Talk:Benzodiazepine/Archive 2

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

For example, one of the references used in the article ^[1] 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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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

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

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)[reply]

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)[reply]

"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)[reply]

"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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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.^[2] 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)[reply]

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)[reply]

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)[reply]

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)[reply]

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); 01:49, 23 June 2009 (UTC)~~ 06:56, 23 June 2009 (UTC)[reply]

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)
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)
Barker et al. 2004 (PMID 14731058)
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. 20 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)
Bogan 2008 (PMID 18824834)
Lader 2008 (PMID 18671662)
Olkkola & Ahonen 2008 (PMID 18175099)
Saïas & Gallarda 2008 (PMID 18922233)
Tariq & Pulisetty 2008 (PMID 18035234)
Zimbroff 2008 (PMID 18278976)
ElDesoky 2007 (PMID 17890940)
Kintz 2007 (PMID 17340077)
Lemmer 2007 (PMID 17049955)
Perugi et al. 2007 (PMID 17696574)
Bain 2006 (PMID 16860264)
Ebell 2006 (PMID 16623205)
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)
Otto et al. 2005 (PMID 15762818)
Stevens & Pollack 2005 (PMID 15762816)
Stewart 2005 (PMID 15762814)
Verdoux et al. 2005 (PMID 15841867)
Ashton 2004 (PMID 7525193)
Bogunovic & Greenfield 2004 (PMID 15001721)
Chouinard 2004 (PMID 15078112)

Doyle & Pollack 2004 (PMID 15078115)

DTB 2004 (PMID 15587763)
Faught 2004 (PMID 16400293)
Seger 2004 (PMID 15214628)
Wafford et al. 2004 (PMID 15157182)
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)
Mañon-Espaillat & Mandel 1999 (PMID 9929772)
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)
Ashworth & Gerada 1997 (PMID 9270461)
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)
Ayers et al. 2007 (ISBN 978-0521879972)
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)
Haddad et al. 2004 (ISBN 978-0198527480)
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)
Palmer et al. 1996 (ISBN 978-0803974777)

Biomedical websites. Looks OK.

Government-maintained websites. The first is authoritative for its point. Barbui & Cipriani 2009 is a bit iffy, as it's just a proposal. Can we find a better source for that claim?

History articles. These look good.

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

Summary websites. These look fine too.

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); 01:49, 23 June 2009 (UTC)~~ 06:56, 23 June 2009 (UTC)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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

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)[reply]

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

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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

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)[reply]

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)[reply]

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)[reply]

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

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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)[reply]

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

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)[reply]

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)[reply]

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

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)[reply]

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

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

^ Trevor R Norman,. "Benzodiazepines in anxiety disorders: managing therapeutics and dependence" (PDF). The Medical Journal of Australia. Retrieved 11 December 2008. {{cite web}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: extra punctuation (link)
^ Atack JR (2003). "Anxioselective compounds acting at the GABA_A receptor benzodiazepine binding site". Curr Drug Targets CNS Neurol Disord. 2 (4): 213–32. doi:10.2174/1568007033482841. PMID 12871032.

[biadmtad-1] Trevor R Norman,. "Benzodiazepines in anxiety disorders: managing therapeutics and dependence" (PDF). The Medical Journal of Australia. Retrieved 11 December 2008. {{cite web}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: extra punctuation (link)

[pmid12871032-2] Atack JR (2003). "Anxioselective compounds acting at the GABA_A receptor benzodiazepine binding site". Curr Drug Targets CNS Neurol Disord. 2 (4): 213–32. doi:10.2174/1568007033482841. PMID 12871032.

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