it is an unlicensed indication. Benzodiazepines are not licensed for long term use in any Western country (as far as I know). In USA FDA accepts evidence for efficacy of up to 8 or 9 weeks for alprazolam in panic disorder but not beyond that. Thanks for your additional suggestions. Have tried to resolve them but have to go out now, will try and work a bit more on it later.--Literaturegeek | T@1k? 12:00, 16 June 2009 (UTC)

Here is one national guideline:

• Nelson J, Chouinard G (1999). "Guidelines for the clinical use of benzodiazepines: pharmacokinetics, dependency, rebound and withdrawal". Can J Clin Pharmacol. 6 (2): 69–83. PMID 10519733. These Canadian guidelines are freely available from the Pulsus Group but are behind a screwy web interface that we can't directly link through.

Eubulides (talk) 23:02, 16 June 2009 (UTC)

Those are not official Canadian national guidelines, it is not a policy document. That is just an ordinary review published in a journal paper written up by a group of senior pharmacists who happened to call the title guidelines.--Literaturegeek | T@1k? 20:55, 17 June 2009 (UTC)

Ah, I had thought from the PubMed entry that it was a document of the The Canadian Society for Clinical Pharmacology (now the Canadian Society of Pharmacology and Therapeutics). This is not a government body, but then again the American College of Physicians is not a government body either, and yet the ACP guidelines would be an excellent source if they had a guideline on benzos (which they don't). I now see that the document itself does not state that it is an official guideline of the society, so perhaps you're right that it's just a couple of experts. Still, couldn't it be a reasonable source for guideline-related info? Eubulides (talk) 22:52, 17 June 2009 (UTC)

I would say they are experts (or senior) pharmacists but I can tell that they are not experts in the topic that they are writing on. There was a lot of good/accurate points in it but a lot of other points that they got wrong in my opinion. It is not a systematic review but I would say a review by cherry picking of primary sources by non-experts in the subject matter. Therefore I don't think that we should use it to either supplement or challenge more authoritative sources such as the National Institute of Excellence or to supplement agree with or challenge systematic reviews or official prescribing indications and so forth.

A more pressing issue I feel is that you claimed that the article has had increasing amounts of primary sources and older reviews added when I believe that you know the opposite is true. I would like you to retract that comment on the featured article review page as it is inaccurate and misleading to other reviewers who have not been following the article's development intensely and thus could mess up all of our work.--Literaturegeek | T@1k? 23:16, 17 June 2009 (UTC)

That comment was true when made, but it's been fixed now, so I'll go strike it. As can bee seen from #Catalog above, the sources are in pretty good shape now (thanks), and I'll mention that on the FAC page. So the only remaining point from my point of view is prose quality, which we can turn to next. Eubulides (talk) 06:51, 18 June 2009 (UTC)

I don't think we need to find new reviews or refs for the indications section unless something factual is left out of it which needs added. One or two refs per fact should be sifficient.--Literaturegeek | T@1k? 23:21, 17 June 2009 (UTC)

I think that we need to decide is the article ready to be supported for FA or if not what problems remain. I am getting burnt out from the editing but appreciate that big improvements have been made. I really think it is above the standard of other pharmacology FA articles.--Literaturegeek | T@1k? 23:25, 17 June 2009 (UTC)

Withdrawal section

I have done some major rewriting of the withdrawal section. There really was very little on tolerance, its mechanisms, why it happens, how fast it happens to various therapeutic effects etc etc so found a ref and used it. I also added in certain important aspects which I felt were left out. I now feel that the section is comprehensive and informative with all major points addressed. I felt it needed more work done on it because it is one of the most important areas of benzodiazepines. Someone had also used a source where in the opinion of a doctor "some people may need benzos long term for anxiety" and then a 2nd source which stated tolerance to anxiety effects has been demonstrated in animals to say tolerance does not happen to the anxiety effects. The sources were either not striong enough "opinion of an individual doctor and then a paper which contradicted it with animal studies. It seemed a mixture of poor sourcing with a bit of original research thrown in as well not to mention conflicting sources. Opinions are welcome.--Literaturegeek | T@1k? 02:21, 18 June 2009 (UTC)

Do not want an edit war. Sceptical keeps deleting anything related to tolerance to the anxiolytic effects of benzodiazepines. This disputes the National Institute of Clinical Excellence which says that long term treatment of panic disorder with benzodiazepines "does not have a good outcome".[14] Disputes this review which says "there is little evidence to indicate that benzodiazepines retain their efficacy after four to six months of regular use."[15] It also disputes this body from a national advisorary body to NHS physicians which says "Tolerance to the anxiolytic effects is slower and appears over a few months of use."[16] The headquarters of Roche Pharmaceuticals in Switzerland published this paper which stated that "Potential development of tolerance to and dependence on benzodiazepine tranquilizers often limit their use for long-term treatment of epilepsy, anxiety and insomnia".[17] The world council of anxiety stated that benzodiazepines are not recommended long term for generalised anxiety because of tolerance and other adverse effects.[18] It also disputes the Committee on the safety of Medicines.[19] Also any reference to improvements in health and wellbeing following benzodiazepine withdrawal keeps getting deleted despite being referenced to good sources and no sources provided to dispute improvements in cognition and physical and mental health. The only reason that the refs to improved mental and physical well being post withdrawal that I can see is due to someone thinking "I don't agree with that". The reality is sedative hypnotics (barbiturates, alcohol and benzodiazepines) are well known from long term use for causing profound changes in brain chemistry due to tolerance and dependence and are associated with at least in some users (not all) neuropsychiatric and cognitive impairments. I would like to discuss this evidence base and find consensus.--Literaturegeek | T@1k? 15:22, 18 June 2009 (UTC)

What does "does not have a good outcome" mean? That it does not work, or that it has a harmful outcome, or what? Regards, —Mattisse (Talk) 21:04, 19 June 2009 (UTC)

NICE are referring to effectiveness of treatment, i.e tolerance, that is what the document implied to me when I read it. :) Thanks for all of the work you have done today and last night to this article. One spelling question though, should pre medication not be "premedication"?--Literaturegeek | T@1k? 21:28, 19 June 2009 (UTC)

Yes, you are right. —Mattisse (Talk) 21:37, 19 June 2009 (UTC)

Please address issues on talk page Sceptical

I have requested content disagreements are discussed on talk page but we seem to be on the verge of edit warring.

Problem 1.

This edit was used to dispute text. Can I just point out that CT scans can only detect only structural brain damage (brain shrinkage, tumors, loss of brain tissue) not neuronal damage or dysfunction. You would need a PET, spect or perhaps an MRI scan to find those types of findings. These studies have never been done.

Problem 2

You seem to have totally misrepresented the findings of the review and meta-analysis.[20]--Literaturegeek | T@1k? 17:24, 20 June 2009 (UTC)

Problem 3

The quote marks are back in the article e.g. "involvement with other issues" and the reference with a long quotation from the article does not seem to contain the phrase "involvement with other issues" so it is not a direct quote and should not be in quotes. Further, is there justification for such a long quote in the references from a copy righted work (ref 15), as it does not seem to add necessary information to the article? Regards, —Mattisse (Talk) 17:47, 20 June 2009 (UTC)

RE Problem 3. You (Matisse) changed the correct "problems" to incorrect "issues" when removing the quotation, diff here [[21]]. I did not notice it when I restored the quotation marks. Now fixed... As for the long citation, I thought you asked for it... Please pare it as you see needed.The Sceptical Chymist (talk) 19:10, 20 June 2009 (UTC)

RE: Problem 1. On one side there are outdated speculations by Ashton (1991) that there may be neurological damage. On another side, a clear negative result from a CT study cited in a recent meta-analysis. IMHO, the experimental study (despite its limitations) is sufficient to remove mere speculations. The Sceptical Chymist (talk) 19:13, 20 June 2009 (UTC)

Obviously source was a non-systematic review of the literature and thus just the opinion of the author using a biased sampling of the literature. See, [22] and, [23]. There are other studies done in high benzo abusers as well. Anyway you have not responded to me pointing out that CT scans do not detect neurona damage/dysfunction. So you are using an irrelevant ref to dispute it. That is my point. If you want to dispute a ref based on the "age of the ref", then fine lets discuss that.

Further, who says it is outdated? Have you got a relevant ref to dispute it?--Literaturegeek | T@1k? 19:41, 20 June 2009 (UTC)

I don't mean any disrespect but do you understand the difference between a neuron and a brain structure?--Literaturegeek | T@1k? 19:45, 20 June 2009 (UTC)

Ashton (1991) is outdated because it is 18 years old. The possibility of neural damage is her own speculation because she does not back it up by citations. This outdated speculation about neurons goes against recent negative experimental results regarding brain structures. That is how a recent review treats it PMID 14731058 PMID 15762814:

Are Benzodiazepines Associated With Physiologic Changes in the Brain?

Given the degree of cognitive changes reported with

benzodiazepine treatment, several researchers have proposed

that anatomic or physiologic changes in the brain

should be demonstrable in patients with cognitive changes

due to benzodiazepine use. Positron emission tomography

research is sparse but thus far seems to indicate that

changes are measurable only during benzodiazepine use

and then disappear shortly after dose administration without

having a measurable effect on function. For example,

although cerebral blood flow to the prefrontal cortex was

found to be lower in the presence of midazolam, there was

no difference in cerebral blood flow to functioning regions

of the brain used during memory tasks between unmedicated

controls and patients who took midazolam.16 Therefore,

despite benzodiazepine-induced changes in the prefrontal

cortex, the brain was still able to perform cognitive

functions. Computed tomographic (CT) scans of patients

taking benzodiazepines long term were compared with

those of age- and sex-matched controls by Busto et al.,17

but the authors found no difference in brain atrophy in the

2 groups and concluded that long-term benzodiazepine use

does not appear to be associated with brain abnormalities

as assessed by CT. The Sceptical Chymist (talk) 20:12, 20 June 2009 (UTC)

But the conclusion in the abstract of the paper you cite above is: "CONCLUSION: Moderate-to-large weighted effect sizes were found for all cognitive domains suggesting that long-term benzodiazepine users were significantly impaired, compared with controls, in all of the areas that were assessed. However, this study has several limitations, one being that it includes a relatively small number of studies. Further studies need to be conducted; ..." I do not have access to the complete pager. You appear to be quoting from the literature review of the paper, which is not a reliable source for this sort of conclusion. A paper's literature review is not to be used to draw conclusions. —Mattisse (Talk) 20:24, 20 June 2009 (UTC)

I apologize for giving wrong PMID. I just corrected it. The Sceptical Chymist (talk) 20:33, 20 June 2009 (UTC)

Midazolam study sounds like an acute benzo dose study. It is using a short-term study to state long-term effects. I already showed that the literature is conflicting regarding CT scans. These studies are NOT on protracted withdrawal and thus are not relevant.--Literaturegeek | T@1k? 20:19, 20 June 2009 (UTC)

What I cite is a much newer review than Ashton's. The Sceptical Chymist (talk) 20:35, 20 June 2009 (UTC)

Why will you not address my points? I stated midazolam was a short term study assessing acute effects. I want to use the best quality literature, you seem to be determined to use the most dubious quality oif literature even after its faults have been pointed out. I want this to be a top quality article. What do you want?--Literaturegeek | T@1k? 20:47, 20 June 2009 (UTC)

The issue is what review Ashton (1991) or Stewart (2005) we prefer. Ashton's is old and does not cite any evidence. Stewart is new and cites several studies. The Sceptical Chymist (talk) 21:18, 20 June 2009 (UTC)

You ignor all my points, please address them.--Literaturegeek | T@1k? 21:26, 20 June 2009 (UTC)

RE: Problem 2.

My edit However, researchers often hold contrary opinions regarding the effects of long-term administration. PMID 15762814: "Among the most controversial of these effects are cognitive effects...The literature is divided, however, on the persistence of cognitive effects in patients taking benzodiazepines long term." PMID 14731058: "The literature that is available is difficult to interpret due to conflicting results as well as a variety of methodological flaws."

My edit: One view is that many of the short-term effects continue into the long-term and may even worsen, and are not resolved after quitting benzodiazepines. PMID 15762814: "Long-term treatment with benzodiazepines has been described as causing impairment in several cognitive domains... The Barker et al. group followed up their first metaanalysis by addressing a question that naturally ensues: if long-term benzodiazepine use affects cognition, are these cognitive changes reversible upon withdrawal of benzodiazepines"

My edit: Another view maintains that cognitive deficits in chronic benzodiazepine users occur only for a short period after the dose, or that the anxiety disorders is the cause of these deficits. PMID 15762814: "Alternatively, long-term benzodiazepine use has been reported as being unassociated with cognitive dysfunction...Often, even when cognitive effects have been observed in patients taking benzodiazepines, the effects are attributed to sedation or impaired attention; additionally, several studies report memory changes only when benzodiazepines have reached their peak plasma level, suggesting that specific cognitive changes are temporary and linked to time since last dose... Complicating the issue of the cognitive effects of longterm benzodiazepine treatment are cognitive changes associated with anxiety itself... dysfunction. Anxiety disorders have been shown to impair attention and concentration, 11 so arguably relief of anxiety may improve cognition." PMID 14731058: "In contrast, some researchers claim little or no memory effect caused by long-term benzodiazepine use. Golombok et al. found no evidence of memory impairment in 50 patients who had used benzodiazepines for >1 year. These authors argued that there was a strong relationship between the sedative and amnesic effects of the drugs, suggesting that as patients become tolerant to the sedative effects of the drugs, memory deficits were no longer apparent. Similarly, Lucki et al. found that any impairment evident in their group of 43 long-term benzodiazepine users appeared to diminish with time after the last dose was increased. These results suggest that memory impairments, if they do occur, may be due to the acute effects of the drug and do not support the hypothesis that long-term benzodiazepine use leads to permanent memory impairment." The Sceptical Chymist (talk) 20:02, 20 June 2009 (UTC)

But you are cherry picking mentions of primary sources in review articles to dispute conclusions of a meta-analysis. See conclusion. "CONCLUSION: Moderate-to-large weighted effect sizes were found for all cognitive domains suggesting that long-term benzodiazepine users were significantly impaired, compared with controls, in all of the areas that were assessed."

I would liuke to make a third attempt to request you to address my point of using a CT scan to remove a statement on neurons.--Literaturegeek | T@1k? 20:08, 20 June 2009 (UTC)

Same with this rebiew, here are their conclusions. "to settle this debate, meta-analyses of peer-reviewed studies were conducted and found that cognitive dysfunction did in fact occur in patients treated long term with benzodiazepines, and although cognitive dysfunction improved after benzodiazepines were withdrawn, patients did not return to levels of functioning that matched benzodiazepine-free controls."

You seem to be using mentions of primary sources to challenge the conclusions of the authors, like doing your own review of their review which is original research.--Literaturegeek | T@1k? 20:10, 20 June 2009 (UTC)

How is it that I am cherry-picking? I am giving whole paragraphs of quotations. You wish to present only one side of the issue. However, if you read both articles you will find that they review the state of the art. Both state that there is a controversy and give arguments of both sides in details. The meta-analysis weighs overall balance somewhat in favor of reality of cognitive defects. That is what I did also by giving it more room. I can expand on the meta-analysis, if you wish. The Sceptical Chymist (talk) 20:24, 20 June 2009 (UTC)

The Sceptical Chymist, what you are doing is considered original research and is not allowed on Wikipedia. Please read reliable sources for medicine-related articles. —Mattisse (Talk) 20:30, 20 June 2009 (UTC)

No I am not doing OR. I am using reviews, citing them almost exactly. The Sceptical Chymist (talk) 20:41, 20 June 2009 (UTC)

I would like to support Literaturegeek | T@1k? on this issue, as I read the very thorough paper on the meta-analyses, and this is indeed the conclusion it reached. It also concluded that the cognitive dysfunction might not be noticeable in everyday life, but it did conclude that it existed. —Mattisse (Talk) 20:17, 20 June 2009 (UTC)

Yes, that is exactly what I wrote. That "the former view [many of the short-term effects continue into the long-term and may even worsen, and are not resolved after quitting benzodiazepines] recently received support from a meta-analysis of 13 small studies." The Sceptical Chymist (talk) 20:41, 20 June 2009 (UTC)

You are doing your own review on a review article by using primary sources cited in the review to cast doubt on the conclusions of the authors so it is original research of the worst kind. It wouldn't be so bad if it was OR which was in keeping with the line the sources were on but you are casting doubt on the conclusions by doing your own review like making a minority opinion in the literature equal to the conclusion, i.e.e you are distorting the paper. Please quit edit warring over this!--Literaturegeek | T@1k? 21:12, 20 June 2009 (UTC)

RE: Problem 2. (contd.)

My edit: While the definitive studies are lacking... PMID 14731058 (the meta-analysis itself): From the introduction -- "Clearly, well controlled, methodologically sound studies are required which involve heterogeneous groups of subjects and multiple measures of cognitive functioning. The feasibility of such large scale studies may be limited." From the results-- "An analysis of heterogeneity was considered inappropriate due to the small number of studies that met the inclusion criteria in this meta-analysis, and the limited information provided on relevant characteristics... The small number of studies included in the meta-analysis also resulted in insufficient data to conduct a thorough investigation of the contribution of moderator variables." From the Conclusion -- "In order to fully investigate the nature of impairment after long-term use of benzodiazepines larger-scale studies, which examine many areas of memory are needed. Clearly, this is not feasible and a more likely scenario is one that involves conducting many smaller, well designed studies that thoroughly investigate certain areas of cognitive functioning and present data in such a way so as to be amenable to inclusion in a meta-analysis. Incorporating this information into a larger meta-analysis would allow for a more thorough and statistically sound investigation of the effects of moderator variables – an obvious shortcoming of the current investigation associated with the dearth of literature available." Review PMID 15762814 discussing the meta-analysis: "In their introduction to the first metaanalysis, the authors acknowledged the small number of studies and addressed the limitations of comparing studies with different methodologies. The most obvious problems in comparing studies include variable definitions of longterm use with a wide range of doses and duration of use represented, poorly defined coexisting drug and alcohol use, and the heterogeneity of psychiatric diagnoses in both subjects and controls. Also, some studies do not define the length of time from benzodiazepine dose to cognitive testing, which may create problems differentiating acute from chronic effects. Among these limitations, heterogeneity of psychiatric diagnosis is perhaps the most significant in evaluating the meaning of results. Subjects are often selected for benzodiazepine use, not necessarily for psychiatric diagnosis, and since benzodiazepines are prescribed for a wide variety of conditions, it may be that patients with different disorders will also vary with regard to side effects and risk:benefit ratio. Furthermore, Barker et al.9 noted that subjects are frequently recruited from withdrawal clinics, which may create a sampling bias because such subjects typically have heightened concern about problems attributable to benzodiazepine use." The Sceptical Chymist (talk) 21:07, 20 June 2009 (UTC)

My edit: ...the former view [many of the short-term effects continue into the long-term and may even worsen, and are not resolved after quitting benzodiazepines] recently received support from a meta-analysis of 13 small studies. PMID 14731058 (the meta-analysis itself): "Of the 13 independent studies used in the meta-analysis,all were published in peer-reviewed journals. The overall mean number of patients who were benzodiazepine users was 33.5 (SD ± 28.9; range 10–96; median 21) and the mean number of controls was 27.9 (SD ± 19.6; range 10–56; median 20)." The Sceptical Chymist (talk) 21:16, 20 June 2009 (UTC)

Please stop edit warring over your original research Sceptical. We do not need to find consensus regarding original research, it is not allowed. Take debate to WP:MEDRS and try to persuade them to allow OR in FA articles.--Literaturegeek | T@1k? 21:12, 20 June 2009 (UTC)

Since when summarizing reviews is OR? According to WP:OR, "Summarizing or rephrasing source material without changing its meaning is not synthesis — it is good editing. Best practice is to write Wikipedia articles by taking material from different reliable sources on the topic and putting those claims on the page in your own words, with each claim attributable to a source that explicitly makes that claim." On the other hand, picking out only the sentences you like is POV since WP:NPOV policy "requires that where multiple or conflicting perspectives exist within a topic each should be presented fairly." The Sceptical Chymist (talk) 21:26, 20 June 2009 (UTC)

"without changing its meaning".--Literaturegeek | T@1k? 21:50, 20 June 2009 (UTC)

Anxiolytic tolerance

O'Brien paper used to debunk authoritative bodies etc. Sceptical claims it is "latest evidence but O'Brien study cites an opinion piece from the early 1970's from Marks J a doctor from Hoffman La Roche". Tolerance and dependence was not even accepted back in the 70's and was denied until the 1980's. The next study cited in O'Brien non-systemic review is a primary source where long term users on benzos were giev a small dose increase, no increased sedation occured but feelings of tranquility were felt when dose was temporarily increased. First off tolerance is actually defined by "having to increase the dose to achieve the same effect" so their findings are worthless. Secondaly they made a big issue out of how sleep inducing effects were not seen from dose increase but anxiolytic effects were seen. This can be explained simply by the fact (which the authors seemed ignorant of) that hypnotic effects require a larger dose of benzos!!! Sounds like a paper by authors who are not specialits in the area that they are researching! This weak review paper has been used to delete the reviews by experts in the fiel eg Ashton and disagree with expert panels, (See above).--Literaturegeek | T@1k? 20:44, 20 June 2009 (UTC)

It is not a good practice to represent only one view in a clearly controversial topic. Many psychiatrists in the US believe that the UK point of view represented by NICE is extreme. This found reflection in multiple articles and textbooks edited by the US-based scientists. The Sceptical Chymist (talk) 21:34, 20 June 2009 (UTC)

Where on earth did you get this statement from? It certainly wasn't in the references. "The development of tolerance has not been demonstrated in controlled studies, while anecdotal evidence goes both ways."

Only anecdotal evidence exists? Not in ref. Stop intentionally faking data and doing original research and then fighting about it. I will never compromise with faked data. Science works on evidence, please find me strong evidence, not "a doctor" who cherry picked one or 2 sources and came to dubious conclusions which you grossly worsened by adding fake facts. please find a systematic review of the peer reviewed literature and stop using weaker opinion pieces by individual doctors. I have no problem if you want to cite that some doctors disagree with this but you are faking refs, doing original research on some mission to insert what you think is "the truth".--Literaturegeek | T@1k? 21:47, 20 June 2009 (UTC)

The development of tolerance has not been demonstrated in controlled studies PMID 15762817: "Tolerance. While there is controversy about whether or not patients develop tolerance to the anxiolytic effects of benzodiazepines, tolerance to some of the other effects, including the sedation generally brought on by benzodiazepines, does develop...This disapproval of long-term use was supported with the hypothesis that patients develop a tolerance to the antianxiety effects of benzodiazepines, which, if true, would mean that benzodiazepines would be medically useful only for short-term treatment, and patients would not need to use benzodiazepines long enough to develop a dependence. However, clinical evidence does not support the development of this tolerance"

while anecdotal evidence goes both ways. Anecdotal evidence against tolerance to anxiolytic effects -- PMID 15762817: "in fact, anecdotal evidence from prescribing psychiatrists often indicates long-term anxiolytic effectiveness of benzodiazepines." Anecdotal evidence in favor of tolerance to anxiolytic effects, see PMID 16639148. The Sceptical Chymist (talk) 22:14, 20 June 2009 (UTC)

POV tag

A POV tag was dded because two editors myself and Mattisse regarded edits to be original research and agreed that review articles should not be rereviewed and have doubts cast on conclusions and that we should stick to the conclusions of the author. Consensus can never be reached because original research is not allowed on wikipedia especially FA articles.--Literaturegeek | T@1k? 21:56, 20 June 2009 (UTC)

I have now cited both sides of the debate using good quality sources, citing that long term use of benzos may help anxiety (took ref from anxiety section of therapeutic uses) and the review saying benzos may worrsen anxiety. As i said in ref summary, who knows perhaps both arguments are correct, perhaps some people get continued benefits on benzos and some get "ill" on benzos, long term. I have no problem bringing balance to the article. I just simply do not like refs being faked and reviews being rereviewed, i.e. original research.--Literaturegeek | T@1k? 22:16, 20 June 2009 (UTC)

History

It is a minor point, but could the manufacturer of Valium be clearer in the History section. Snowman (talk) 23:03, 18 June 2009 (UTC)

Someone added that Roche Pharm patented and manufactured Valium. :)--Literaturegeek | T@1k? 21:33, 19 June 2009 (UTC)

Pharmacophore graphic

Pharmacophore model of the benzodiazepine binding site on the GABA_A receptor.(Madsen et al.) White sticks = carbon atoms of diazepam, green = carbon atoms of CGS-9896, red = oxygen, blue = nitrogen. The red spheres labeled H1 and H2/A3 are presumed hydrogen bond donating and accepting sites respectively in the receptor. L1, L2, and L3 represent lipophilic binding sites.

To the right is a proposed figure for the Benzodiazepine#Chemistry section. Before adding it to the article, I thought I would first bring up the proposal here. Is the figure and caption too technical for a FAC? Suggestions are welcome. Boghog2 (talk) 21:44, 20 June 2009 (UTC)