Talk:Alprazolam/Archive 2

Archive 1

Archive 2

Archive 3

Request for edit to update drugbox

Updated drugbox

Alprazolam/Archive 2 Clinical data Trade names Xanax AHFS/Drugs.com Monograph MedlinePlus a684001 Routes of administration Oral ATC code N05BA12 (WHO) Legal status Legal status UK: POM (Prescription only) US: Schedule IV Pharmacokinetic data Bioavailability 80–90% Metabolism Hepatic, via Cytochrome P450 3A4 Elimination half-life Immediate release: 11.2 hours, Extended release: 10.7–15.8 hours Excretion Renal Identifiers IUPAC name 8-chloro-1-methyl-6-phenyl-4H- [1,2,4]triazolo[4,3-a][1,4]benzodiazepine CAS Number 28981-97-7 PubChem CID 2118 DrugBank DB00404 ChemSpider 2034 Y UNII YU55MQ3IZY KEGG D00225 Y ChEBI CHEBI:2611 Y ChEMBL ChEMBL661 Y Chemical and physical data Formula C17H13ClN4 Molar mass 308.765 g·mol−1 3D model (JSmol) Interactive image SMILES Clc3cc2\C(=N/Cc1nnc(n1c2cc3)C)c4ccccc4 InChI InChI=1S/C17H13ClN4/c1-11-20-21-16-10-19-17(12-5-3-2-4-6-12)14-9-13(18)7-8-15(14)22(11)16/h2-9H,10H2,1H3 Y Key:VREFGVBLTWBCJP-UHFFFAOYSA-N Y   (verify)

— Preceding unsigned comment added by Boghog (talk • contribs) 14:43, 13 August 2011 (UTC)

Not as clear as it could be on the intro

Alprazolam has a fast onset of symptom relief (within the first week). It is unlikely to produce dependency or abuse. No tolerance has been reported, but withdrawal and rebound symptoms necessitate a gradual reduction in dosage to minimize withdrawal effects when discontinuing.[5][6] It is a C IV controlled substance by the DEA. Alprazolam is the most prescribed[7] and the most abused benzodiazepine in the US.[8]

So it is unlikely to produce abuse while it is the most abused benzodiazepine. A little logic shows that either this is contradictory or benzodiazepines as a class are not commonly abused in the US. — Preceding unsigned comment added by 187.37.4.36 (talk) 19:06, 18 August 2011 (UTC)

The issue appears to have to due to the age of the evidence. At one point it was believed to be of low risk. This now no longer appears to be the case. Doc James (talk · contribs · email) 06:36, 19 August 2011 (UTC)

In fact the ref reports the situation from use in anxiety patients, where it is unlikely to produce abuse and dependence, that is what the review article was about. And this didn't change but still holds. That benzodiazepines are abused e.g. by underage persons, who cannot buy alcohol, because such sedatives may substitute for alcohol is a different issue and a reason for concern. Benzodiazepines are not commonly abused, compared to the volume of prescriptions in the US - 44Mio p.a. alone for alprazolam. 70.137.130.19 (talk) 10:15, 19 August 2011 (UTC)

Edit request from Peterbarglowmd, 19 August 2011

There is a clear contradiction in paragraph II. Note line 10 beginning with "Alprazolam has a fast onset...." Sentence two, (2) starts,"It is unlikely to produce dependency or abuse. (3) No tolerance has been reported, but....". Sentence #(5) reads "Alprazolam is the most prescribed (Ref 7) and the most abused benzodiazepine in the US (Ref 8)".

All specialists in Addiction Medicine and almost all doctors agree that Alprazolam (Xanex) produces rapid tolerance (higher doses needed to get a target effect, or prescribed doses become insufficient to produce results), and that the agent is likely to produce substance dependence and/or abuse. The last two terms refer in the current, 2011 DSM IV-TM diagnostic code to 1. tolerance; 2. a withdrawal syndrome or disagreeable mental-physical condition when stopped; 3. a toxic response with excessive doses of the agent; 4. an interference with normal usual daily functioning. The above clear contradiction in the Wikipedia information is confusing at best, and at worst is dangerous to the health of patients using this popular anti-anxiety medicine.

Peterbarglowmd (talk) 05:48, 19 August 2011 (UTC)

It is indeed "unlikely" to be abused by the persons, to whom it is prescribed. However, there is still a low-to-moderate (as reflected by C IV) abuse liability. Compared to the huge volume in which alone Alprazolam is prescribed, namely 44 Mio. prescriptions per year in the US, the abuse figures are still very low. That it is the most abused benzodiazepine in the US largely reflects that it is also the most prescribed in the US. In other countries other benzodiazepines are abused. Over all, the abuse of benzodiazepines, according to some other sources, largely occurs in people who tend to become dependent on alcohol. The regular patients usually do not describe euphoria as a side effect (e.g. only in around 1% of the cases for the sleeping medication temazepam, which otherwise has been alleged to be abused more frequently than other benzodiazepines). The large majority of prescription patients with a genuine need for the medication tend to feel other unpleasant side effects like drowsiness and a sleepy feeling, which they describe as unpleasant and a reason to discontinue the medication. The abuse of benzodiazepines by e.g. underage people who got kicked out of the liquor store or Systembolaget alcohol shop in some countries with controlled sale of alcohol and high penalties for underage drinking is a different issue. These are not patients who use the prescription for a legitimate purpose, but young drunkards who try to find a substitute for alcohol. This kind of abuse is generally a reason for concern for all kinds of sedatives, as they to some degree may substitute for alcohol. Hope this explains it. 70.137.130.19 (talk) 06:10, 19 August 2011 (UTC)

The given reference finds, what has been cited. Common sense and alleged "agreed common knowledge of addiction specialists and almost all doctors" is not sufficient for inclusion in the article or for your edit request, what we need is WP:MEDRS sources for that. The cited review article comes to different conclusions. 70.137.130.19 (talk) 06:16, 19 August 2011 (UTC)

N Not done. Peterbarglowmd, I cannot act on your request because you have not told us which specific change you propose.  Sandstein  21:21, 20 August 2011 (UTC)

Text

So are you okay with "The risk of dependency and abuse is low similar to that of other benzodiazepines. Tolerance developing to it anxiolytic effects has not commonly been reported Doc James (talk · contribs · email) 16:16, 20 August 2011 (UTC)

Sounds ok. to me. What is the uptodate.com source? Is it a viable WP:MEDRS source? 70.137.130.120 (talk) 16:55, 20 August 2011 (UTC)

Yes it is a high quality source. The problem is that one must pay $400 USD a year for access. UpToDate Doc James (talk · contribs · email) 17:09, 20 August 2011 (UTC)

The 400 bucks, that sucks, can we substitute something equally high quality which is clickable, at least in the abstract, e.g. PMID with abstract? Are there newer review articles, or can we archive or include a snippet from uptodate into citation? 70.137.130.120 (talk) 17:26, 20 August 2011 (UTC)

This ref states "These symptoms may reflect the development of tolerance or a time interval between doses which is longer than the duration of clinical action of the administered dose." [1] Doc James (talk · contribs · email) 17:54, 20 August 2011 (UTC)

In fact they offer an explanation for rebound symptoms without stating clearly what tolerance they are talking about and why. Is too diffuse to be used as a ref for tolerance. Could be this or that... depends on the question if it overshoots base line. Could be intermittent discontinuation symptom, like seen in triazolam. Anyway, text looks ok. to me. 70.137.130.120 (talk) 18:16, 20 August 2011 (UTC)

clickable links below: Boghog (talk) 17:34, 20 August 2011 (UTC)

We have to substitute clickable for the uptodate, its subscriber only. 70.137.130.120 (talk) 18:20, 20 August 2011 (UTC)

Another try

"The risk of dependency and abuse is low similar to that of other benzodiazepines. Tolerance does not appear to develop to the anxiolytic effects but may develop to the sedative effects within a couple days."Doc James (talk · contribs · email) 18:26, 20 August 2011 (UTC)

I have not checked against ref Pavuluri et al. yet, but sounds ok. 70.137.130.120 (talk) 18:35, 20 August 2011 (UTC)

Great, so unless there are concerns in the next day or so I will go ahead and update the article with this.Doc James (talk · contribs · email) 18:39, 20 August 2011 (UTC)

Page 535 is not viewable in ref Pavuluri et al., google-books. 70.137.130.120 (talk) 19:06, 20 August 2011 (UTC)

Visible where I am. If I have an email address I could sent you that page.Doc James (talk · contribs · email) 21:06, 20 August 2011 (UTC)

With the new link included I can now see it. Regarding tolerance it says: Nagy et al. ... found... indicating that tolerance did not develop... Nagy et al. found that patients sustained improvement with lower doses, and others report similar findings (94,100). By contrast Rashid et al. (101) found a need to increase dose over time. Regarding tolerance to the sedative side effect(!) it says that tolerance or partial tolerance may develop within a few days... or in other patients (48% and 39%)... in the Cross Collaborative study still did not develop at week 4 and 8. So the picture is not completely clear. I have no access to their refs. I guess a newer review article would be helpful as a secondary source, so that we avoid synthesis from this ref. I think we have to cite may develop within a few days, or not develop within 4 to 8 weeks or the like to be precise. The typically is too strong. We have to take care that the intro is not too bulky and still avoid synthesis. 70.137.144.158 (talk) 04:07, 21 August 2011 (UTC)

Agree and changed to "may" Doc James (talk · contribs · email) 05:31, 21 August 2011 (UTC)

Ok then insert that before the "need to taper" as is now in the article and the C IV. I think its ok. We are settled. Don't expect that this will stop protests in the future, like the ones above. 70.137.137.92 (talk) 05:50, 21 August 2011 (UTC)

Regarding tolerance, the dissenting report by Rashid (ref 101 in your ref Pavaluri) has already been cited by Ayd FJ et al. in 1986/1988, so it must be very dated. Can you check? I don't find it in Pubmed. He also claims the maximum daily dose of alprazolam may not exceed 1mg. I believe that is too old to cite. 70.137.145.36 (talk) 12:05, 22 August 2011 (UTC)

You are wanting a copy of Rashid? Not sure how to get access to it. Doc James (talk · contribs · email) 16:17, 22 August 2011 (UTC)

Well I thought you may have a subscription to fulltext services or extended search services at work. What is your opinion? 70.137.151.53 (talk) 17:23, 22 August 2011 (UTC)

Found the book in question on google books. If you have the PMID or the full title I may be able to get access to the paper in question.Doc James (talk · contribs · email) 17:29, 22 August 2011 (UTC)

It is ref 101 in above ref Pavuluri. I cannot acces the page with ref 101, on google books, maybe you try. I found a citation to a ref by Rashid about alprazolam. It was from 1986/1988. I believe this was it. Seems obscure. 70.137.151.53 (talk) 17:36, 22 August 2011 (UTC)

Yes unable to access 101 either. The ref is this textbook and not what it is referring to however.Doc James (talk · contribs · email) 17:39, 22 August 2011 (UTC)

Ok., as we already have this textbook plus ref Verster et al. I will not insist that we dig deeper. 70.137.151.53 (talk) 17:48, 22 August 2011 (UTC)

There are also no review articles on alprazolam, newer than Verster, on Pubmed. So this looks like best we can do. 70.137.151.53 (talk) 17:58, 22 August 2011 (UTC)

Here fulltext Verster et al.

http://www.ambrosecriminallaw.com/images/Review%20of%20Clinical%20Alprazolam%20Study.pdf

70.137.151.53 (talk) 20:43, 22 August 2011 (UTC)

Licensing

Are these FDA labels in the public domain? causa sui (talk) 00:13, 15 September 2011 (UTC)

They are the reference text at the FDA gov site and have regulatory character. Like with laws they are public. 70.137.129.34 (talk) 00:17, 15 September 2011 (UTC)

You know, Wikipedia is not supposed to give people medical instruction, or any kind of instruction. WP:NOTHOW For example, the entry on USB drives doesn't explain to people how to install a USB drive.

This entry shouldn't come too close to giving physicians or patients instructions on how alprazolam should be used.

Good science writing doesn't give people a lot of data. It explains the scientific principles behind that data.

If physicians should periodically reassess the usefulness of the drug for the individual patient, it's not a good enough reason to say that the FDA label says so. The reason is that the good-quality studies of alprazolam only lasted 8 weeks. We're not giving prescribing information. We're helping people understand pharmacology.

Similarly, the long lists of side effects don't tell you anything that you couldn't get more easily and reliably from the package insert. We should only give side effects if (1) they're clinically important enough to affect the drug's use (2) they illustrate something about the pharmacology of the drug, for example, if they bind to the same receptor which has a distribution in the brain, the GI system, and the eye.

The more information we put in that doesn't have an educational purpose, the more likely it is for a reader to be confused and not get to the end. --Nbauman (talk) 16:54, 15 September 2011 (UTC)

Well it is an encylopedia, not pop-scientopedia, so it should be informative to academics too. But I agree that e.g. "death" does not belong with the side effects, and your general idea about useful and understandable info is ok. and I support it. 70.137.156.237 (talk) 19:47, 15 September 2011 (UTC)

why can't I see the section panic disorder any more? i get inconsistent display, the diffs still show it but not the article? 70.137.156.237 (talk) 19:09, 15 September 2011 (UTC)

found it causa garbled ref syntax, thats why it displayed funny. Besides why 1RR, the dispute is already resolved? 70.137.156.237 (talk) 19:26, 15 September 2011 (UTC)

I suggested 1RR because (as I saw the timeline): you added the same cautioning statement verbatim twice in the article, which may be informative but is definitely bad writing; I removed one instance citing the redundancy; and you simply reinserted it, giving rationale in your edit summary. While not a flagrant rule violation, it's bad manners, so I pointed you to WP:1RR: if someone is reverting you, it means they disagree with what you are doing, and so you should probably take it to talk at that point. I hope that helps. causa sui (talk) 20:01, 15 September 2011 (UTC)

I am satisfied with your edit, thats ok. But I do not agree, that replicating statements to several sections or chapters is bad writing. It is done intentionally, to enable a text that is complete for each section, such that you can skip and read sections by themselves, without having to read a whole prologue. It is frequently done in scientific and technical writing and documentation, to enable selective reading of chapters or sections. In this case, if I am interested in the panic disorder section, I need only to read this. Same for the anxiety disorder section etc. I know that they teach kids in school that it is bad writing. But this is not an essay. Trust me. 70.137.156.237 (talk) 00:10, 16 September 2011 (UTC)

No, this is not an essay, and I am not a kid in school either. You seem determined to condescend to others. The writing is bad because this is an encyclopedia and not a medical textbook. causa sui (talk) 15:22, 16 September 2011 (UTC)

Besides, the "tome above" which you mentioned earlier, is not by me, but by 76.xxxx, I am usually concise. 70.137.156.237 (talk) 00:51, 16 September 2011 (UTC)

You should register an account to avoid the confusion. causa sui (talk) 15:22, 16 September 2011 (UTC)

You should just try to remember two digits, namely 70 vs 76, then you would avoid confusion. It is again the "cross eyed judge" effect, which is counterproductive. 70.137.145.194 (talk) 16:58, 17 September 2011 (UTC)

New section by User:76.231.190.217

To Wikipedia Regarding misinformation in the entry for Xanex, Alprazolam August 25, 2011

We realize that the commentary below is relatively lengthy. It may be more easily readable as the PDF that we created to hold our remarks. For your convenience, we have posted that to the website: www.barglow.com/WikipediaXanax.pdf.

We note recent changes to this Wikipedia entry, and object to the current sentence: “The risk of dependency and abuse is low[5] similar to that of other benzodiazepines.[6]”

It’s true that Alprazolam is similar in its effects to other benzodiazepines, due to the chemical similarity of all Benzodiazepines (BZDs). But the “risk of dependency and abuse” is high not low, as is claimed in the Wikipedia description. We note moreover that the phrase being contested occurs near the beginning of the Wikipedia entry. And although this phrase is qualified by later material in the entry itself, many if not most readers may not read the article carefully all the way through, and may therefore come away from the entry with a faulty understanding based on reading only its first couple of paragraphs. Hence our request in this communication to you that the phrase in question be changed or dropped.

We do recognize the therapeutic usefulness of benzodiazepines such as Alprazolam. Properly used, they alleviate distressing physical and emotional symptoms and relieve suffering. But of course it’s important to use them thoughtfully and cautiously, which requires that we – as prescribers or users or prospective users of these substances -- take into full account the wide range of consequences that use carries, including the risk of dependency and abuse.

Our attention was first drawn to this Wikpedia entry when a patient of Dr. Peter Barglow printed out a sentence in the entry that minimizes the addictive danger of Alprazolam. The patient then highlighted with a marking pen the claim in the Wikipedia entry minimizing the risk of addiction “It [Alprazolam] is unlikely to produce dependency or abuse.” Unfortunately, this patient is currently suffering from an addiction to this agent. He reported to Dr. Barglow that, basing his understanding on this Wikipedia entry, he was reassured that he would not become addicted through the use of Alprazolam (or “Xanax,” as he called it).

What do the terms “dependence (or dependency)” and “abuse” mean? The most widely accepted definition of dependence – a term that has advantages over the more stigmatizing word “addiction” -- has been given by the American Psychiatric Association and receives expression in the 1994 DSM IV Psychiatric criteria for the diagnosis, “Substance Dependence”:

Substance dependence is defined as a maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by three (or more) of the following, occurring any time in the same 12-month period: 1. Tolerance, as defined by either of the following: (a) A need for markedly increased amounts of the substance to achieve intoxication or the desired effect or (b) Markedly diminished effect with continued use of the same amount of the substance. 2. Withdrawal, as manifested by either of the following: (a) The characteristic withdrawal syndrome for the substance or (b) The same (or closely related) substance is taken to relieve or avoid withdrawal symptoms. 3. The substance is often taken in larger amounts or over a longer period than intended. 4. There is a persistent desire or unsuccessful efforts to cut down or control substance use. 5. A great deal of time is spent in activities necessary to obtain the substance, use the substance, or recover from its effects. 6. Important social, occupational, or recreational activities are given up or reduced because of substance use. 7. The substance use is continued despite knowledge of having a persistent physical or psychological problem that is likely to have been caused or exacerbated by the substance (for example, current cocaine use despite recognition of cocaine-induced depression or continued drinking despite recognition that an ulcer was made worse by alcohol consumption).

The 1994 DSM IV defines “Substance Abuse” as follows:

Substance abuse is defined as a maladaptive pattern of substance use leading to clinically significant impairment or distress as manifested by one (or more) of the following, occurring within a 12-month period: 1. Recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home (such as repeated absences or poor work performance related to substance use; substance-related absences, suspensions, or expulsions from school; or neglect of children or household). 2. Recurrent substance use in situations in which it is physically hazardous (such as driving an automobile or operating a machine when impaired by substance use) 3. Recurrent substance-related legal problems (such as arrests for substance related disorderly conduct) 4. Continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance (for example, arguments with spouse about consequences of intoxication and physical fights). Source: American Psychiatric Association. 1994. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. Washington D.C.: American Psychiatric Association. (pp. 181-183)

The above criteria are identified and relied upon thousands of times in psychiatric, psychological, and addiction-related articles.

By these criteria, the Wikipedia entry claim that “The risk of dependency and abuse is low[5] similar to that of other benzodiazepines.[6]“ is clearly false, and we ask that it be changed or removed. The research evidence against the claim is abundant and conclusive. In what follows, we will present a small but representative fraction of that evidence, in the hopeful expectation that, in conjunction with your own investigation, you will be persuaded to make the modification we are requesting.

We offer the following considerations:

I. Low risk? What is the meaning of “low” risk in the phrase whose truth we are contesting? “Low” compared to what? Nutt et. al. published in Lancet in 2007 an article in which a group of expert scientists compared 20 agents widely considered to be addicting. (Nutt, D., King, L. A., Saulsbury, W., & Blakemore, C. (2007) “Development of a rational scale to assess the harm of drugs of potential misuse.” Lancet, 369, 1047-1053) The comparison was based on 16 criteria, 9 related to harm of the drug to the individual and 7 related to estimation of its harmful effects upon other persons. The 20 drugs were rated in regard to dependence, withdrawal reactions, reinforcement of negative behaviors and intoxication risk. Benzodiazepines (BZDs) ranked higher on dependence, with a score of 1.83, than amphetamines (1.67) and marijuana (1.51), but lower than tobacco (2.21). On the social harm criterion, BZDs ranked higher than the three other substances, with a score of 1.65, compared with amphetamines and marijuana (each scoring 1.50), and tobacco (1.42).

II. Pfizer specifications. Pfizer (the US manufacturer of Xanex) publishes this description of the drug on the company’s web site: http://labeling.pfizer.com/ShowLabeling.aspx?id=547. On page 5 this description states that “Certain adverse clinical events, some life-threatening are a direct consequence of physical dependence to XANAX. These include a spectrum of withdrawal symptoms. Even after relatively short term use and doses recommended for treatment of transient anxiety and anxiety disorders, there is some risk of dependence.”

Note Pfizer’s acknowledgement that withdrawal symptoms are closely affiliated to substance dependency. Indeed, the DSM IV definition of substance dependence lists withdrawal as one of the criteria for dependence.

On page 7 it is stated that “Withdrawal reactions may occur when dosage reduction occurs for any reason.”

On page 18 it is stated that “While the severity and incidence of withdrawal phenomena appear to be related to dose and duration of treatment, withdrawal symptoms, including seizures, have been reported after only brief therapy with XANAX at doses within the recommended range for the treatment of anxiety (eg, 0.75 to 4 mg/day).… Psychological dependence is a risk with all benzodiazepines, including XANAX. The risk of psychological dependence may also be increased at doses greater than 4 mg/day and with longer term use, and this risk is further increased in patients with a history of alcohol or drug abuse.”

Pfizer, with an explicit interest in increasing sales, would be unlikely to publicize adverse addictive qualities (dependency and withdrawal symptoms) of a popular drug it manufactures unless these qualities really do characterize the drug.

III. The US Drug Enforcement Agency assigns Xanex to a Schedule C-IV category of “Controlled Substances” that requires a physician to have a DEA license to prescribe them. The agency states: “Controlled Substances are drugs or other chemicals that have the potential to be ‘addictive or ‘habit forming’.”

IV. Additional authorities and studies.

1.National Institute on Drug Abuse: http://www.nida.nih.gov/researchreports/prescription/prescription3.html (this website was updated in 2005, as confirmed by a phone call to NIDA on Aug. 27, 2011): “Despite their many beneficial effects, barbiturates and benzodiazepines have the potential for abuse and should be used only as prescribed…. If one uses these drugs long term, the body will develop tolerance for the drugs, and larger doses will be needed to achieve the same initial effects. Continued use can lead to physical dependence and - when use is reduced or stopped - withdrawal.”

2.“Chronic benzodiazepine administration. I. Tolerance is associated with benzodiazepine receptor downregulation and decreased gamma-aminobutyric acidA receptor function.” Miller LG, Greenblatt DJ, Barnhill JG, Shader RI., J Pharmacol Exp Ther. 1988 Jul;246(1):170-6. http://www.ncbi.nlm.nih.gov/pubmed/2839660 This reference is to an older, but classic and unrefuted, study, finding that “Tolerance occurs to a number of the pharmacodynamic effects of benzodiazepines…. downregulation of benzodiazepine receptor binding and of gamma-aminobutyric acid GABA receptor function is closely associated with behavioral tolerance to benzodiazepines.”

3.“Addiction: Part I. Benzodiazepines--Side Effects, Abuse Risk and Alternatives” by Lance P. Longo, M.D. University of Wisconsin Medical School, Milwaukee, Wisconsin; Brian Johnson, M.D. Harvard Medical School, Boston, Massachusetts Am Fam Physician. 2000 Apr 1;61(7):2121-8. http://www.aafp.org/afp/20000401/2121.html/ Quoting from this study:

“Benzodiazepines enhance the affinity of the recognition site for GABA by inducing conformational changes that make GABA binding more efficacious. Activation of the benzodiazepine-GABA- chloride ionophor complex is responsible for producing the therapeutic anxiolytic effects of benzodiazepines and for mediating many of the side effects and, possibly, dependence and withdrawal from these drugs.6 …

With long-term high-dose use of benzodiazepines (or ethanol), there is an apparent decrease in the efficacy of GABA-A receptors, presumably a mechanism of tolerance.6,7 When high-dose benzodiazepines or ethanol are abruptly discontinued, this "down-regulated" state of inhibitory transmission is unmasked, leading to characteristic withdrawal symptoms such as anxiety, insomnia, autonomic hyperactivity and, possibly, seizures….

The development of physiologic dependence is somewhat predictable and is proportional to the total benzodiazepine exposure (dose 3 duration of treatment), although significant variability may exist among patients. …

When used alone, benzodiazepines carry an extremely low risk of acute toxicity. However, benzodiazepines often are used with other types of medications, including other drugs with abuse potential, and these drugs can enhance the toxic effects of benzodiazepines. The latter interact synergistically with other central nervous system depressants, including other hypnotics, sedating antidepressants, neuroleptics, anticonvulsants, antihistamines and alcohol.8 Fatal overdoses in addicted patients often involve the combination of benzodiazepines and alcohol, with or without opiates. In addition, pharmacokinetic drug interactions may occur…

Tolerance to all of the actions of benzodiazepines can develop, although at variable rates and to different degrees. Tolerance to the hypnotic effects tends to develop rapidly, which may be beneficial in daytime anxiolysis but makes long-term management of insomnia difficult.17 Patients typically notice relief of insomnia initially, followed by a gradual loss of efficacy.18 Tolerance to the anxiolytic effect seems to develop more slowly than does tolerance to the hypnotic effects, but there is little evidence to indicate that benzodiazepines retain their efficacy after four to six months of regular use.19,20 Benzodiazepine therapy is often continued to suppress withdrawal states, which usually mimic symptoms of anxiety. Dosage escalation often maintains the cycle of tolerance and dependence, and patients may have difficulty discontinuing drug therapy.”

V. Wikipedia. Several statements affirming the drug dependence qualities of BDZs appear in the current Wikipedia Alprazolam entry. In paragraph 2: “Tolerance … may develop to the sedative effects within a couple of days.[7] Withdrawal and rebound symptoms do occur commonly and necessitate a gradual reduction in dosage to minimize withdrawal effects when discontinuing.[5][8]”

Note that tolerance and -- as we say in consideration II above -- withdrawal symptoms are among the criteria for dependence. They do not, taken in isolation, produce dependence or addiction, but they are nevertheless central to these conditions.

The Wikipedia entry continues: “Alprazolam is the most prescribed and the most abused benzodiazepine in the US.” Now, it’s true that high abuse of Alprazolam reflects in part the very large number of prescriptions that are given for this drug annually. Still, as we’ve noted above, it is inadvisable to sanction such abuse by giving a misleading characterization of the drug right near the beginning of the Wikipedia entry.

The Wikipedia Alprazolam section on “Dependence and Withdrawal” states that:

“Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor. When bound to these sites, which are referred to as benzodiazepine receptors, it modulates the effect of GABA A receptors and, thus, GABAergic neurons. Long-term use causes adaptive changes in the benzodiazepine receptors, making them less sensitive to stimulation and less powerful in their effects.[50]”

This is a clear statement describing the mechanism of dependence that stems from long-term use of benzodiazepines such as Alprazolam. However, the following Wikipedia paragraph is a little confusing:

“Not all withdrawal effects are evidence of true dependence or withdrawal. Recurrence of symptoms such as anxiety may simply indicate that the drug was having its expected anti-anxiety effect and that, in the absence of the drug, the symptom has returned to pretreatment levels. If the symptoms are more severe or frequent, the patient may be experiencing a rebound effect due to the removal of the drug. Either of these can occur without the patient's actually being drug-dependent.[50]“

Yes, discontinuation may produce a rebound effect. But discontinuation can and often does produce a withdrawal effect, and such an effect is one of the criteria for drug dependence.

The Wikipedia entry on “Benzodiazepine Dependence” documents the addictive qualities of BDZs. For example: “Physical dependence occurs when a person becomes tolerant to benzodiazepines and, as a result of both physiological tolerance and withdrawal symptoms, they develop a physical dependence, which can manifest itself upon dosage reduction or cessation as the benzodiazepine withdrawal syndrome. Addiction, or what it is sometimes referred to as psychological dependence, includes people misusing and/or craving the drug not to relieve withdrawal symptoms but to experience its euphoric and/or intoxicating effects.”

Please note that there are additional references to research documenting addictive qualities in the following sections of this Wikipedia entry:

  Tolerance and Physical Dependence
  Cross tolerance
  Physiology of withdrawal
  Withdrawal
  The Committee on the Review of Medicines (UK)

VI. Critique of Currently Cited References. There are weaknesses or contradictions in sources referenced by notes 5, 6, and 7 of the Alprazolam Wikipedia entry, all provided in support of the assertion of a low risk of abuse and dependency of BZDs. Verster (#5) makes the statement, “no tolerance to its therapeutic effect has been reported”. This negative existential statement is not convincingly backed up by any evidence that Verster adduces. And Verster is overlooking here the considerable amount of reported evidence that does affirm such tolerance. As indicated above in Consideration III, some of that research is referenced by the Wikipedia entry on “Benzodiazepine Dependence.”

On page 53 Verster writes that “The incidence of abuse and dependence in BDZ patient populations is very low,” citing the work of Romach. In checking this study, we see that only 34 users of Xanex on low doses were studied. (Romach, in the American Journal of Psychiatry 1995, 152:1161-1167). Such a small patient population, given low doses, does not yield statistical validity; hence Romach’s results give only weak support to Verster’s claim about “very low” incidence of abuse.

Refererence #6 from the Wikipedia entry references the American Society of Health-System Pharmacists. This reference may confuse the reader, since the authority cited substantiates the second but not the first part of the Wikipedia statement that “The risk of dependency and abuse is low[5] similar to that of other benzodiazepines.[6]” That is, the American Society Health System Pharmacists web page cited does not support the claim that the risk of dependency is low.

Reference #7 from Pavuluri’s textbook Principles and Practice of Psychopharmacotherapy is cited to support the safety of BZDs: “Tolerance does not appear to develop to the anxiolytic effects”. This isolated reference is insufficient to establish absence of tolerance to anxiolytic effects. We note the statement in the Wikipedia entry for “Benzodiazine dependence” that “after 4 months there is little evidence that benzodiazepines retain their anxiolytic properties.” There is ample evidence for substantial tolerance to the major therapeutic effects of the benzodiazepines. Some of that evidence is referenced, for instance, in the Wikipedia entry for “Benzodiazine dependence.”

The Pavuluri sections on BZD in his recent general pharmacology textbook do minimize the significance of dependence. The textbook is very unusual in this regard. We, the authors of this letter to you, know of no other existing US or European textbook that concentrates on the topic of addiction and makes this error. See for example the 1110 page comprehensive textbook Substance Abuse edited by Lowinson, Ruiz, Millman, and Langrod. This text extensively describes and documents, in Chapter 20 the “Epidemiology of Benzodiazepine Abuse.” This concern is buttressed strongly by the scientific articles of Smith, and Wesson, active researchers who still do research and publication here in the San Francisco/Bay area. (References #s 41, 42, 46 on page 279 of this textbook.)

An Internet search for articles on the abuse and dependence potential of benzodiazepines like Xanex yields hundreds of articles published during the past decade. Unfortunately, there is also much misinformation on Web sites, especially those most frequently accessed by lay people seeking information about medications.

Summarizing, we respectfully request the removal of the incorrect statement about Alprazolam: “The risk of dependency and abuse is low[5] similar to that of other benzodiazepines.[6]” Since the stakes are so high for so many patients who are either taking or considering taking a drug like Alprazolam, we are relying on those responsible for this Wikipedia entry to revise its presentation of incorrect or misleading information.

We welcome further discussion on the addictive risks of Xanax-Alprazolam. Please contact either or both of us if you have any questions or responses to our findings. We’ll also look for these in the official Wikipedia discussion of Xanax-Alprazolam.

Thank you for your attention to this matter, and we look forward to seeing the revised Wikipedia entry.

  Peter Barglow, MD
  Raymond Barglow, PhD
  Berkeley, CA
  ph. 510 540 8156

Peter Barglow currently is a Clinical Professor of Medicine at UC Davis Medical School. He was a tenured Professor of Psychiatry at Northwestern University Medical School. Raymond Barglow has a Ph.D. in psychology from the Wright Institute in Berkeley. 76.231.190.217 (talk) 01:17, 1 September 2011 (UTC)

Please consider following ref http://www.psychiatryonline.com/pracGuide/PracticePDFs/PanicDisorder_2e_PracticeGuideline.pdf

Major concerns about benzodiazepine tolerance and

withdrawal have been raised. However, according to the

report of the APA Task Force on Benzodiazepine Dependence,

Toxicity, and Abuse, “There are no data to suggest

that long-term therapeutic use of benzodiazepines by patients

commonly leads to dose escalation or to recreational

abuse” (294). The studies of long-term alprazolam

treatment for panic disorder show that the doses patients

use at 32 weeks of treatment are similar to those used at 8

weeks, indicating that, as a group, patients with panic disorder

do not escalate alprazolam doses or display tolerance

to alprazolam’s therapeutic effects, at least in the first

8 months of treatment. Furthermore, data in the more severely

ill Medicaid population with a mix of mostly mood

and anxiety disorder diagnoses show that long-term use of

benzodiazepines (at least 2 years) does not typically result

in dose escalation, with the incidence of escalation to a

high dose being 1.6% (346).

(from APA guidelines for panic disorder, link above.)

Do not use other wikipedia articles as a ref. They mostly rely on primary sources as references, in particular the "Benzodiazepine dependence" article is highly biased by using an assortment of primary sources to defend a POV against secondary sources. Primary sources and case reports are not viable references according to guidelines for reliable medical sources WP:MEDRS. Please provide appropriate WP:MEDRS conformant sources to support your objections. Even if you are professionals, please do not introduce your own judgement of primary sources into the references and do not weight your own judgement of primary evidence against secondary sources, which support the current article. Neither do introduce your own judgement of the matter as original research according to editing guideline WP:OR. Feel free to support your viewpoint with contemporary peer reviewed clinical review articles or widely recognized contemporary textbooks.

70.137.129.5 (talk) 10:49, 2 September 2011 (UTC)

Furthermore, the existence of discontinuation symptoms, which require tapering to avoid, and withdrawal symptoms on too rapid tapering, has already been cited to Verster et al. in the article. The APA guidelines above say this as well. The labeling text also refers to discontinuation symptoms. This is however not indicative of the development of addiction in the patients. A diagnosis of addiction would require withdrawal symptoms, dose escalation, drug seeking behavior, control loss, negative social consequences and deterioration, a lack of insight in the own condition. I may remind you that common blood pressure medications have to be tapered as well, because of the existence of discontinuation and rebound symptoms. They cause a physical dependence, without having any abuse potential. Verster et al. entirely talk about anxiety/panic patients, as does above APA reference. The sole existence of discontinuation symptoms is not indicative of addiction, as the other symptoms of addiction are missing.

The abuse of the substance for recreational purposes and the resulting addiction is an entirely different issue. I have already answered to this on your first inquiry ibd., it are essentially people who develop a sedative/alcoholic type of addiction to alprazolam without a legitimate medical need, often because they use it instead of alcohol in case of restricted access to alcohol, as in juveniles or in Islamic states. 70.137.129.5 (talk) 11:21, 2 September 2011 (UTC)

Peter first of all welcome to Wikipedia. Please take some time to read the references mention. Also typically we base articles on reviews published preferably in the last 5-10 years. If you provide some of these we are happy to look at them and adjust the text here accordingly.Your Sincerely James Heilman, MD Doc James (talk · contribs · email) 11:09, 2 September 2011 (UTC)

Hello again James and others. We're doing some additional investigation on the subject of Alprazolam. When we finish our review, we'll communicate with you again. Thanks. Peter Barglow, MD and Raymond Barglow, PhD — Preceding unsigned comment added by 76.231.190.217 (talk) 16:28, 8 September 2011 (UTC)

Dear 76.231.190.217 ,

I made this last edit [[2]] before I read this discussion.

When I said that Wikipedia does not give medical advice, I was referring to WP:MEDICAL.

Even though you may be quoting directly from the package insert, it still doesn't belong in Wikipedia, because we have a strong rule against giving medical advice or recommending particular practices.

Be sure to read WP:MEDMOS carefully, particularly:

Do not address the reader directly. Ensure that your writing does not appear to offer medical advice. However, a disclaimer to this effect is never required[4] since the general disclaimer can be accessed from any page on Wikipedia. Statements using the word should frequently provide inappropriate advice (e.g., "People with this symptom should seek medical care") instead of plain statements of facts.

I think it's interesting that a patient came to your office seeking a prescription for alprazolam and highlighted the section on Wikipedia claiming that the risk of dependency and absue was low. We should be aware that people use Wikipedia that way. We should also address that specific issue about alprazolam in the article. That Verster and Volkerts (2004) article cited does say, "the risks of dependence and abuse are small."

Is there a more recent article, from a good peer-reviewed source, that clearly states that alproazolam has a potential for abuse or addiction? 7 years is pretty old for a review article. If there are reliable sources (that is, WP:RS) to indicate that current opinion has changed, I would be happy to give the citations and change that statement.

Wikipedia works a certain way, and we have to follow those procedures -- it's like establishing admissibility in a courtroom. But when those procedures are followed, Wikipedia turns out to be surprisingly accurate, according to reviews in journals like Nature. --Nbauman (talk) 16:43, 14 September 2011 (UTC)

Editing areas of one's own expertise is a tricky thing in Wikipedia. In particular, experts are prone to adding their own original research to articles and declining to source it, citing their own claims of expertise or certifications as a substitute for core content policies. The result has been that controversial ideas within a discipline get added to Wikipedia as Fact(tm), which is unacceptable. It is important that experts in any field use their knowledge of the discipline in the service of Wikipedia's verifiability, neutrality, and original research policies by identifying relevant peer-reviewed sources, especially meta-analysis of existing sources, and adding encyclopedic content to the article that is supported by those sources.

With that said, I agree with Nbauman's edit here [3]. The temptation by a medical practitioner to use Wikipedia as a platform for distributing sound medical advice is perfectly understandable -- what better platform from which to educate people about health and wellness? -- but equally unacceptable. If the content of the article is misleading, it will have to be corrected through our usual means, focusing on Wikipedia's nature as an online encyclopedia. I hope this helps. Regards, causa sui (talk) 17:57, 14 September 2011 (UTC)

Nbaumann, the question is not "if it has a potential for abuse or addiction", of course it has, reflected by DEA C IV and cited already to ER room statistics. The point was that Verster et al. as well as numerous other contemporary sources like the APA guide say, that it is "unlikely to be abused by patients with a legitimate need." This is current consensus. I believe the guide of the American Psychiatric Association is an authoritative source and reflects mainstream medical opinion, as reflected also in the review article by Verster et al. I already said that abuse and addiction in people without a medical need, recreational abusers, is a different issue. These show up in the ER statistics. 70.137.129.34 (talk) 19:31, 14 September 2011 (UTC)

Besides we have not cited the label from the package insert, which would be OR. We have cited the regulatory text from the FDA website, and we need a newer version, as certain restrictions have been dropped in 2005. I think we have to cite precisely, if we say "it is FDA approved for..." I think the current text is ok. with a minor change I applied. Please see there. But we have to update the labeling info to the 2011 version. the 2003 ref is outdated. 70.137.129.34 (talk) 19:37, 14 September 2011 (UTC)

Causa sui, this was not sound medical advice by a tempted WP editor, who is a MD, but it was the quotation from the regulatory text at FDA, for what alprazolam is approved, and how. 70.137.129.34 (talk) 19:51, 14 September 2011 (UTC)

It was cited to [4], which is a broken link. Is there another citation? causa sui (talk) 21:29, 14 September 2011 (UTC)

I googled and found a mirror, I think [5]. The direct quote I think you are looking for is on page 4: "The longer-term efficacy of XANAX XR has not been systematically evaluated. Thus, the physician who elects to use this drug for periods longer than 8 weeks should periodically reassess the usefulness of the drug for the individual patient." That's good enough for me - and would have been much more to the point than the tome above. :-) causa sui (talk) 21:34, 14 September 2011 (UTC)

Causa sui, done. Inserted last revision of FDA label and adjusted text accordingly. Please take a look. 70.137.129.34 (talk) 23:23, 14 September 2011 (UTC)

Dear Xanax Wikipedians,

We would like to draw your attention to yesterday's article in the New York Times: “Abuse of Xanax Leads a Clinic to Halt Supply”(Sept. 14), written by Abby Goodnough. We have written a letter to the editor, linking the article to our effort to correct the Wikipedia entry on Xanax, as it currently stands. We include the content of our letter below.

As we say in the letter, we hope that you will review the evidence on this subject and will correct the false statement that "The risk of dependency and abuse is low similar to that of the other benzodiazepines."

We are gathering additional evidence and hope to present it to you soon.

Thanks,

Peter Barglow, MD Raymond Barglow, PHD

From: peter@barglow.com Sent: Wednesday, September 14, 2011 6:36 PM To: letters@nytimes.com Subject: Abuse of Xanax

To the Editor,

Abby Goodnough’s article “Abuse of Xanax Leads a Clinic to Halt Supply” (Sept. 14) corrects a common misperception that this drug is safe. Wikipedia, the most frequently accessed on-line source of information in the world, mistakenly reports in its entry* on Xanax, that “The risk of dependency and abuse is low similar to that of other benzodiazepines.” This view is contradicted also by the labeling instructions of the agent's manufacturer (Pfizer), by the US Drug Enforcement Agency's categorization of the drug as a Class IV controlled substance, and by almost every pharmacology textbook published over the past decade.

The Wikipedia entry was brought to our attention when a patient addicted to Xanax reported that Wikipedia’s description of the drug had reassured him that the risk of using it was low.

A month ago, we contacted the administrators of the Wikipedia “Xanax” page, requesting correction of this misinformation. They have rejected this request, but we remain hopeful that they will review the evidence and edit their Xanax page accordingly.

Peter Barglow, M.D. Raymond Barglow, Ph.D. Berkeley California

• http://en.wikipedia.org/wiki/Alprazolam — Preceding unsigned comment added by Rbarglow (talk • contribs) 00:01, 16 September 2011 (UTC)

Well, if this is so notable, then I hope this will soon show up e.g. in the APA guidelines, rather than in a newspaper. But sofar we are relying on peer reviewed clinical review articles and widely recognized textbooks, not on the popular press, which has usually been written by journalists. We hoped that you would provide sources, which satisfy WP:MEDRS criteria, and we are still hoping. The voice of the popular press and the voice of the street is not yet reliable and encyclopedic enough for inclusion, see WP:MEDRS. I suggest that you take the issue to the APA and ask them for inclusion in their guidelines, or at least ask them for an explanation. Maybe they can explain it. 70.137.156.237 (talk) 09:11, 16 September 2011 (UTC)

Have left this user a note on their talk page. Happy to review the evidence to back up the statement made above but per WP:V must wait for said sources.Doc James (talk · contribs · email) 00:32, 20 September 2011 (UTC)

Onset of action

We need to go with what reliable references say. Please discuss here rather than continuing to revert.Doc James (talk · contribs · email) 19:23, 29 September 2011 (UTC)

BTW the onset of action will depend on which indication one is referring to (GAD verses panic attacks). Thus I assume both of you are right. But please find refs and discuss here. Also it is useful to put the exact quote from the paper in the ref "quote=text"Doc James (talk · contribs · email) 19:26, 29 September 2011 (UTC)

Lexicomp says 1 hour is onset of action http://www.uptodate.com/contents/alprazolam-drug-information?source=search_result&search=alprazolam&selectedTitle=1%7E38 --Doc James (talk · contribs · email) 19:28, 29 September 2011 (UTC)

This ref shows about 1 week before onset for GAD. http://books.google.ca/books?id=Eia6OmLNf2QC&pg=RA1-PT338&dq=alprazolam+onset+of+action+generalized+anxiety+disorder&hl=en&ei=K8eETsvjMorkiAKsoJS8DA&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCwQ6AEwAA#v=onepage&q=alprazolam%20onset%20of%20action%20generalized%20anxiety%20disorder&f=false The ref however is not ideal as it is a graph . --Doc James (talk · contribs · email) 19:36, 29 September 2011 (UTC)

The previously cited review article Verster et al already says "in the first week", I believe we need a secondary source to deviate from this exact citation of a secondary source. I believe the primary ref cited now is not valid according WP:MEDRS - use secondary sources, as it is a small experimental uncontrolled study, a typical less preferred primary source. I propose we do not change the exact previous citation from the secondary source without consensus. 70.137.159.50 (talk) 19:47, 29 September 2011 (UTC)

Editor182, you have added two primary sources, which do not outweigh the cited secondary source according to MEDRS. common sense does not count. You are already 3rr. 70.137.159.50 (talk) 20:01, 29 September 2011 (UTC)

Can you provide the whole sentence from Verster? Doc James (talk · contribs · email) 20:03, 29 September 2011 (UTC)

There are currently two reliable sources which I've added. Alprazolam does not take a week to start working for any anxiety disorder. It's unlike other anxiolytic or antidepressant agents, such as SSRIs, which can take up to 4 weeks to begin working for depression, and 12 weeks to begin working for OCD. The sources are there, and it really is common sense for those who have knowledge on the subject. Until this persons whim is satisfied with a consensus here, we should keep the revision without the "1 week" claim. I've added my two cents. Editor182 (talk) 20:07, 29 September 2011 (UTC)

Review article

Clinical pharmacology, clinical efficacy, and behavioral toxicity of alprazolam: a review of the literature. Verster JC, Volkerts ER. Source

Utrecht Institute for Pharmaceutical Sciences, Department of Psychopharmacology, University of Utrecht, P. O. Box 80082, 3508 TB, Utrecht, The Netherlands. j.c.verster@pharm.uu.nl. Abstract

Alprazolam is a benzodiazepine derivative that is currently used in the treatment of generalized anxiety, panic attacks with or without agoraphobia, and depression. Alprazolam has a fast onset of symptom relief (within the first week); it is unlikely to produce dependency or abuse. No tolerance to its therapeutic effect has been reported. At discontinuation of alprazolam treatment, withdrawal and rebound symptoms are common. Hence, alprazolam discontinuation must be tapered. An exhaustive review of the literature showed that alprazolam is significantly superior to placebo, and is at least equally effective in the relief of symptoms as tricyclic antidepressants (TCAs), such as imipramine. However, although alprazolam and imipramine are significantly more effective than placebo in the treatment of panic attacks, Selective Serotonin Reuptake Inhibitors (SSRIs) appear to be superior to either of the two drugs. Therefore, alprazolam is recommended as a second line treatment option, when SSRIs are not effective or well tolerated. In addition to its therapeutic effects, alprazolam produces adverse effects, such as drowsiness and sedation. Since alprazolam is widely used, many clinical studies investigated its cognitive and psychomotor effects. It is evident from these studies that alprazolam may impair performance in a variety of skills in healthy volunteers as well as in patients. Since the majority of alprazolam users are outpatients, this behavioral impairment limits the safe use of alprazolam in patients routinely engaged in potentially dangerous daily activities, such as driving a car. 70.137.159.50 (talk) 20:13, 29 September 2011 (UTC)

Yes. I wondering if it is referring to GAD or PA? I know for PA it works very quickly similar to lorazepam. We need better refs but are you okay with the current wording? Doc James (talk · contribs · email) 20:40, 29 September 2011 (UTC)

Yes thats ok. I had only issues with overriding/removing citation of Verster et al review, with a primary research/small study with 6 people. As it stands now it leaves the Verster citation factually intact. I would appreciate if the discussion is not simply omitted and instead commented with "freaking-unbelievable" instead of a discussion. I am not a cretin who does not know how to cite. 70.137.159.50 (talk) 20:55, 29 September 2011 (UTC)

Yes everyone needs to discuss. Most things can be resolved reasonably.Doc James (talk · contribs · email) 21:03, 29 September 2011 (UTC)

So, to Editor182 the question: Are you aware of WP:MEDRS guidelines, asking for SECONDARY sources, and their definition there? And: do you take it as good style to give edit summaries like "freakin-un-believable" and "ludicrous" instead of a response to factual concerns with citations, is this the academic discussion style in this community? 70.137.159.50 (talk) 22:50, 29 September 2011 (UTC)

I believe in the past discussions it has always been emphasized to use secondary sources, as in primary research virtually everything has been once claimed, disputed, contradicted, conjectured and postulated, so an arbitrary selection of primary refs can almost support every arbitrary claim, to the taste. By such a selection the editor puts himself in a position to write a summary of the selected primary research instead of citing from a review. This is original research and synthesis. I believe I understood from previous discussions that in particular in high-importance pharmaceutical like this we have to be a little bit strict with that. In other research stuff, which has only been fed to rats so far, we will have no choice but to use primary research, as they have not reached a stage, where reviews are available. 70.137.159.50 (talk) 23:09, 29 September 2011 (UTC)

http://www.ambrosecriminallaw.com/images/Review%20of%20Clinical%20Alprazolam%20Study.pdf

here fulltext of review article Verster et al. They claim effect for GAD as well as panic disorder "in the first week". According to this, the onset of effects is within 30 min, 2.8 hours max plasma level oral etc. but the effect against anxiety disorder and panic disorder improves with repeated doses, so they claim, in the first week. I propose to cite this secondary source, as it was. Check yourself. (unfortunately the pdf is not searchable, is a scan) 70.137.159.50 (talk) 03:19, 30 September 2011 (UTC)

please take a look. 70.137.131.115 (talk) 09:30, 30 September 2011 (UTC)

Abuse potential

We currently state "it is unlikely to produce dependency or abuse" and this is indeed what our reference says. PMID 14978513 but this ref is from 2004 and MEDRS states we should use sources from the last 3-5 years. This textbook from the AHFS states "Abuse potential similar to that of other benzodiazepines and related hypnotics." [6] And this textbook acknowledges that initial studies look promising but further clinical experience shows that after several months physical addition occurs.al.], editors, Joyce H. Lowinson... [et (2005). Substance abuse : a comprehensive textbook (4th ed. ed.). Philadelphia, Penns.: Lippincott Williams & Wilkins. p. 306. ISBN 9780781734745. {{cite book}}: |edition= has extra text (help); |first= has generic name (help)CS1 maint: multiple names: authors list (link) Thus we need to update and clarify this content to reflect current understanding.Doc James (talk · contribs · email) 06:22, 19 August 2011 (UTC)

This text mentions alprazolam as having a high risk for abuse.al.], edited by Jimmie C. Holland ... [et (2010). Psycho-oncology (2nd ed. ed.). New York: Oxford University Press. p. 381. ISBN 9780195367430. {{cite book}}: |edition= has extra text (help); |first= has generic name (help) --Doc James (talk · contribs · email) 06:29, 19 August 2011 (UTC)

I suggest we change the current text to "Alprazolam was initially thought to have a low risk of abuse however after further clinical experience it abuse risk appears similar to that of other benzodiazipines" Doc James (talk · contribs · email) 06:33, 19 August 2011 (UTC)

That discontinuation effects necessitate tapering on discontinuation is already cited from the given reference. However, this has nothing to do with abuse liability. Common blood pressure medications also require tapering for their discontinuation effects, but have zero abuse liability. That the abuse potential is similar to other benzodiazepines is out of question and reflected by the C IV classification, which means low-to-moderate abuse liabilty. Discontinuation effects generally have nothing to do with "addiction", which is characterized by dosis increase and drug seeking behavior and an impact on daily functioning as well as control loss. Could you give a verbal citation from your refs?70.137.130.19 (talk) 06:35, 19 August 2011 (UTC)

Believe me I am well aware of the distinction of tapering versus abuse versus dependence. I have cited a number of refs with urls that are clickable so that you can verify the text. The big issue at this point is the 2004 review article is too old and thus fails WP:MEDRS we need to use uptodate literature. Not sure what you refer to by "verbal citation"Doc James (talk · contribs · email) 06:39, 19 August 2011 (UTC)

Lexi-Comp BTW states "Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use (generally >10 days)" This is however a paid source while the others are freely accessible. The FDA classification does not necessarily reflect the current medical opinion. It is more legal in nature. Doc James (talk · contribs · email) 06:42, 19 August 2011 (UTC)

By verbal citation I ment the particular text snippet you were alluding to. I do not even believe that alprazolam was thought to have a lower abuse liability than other benzodiazepines. I propose to include

"The abuse risk is similar to that of other benzodiazepines. It is a C IV controlled substance in the US".

Can we agree on that?

I believe this reflects the agreed abuse potential, even agreed by the DEA. That the abuse liability is still low in patients prescibed the medication for genuine needs is still true, and this is what ref Verster et al. says and what he found in the review. It is also true for other commonly prescribed benzodiazepines. The illegitimate abuse is a different animal, but Verster et al. talks about legitimate patients with anxiety/panic. I do not think that 2004 is too old for MEDRS. There have not been much news recently, except that some of the earlier alarms and restrictions have been mellowed over time. There was a benzo scare in the 90s. 70.137.130.19 (talk) 06:56, 19 August 2011 (UTC)

Yes "The abuse risk is similar to that of other benzodiazepines. It is a C IV controlled substance in the US". I think reflects the literature well. Multiple sources agree that the abuse potential is low and tolerance does not develop to the anxiolytic effects. This does not contradict the fact that it is the most abused benzo. It is the most abused as it is the most prescribed. Maybe we should also change it to "little tolerance has been reported" to acknowledge lexicomp. Doc James (talk · contribs · email) 07:06, 19 August 2011 (UTC)

How about "The risk of dependency and abuse is low similar to that of other benzodiazepines. Tolerance developing to it anxiolytic effects has not commonly been reported but withdrawal and rebound symptoms necessitate a gradual reduction in dosage to minimize withdrawal effects when discontinuing."Doc James (talk · contribs · email) 07:21, 19 August 2011 (UTC)

We better stick to the ref. Tolerance has IMO however been observed to the sedative effect of benzodiazepines, like in sleeping tablets, which is not label use of alprazolam.

How about "tolerance has not been reported in label use" or in use against anxiety, explaining what Verster et al reviewed?

In a review of its use against anxiety... what do you think?

But we are on the same page. 70.137.130.19 (talk) 07:28, 19 August 2011 (UTC)

After all the text is not so controversial as it stands, it just defies common popular opinion of benzos. Besides I believe you slipped a spurious C into schedule IV. It is either C IV or schedule IV. I am a little tired of the situation that every correctly cited ref - and Verster is not outdated, but still reflects current status - is immediately attacked by people from the "anti-addiction league", who want the article turned into an anti-abuse pamphlet. 70.137.130.19 (talk) 09:03, 19 August 2011 (UTC)

If we are going to say "tolerance has not been reported" and base it on a 2004 paper we would need to add "tolerance has not been reported as of 2004". I think we should stay away from "indicated uses" as this is very US centric. This paper from 2007 mentions tolerance PMID 17878744. So "tolererance has not been reported to the anti anxiety effects as of 2004". We could also go with "therapeutic effects". 2004 is a little old per MEDRS. Doc James (talk · contribs · email) 16:15, 19 August 2011 (UTC)

Your paper is a primary source, experiment on 24 healthy volunteers. It is also about the EEG and self reported feeling. It is absolutely useless as a MEDRS source. What we need is a clinical review article, not an experiment on 24 healthy volunteers in some kitchen by some researcher. Please read WP:MEDRS. Case reports and primary sources are not to be used. Next you come with an experiment on ONE single healthy rat who "volunteered", or on our horse Lisa, which was our only experimental animal, which we used for all our experiments in our institute. It since died. Also it is known that tolerance develops to e.g. sedative effects, but not to anti-anxiety, and the above experiment is about something else, not anti-anxiety effect. Intended use is not US-centric, it is what the medication is also intended for by design, with nationally more or less adherence to some medical custom. 70.137.150.187 (talk) 18:59, 19 August 2011 (UTC)

The intended use is absolutely important, as the different effects are mediated by different receptor subtypes and show different tolerance behavior. Find a newer clinical review article, not a lab experiment, which says nothing about clinical use but tries to elucidate a hypothesis. (IMO with a funny experimental design.) 70.137.150.187 (talk) 19:28, 19 August 2011 (UTC) 70.137.150.187 (talk) 02:02, 20 August 2011 (UTC)

I am not suggesting we use the primary research. The thing is you have a review article that comes out and states absolutes. Absolutes are poor form in medicine by the way. All it takes is a single case report to prove the review wrong. Thus we need to add the year the what is supported by the review. Lexicomp comments on the potential of tolerance BTW.Doc James (talk · contribs · email) 06:05, 20 August 2011 (UTC)

A single case report is insufficient to disprove a review, which is a cross section. The review forms a cross section in a statistical sense too, and they found no significant tolerance to the anti-anxiety effect. Case reports are almost worthless, except as a first indication for need for more investigations, if they reach some threshold in numbers. Then this could indicate that something with the previous assumptions is wrong, as in the case of some rare and unexpected side effects. Do you have access to Verster et al. fulltext? Is my statement wrt. different tolerance developments for different effects correct? (anti-anxiety, sedative, anti-epileptic...) 70.137.150.187 (talk) 06:44, 20 August 2011 (UTC)

To be precise, the only way a review article becomes invalidated is by a later review article finding the results invalidated, not by us finding case reports or primary sources invalidating it. We cannot weigh newer primary sources or case reports against review articles and other secondary sources. This would be original research. 70.137.150.187 (talk) 09:00, 20 August 2011 (UTC)

October 3, 2011 To the administrators/editors of the Wikipedia entry on alprazolam (Xanax),

The commentary below is, once again, relatively lengthy. It may be more easily readable as the PDF document that we created to hold our remarks. For your convenience, we have posted that to the website: www.barglow.com/WikipediaXanax.pdf

In our prior correspondence to you, we have objected to the claim, near the beginning of this entry, that “The risk of dependency and abuse is low similar to that of other benzodiazepines.” That statement has recently been changed to read, “The potential for abuse is low and is similar to that of other benzodiazepine drugs.” This new statement is not an improvement. It constitutes a serious danger to patients and to the public at large who read Wikipedia seeking trustworthy information.

We’ll divide the following discussion into six parts: 1. Discussion of the word “abuse.” 2. US Drug Enforcement Agency (DEA) and US Food and Drug Administration and warnings about Xanax/alprazolam. 3. Discussion of therapeutic versus non-therapeutic use of Xanax. 4. Recent published evidence that Xanax use leads to dependence and abuse 5. Criticism of two sources that administrators/evaluators of this Xanax page emphasize and rely upon. 6. Presentation of additional authoritative sources that attest to the substantial risks of Xanax dependence and abuse: Charles Pfizer and National Institute on Drug Abuse (NIDA).

1. DISCUSSION OF THE WORD “ABUSE.” “Abuse” is an often used but imprecise term. Most of the readers of this Wikipedia entry will not be familiar with the technical definition of this term as defined in DSM IV-R. They will interpret “potential for abuse” to mean “potential for harm.” That is, one “abuses” a drug if one’s use does harm to oneself or to others. From a clinical perspective, kinds of harm would include misuse and dependency associated with abuse, tolerance, withdrawal, loss of function, and toxicity. These aspects of risk might not be known to the lay reader.

Assuming this common understanding of “abuse,” there is among scientists and clinicians wide agreement that the ”abuse potential” of benzodiazepines, including Xanax, is substantial, not “low” as the Wikipedia text states. Nutt et. al. published in Lancet in 2007 an article in which a group of expert scientists compared 20 agents widely considered to be addicting. (Nutt, D., King, L. A., Saulsbury, W., & Blakemore, C. (2007) “Development of a rational scale to assess the harm of drugs of potential misuse.” Lancet, 369, 1047-1053) The comparison was based on 16 criteria, 9 related to harm of the drug to the individual and 7 related to estimation of its harmful effects upon other persons. The 20 drugs were rated in regard to dependence, withdrawal reactions, reinforcement of negative behaviors and intoxication risk. Benzodiazepines (BZDs) ranked higher on dependence, with a score of 1.83, than amphetamines (1.67) and marijuana (1.51), but lower than tobacco (2.21). On the social harm criterion, BZDs ranked higher than the three other substances, with a score of 1.65, compared with amphetamines and marijuana (each scoring 1.50), and tobacco (1.42).

The remainder of our commentary will provide further evidence that Xanax carries a high ”abuse” potential, giving to that word the ordinary range of meanings that it carries for lay readers of Wikipedia.

2. US DRUG ENFORCEMENT AGENCY (DEA) AND US FOOD AND DRUG ADMINISTRATION (FDA) AND WARNINGS ABOUT XANAX/ALPRAZOLAM. The DEA categorizes all benzodiazepines as Class IV controlled substances. “Controlled Substances,” according to the FDA, “are drugs or other chemicals that have the potential to be ‘addictive or ‘habit forming’.” The DEA’s 2005 edition of “Drugs of Abuse” states that:

“Although benzodiazepines produce significantly less respiratory depression than barbiturates, it is now recognized that benzodiazepines share many of the undesirable side effects of the barbiturates…. Prolonged use can lead to physical dependence even at doses recommended for medical treatment. …Although primary abuse of benzodiazepines is well documented, abuse of these drugs usually occurs as part of a pattern of multiple drug abuse.” p. 40

The FDA’s evaluation of Xanax, reproduced at www.accessdata.fda.gov/drugsatfda_docs/label/2011/018276s044,021434s006lbl.pdf, is as follows: “Benzodiazepines, even when used as recommended, may produce emotional and/or physical dependence …. When used at doses greater than 4 mg/day, which may or may not be required for your treatment, XANAX has the potential to cause severe emotional and physical dependence in some patients and these patients may find it exceedingly difficult to terminate treatment. In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue medication was measured, 7 to 29% of patients treated with XANAX did not completely taper off therapy. In a controlled postmarketing discontinuation study of panic disorder patients, the patients treated with doses of XANAX greater than 4 mg/day had more difficulty tapering to zero dose than patients treated with less than 4 mg/day.” p. 5

“Even after relatively short-term use at doses of < 4 mg/day, there is some risk of dependence. … Some patients may find it very difficult to discontinue treatment with XANAX XR due to severe emotional and physical dependence…. Because the management of panic disorder often requires the use of average daily doses of XANAX above 4 mg, the risk of dependence among panic disorder patients may be higher than that among those treated for less severe anxiety. Experience in randomized placebo-controlled discontinuation studies of patients with panic disorder showed a high rate of rebound and withdrawal symptoms in patients treated with XANAX compared to placebo-treated patients. Relapse or return of illness was defined as a return of symptoms characteristic of panic disorder (primarily panic attacks) to levels approximately equal to those seen at baseline before active treatment was initiated. Rebound refers to a return of symptoms of panic disorder to a level substantially greater in frequency, or more severe in intensity than seen at baseline. Withdrawal symptoms were identified as those which were generally not characteristic of panic disorder and which occurred for the first time more frequently during discontinuation than at baseline.” p. 6

“Because of its CNS depressant effects, patients receiving XANAX should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle.” p. 7

“Psychological dependence is a risk with all benzodiazepines, including XANAX.” p. 18

The authoritative DEA and FDA warnings above about the abuse potential of Xanax are based on empirical evidence, and we will discuss some of that evidence below.

3. DISCUSSION OF THERAPEUTIC VERSUS NON-THERAPEUTIC USE OF XANAX

According to Wikipedia editor Doc James,
“That Verster and Volkerts (2004) article cited does say, ‘the risks of dependence and abuse are small.’ Is there a more recent article, from a good peer-reviewed source, that clearly states that alproazolam has a potential for abuse or addiction? 7 years is pretty old for a review article. If there are reliable sources (that is, WP:RS) to indicate that current opinion has changed, I would be happy to give the citations and change that statement.” Note that the sentence quoted from Verster and Volkerts that is given here by Doc James has been truncated. When we read the full sentence, it no longer supports Wikipedia’s very general statement that the risk of using Xanax is small. The full sentence reads: “No dose increments are necessary and the risks of dependence and abuse are small *in the patient population*.” (p. 64, our emphasis)

The qualifier “in the patient population” is an essential one, because it excludes from consideration the large number of Xanax users who are not active identified patients, even though they may be suffering from problems caused by the drug. One of the reasons that dependence/abuse of Xanax is fairly common is that the drug is NOT used only by patients under doctor’s orders.

Similarly, Doc James refers to an American Psychiatric Association report that was published in 1990, stating that “according to the report of the APA Task Force on Benzodiazepine Dependence, Toxicity, and Abuse, ‘There are no data to suggest that long-term *therapeutic use* of benzodiazepines by patients commonly leads to dose escalation or to recreational abuse (p. 294, our emphasis).”

But what about NON-therapeutic use, abuse and misuse? Notoriously, Xanax is not used only for therapeutic purposes. Adding the qualifier “therapeutic” to characterization of the use of Xanax -- thereby confining the evaluation of Xanax to situations where it is taken as directed by a medical practitioner -- ignores the large population for whom abuse/dependence is at issue. When abused, Xanax is often procured illegally, “on the street,” or through channels (e.g. from a relative or friend) that are not medically sanctioned. In this social context the drug is more likely to be misused than if it were used strictly according to “doctor’s orders.”

According to Louis A. Pagiaro and Ann Marie Pagliaro, Pagliaro’s Comprehensive Guide to Drugs and Substance Abuse, published by the American Pharmacists Association, 2004, “The benzodiazepines have been and continue to be, used medically for a variety of reasons. However, their medical use has often resulted in both intentional and unintentional abuse by patients and their friends and family members with whom the drug may be shared to relieve conditions similar to those for which it was prescribed.” p. 34

If we limit our evaluation of the use of just about any familiar drug – morphine, for instance – only to the instances of its “therapeutic use,” than of course the drug will score high in terms of safety. But the use of common dependency-inducing or highly addictive agents, morphine included, frequently does not adhere to the prescribed guidelines; we certainly would not say of morphine that “The potential for abuse is low.” Yes, if they were used only according to prescription instructions, agents like morphine or Xanax would be rendered “low risk.” But since that is commonly not the case, the assertion that, for Xanax, “The potential for abuse is low” is empirically unwarranted.

However, in questioning this Wikipedia entry claim, we are not referring here only to use of Xanax that has been obtained illegally on the street, from another user, or in some other irregular way. Even when this drug is prescribed, it is subject to abuse that, by definition, exceeds its therapeutic use. Did the celebrity Michael Jackson use the three benzodiazepines that were considered factors in his death “therapeutically”?

In response to the abuse of *prescribed* Xanax, doctors at a medical center servicing a number of counties in Kentucky have recently stopped writing new prescriptions for this drug. See the article “Abuse of Xanax Leads a Clinic to Halt Supply in the New York Times Sept 14, 2011 issue: http://www.nytimes.com/2011/09/14/us/in-louisville-a-centers-doctors-cut-off-xanax-prescriptions.html These doctors’ experience does not, by itself, constitute compelling scientific evidence, but it indicates the extent of the problems that medical service providers encounter with Xanax. The article reports that

“Because of the clamor for the drug, and concern over the striking number of overdoses involving Xanax here and across the country, Seven Counties took an unusual step — its doctors stopped writing new prescriptions for Xanax and its generic version, alprazolam, in April and plan to wean patients off it completely by year’s end.”

“While Kentucky and other states have focused largely on narcotic painkiller addiction, experts say that benzodiazepines, the class of sedatives that includes Xanax, are also widely misused or abused, often with grim consequences…. The Centers for Disease Control and Prevention last year reported an 89 percent increase in emergency room visits nationwide related to nonmedical benzodiazepine use between 2004 and 2008. And here in Kentucky, the combination of opiate painkillers and benzodiazepines, especially Xanax, is common in fatal overdoses, according to the state medical examiner.”

Abuse of Xanax is amplified by a property intrinsic to the drug: It is well known that Xanax typically causes temporary memory loss. As Ronald W. Pies, MD, notes in the Handbook of Essential Psychopharmacology, 2nd ed 2005, “All BZDs may cause varying degrees of memory impairment…. Thus, a person who has taken a BZD will recall something told to him or her after 1-2 minutes but will be unable to recall this information after 15-20 minutes. P. 306. Such memory loss results in a frequently observed phenomenon: a patient takes Xanax and then forgets that he/she has done so. This may then induce the patient to take the next dose prematurely, i.e. before the prescribed interval between doses has elapsed. Hence the familiar phone call, “Doc, I’ve run out of my meds – I need some more.” If the doctor fails to comply with this request, the patient may find alternative sources. Hence the line between therapeutic and non-therapeutic use becomes a blurred one. Yes, if a patient uses a drug in strict obedience to the prescribed regimen, safety may be high, but do we have any scientific evidence regarding the frequency of such compliance?

4. RECENT PUBLISHED EVIDENCE THAT XANAX USE LEADS TO DEPENDENCE AND ABUSE

Please note the following information sources, all of them more recent than 2000. These sources offer only a representative sampling of expert opinion, and are by no means exhaustive:

A. Ashok Raj MD and David Sheehan, MD, MBA, “Benzodiazepines ,” in Alan E. Schatzberg MD, Charles B Nemeroff MD, PHD, Essentials of Clinical Psychopharmacology, 2006: “Benzodiazepines differ with regard to the degree and timeline for development of tolerance. As a general rule, long half-life benzodiazepines such as flurazepam, quazpam, diazepam, and clonazepam tend to be effective for a month or longer before tolerance is exhibited. On the other hand, short half-life benzodiazepines such as triazolam, alprazolam, temazepam and lorazepam lose some of their initial efficacy sooner, sometimes in just over a week.” p. 187

B. “Sedative-Hypnotics ,” in Alan E. Schatzberg MD, Charles B Nemeroff MD, PHD, Essentials of Clinical Psychopharmacology, 2006: “Dependence, both psychological and physical, occurs wth benzodiazepines as with other sedative-hypnotics.” p. 663.

C. P.G. Janicak et al. Principles and Practice of Psychopharmacoterapy, 4th ed. 2006: “… 10% to 15% of chronic BZD users develop a protracted withdrawal syndrome that may last for months or years. … The protracted phase of BZD withdrawal emerges from the acute phase and is characterized by gradually declining symptoms punctuated by wavelike recurrences interspersed with periods of normalcy. Recovery may not be complete, and long-lasting symptoms may include anxiety, insomnia, depression, various sensory and motor phenomena, and gastrointestinal disturbances.” p. 493
“Although gradual dose reduction may ameliorate the intensity of withdrawal symptoms after long-term therapeutic use of BZDs, mild to moderate symptoms are still likely to occur…. gradual withdrawal may still be difficult. Schweizer et al. (47) found that although the initial 50% dose reduction was characterized by minimal withdrawal severity and could be accomplished fairly rapidly, the majority of symptoms occurred during the last half of the tapering process. Tyrer (267) made a similar observation, stating that “withdrawal symptoms may develop only when patients have reduced to what many clinicians would regard as subtherapeutic doses …” pp. 498-499

D. Joellen Patterson, A. Ari Albala, Margaret E. McCahill, Todd M. Edwards, The Therapist’s Guide to Psychopharmacology, 2010: “After daily use for more than a few weeks, sudden discontinuation of any benzodiazepine is very uncomfortable and can be potentially dangerous or even fatal…. It is also important to remember that some patients – those who metabolize the drug much faster than the average person and who therefore have rapid drops in benzodiazepine blood levels – may occasionally have ‘mini withdrawals’ between doses, characterized by anxiety symptoms … This phenomenon is seen more frequently with those benzodiazepines that have an ultrashort half-life, like lorazepam and alprazolam.” p. 91

E. Alan E. Schatzberg MD, Jonathan Cole MD, and Charles DeBattista, DMH, MD, Manual of Clinical Psyhopharmaology, 2010: “A shift from short-acting benzoiazepines, such as lorazepam or alprazolam, to longer-acting ones like clonazepam can be tried if tapering of the shorter-acting drug leads to uncomfortable symptoms…. Even with systematic inpatient withdrawal, however, there is a significant risk of relapse. A study by Jough et al. (1991) found that most patients with long-term benzodiazepine dependence did not fare well even after successful inpatient detoxification.” p. 578.

F. Stephen M. Stahl, Stahl’s Essential Psychopharmacology: The Prescriber’s Guide,3rd ed. 2009. The Alprazolam entry states that there is a “Risk of dependence, particularly for treatment periods longer than 12 weeks and especially in patients with past or current polysubstance abuse.” p. 7 Stahl goes on to characterize Alprazolam as “Habit-forming … Alprazolam is a Schedule IV drug ... Patients may develop dependence and/or tolerance with long-term use.”

G. Louis A. Pagiaro and Ann Marie Pagliaro, Pagliaro’s Comprehensive Guide to Drugs and Substance Abuse, published by the American Pharmacists Association, 2004: “It has long been recognized that mild to moderate psychological dependence occurs with regular long-term use of the benzodiazepines, at both lower and higher dosages.” p. 33

H. James W Cornish MD, Laura F McNicholas MD, PhD, Charles P.O’Brien MD PHD, in The American Psychiatric Publishing Textbook of Psychopharmacology, Ch. 58, 3rd ed. 2004:
“… although the benzodiazepines , as a class of drugs, are certainly safer in isolated overdoes situations than the older agents, physiological dependence is possible and occurs with long-term use, even at therapeutic levels.” p. 1012.

I. John D. Preston, Psy.D., ABPP; John H. O’Neal, MD, Mary C. Talaga, R.Ph., Ph.D., Handbook of Clinical Psychopharmacology for Therapists, 6th ed., 2010 : “Because of the potential for dependence and abuse, it is best to try to use benzodiazepines only for short-term treatment…. Benzodiazepine withdrawal syndromes are encountered frequently.” p. 214 “… many patients find that it is especially difficult to discontinue the very last does [of a benzodiazepine ], even if discontinuation has proceeded well up to that point. For example, many patients have problems discontinuing the final dose of alprazolam (e.g. 0.25 mg twice a day.” p. 215

J. Jerrold S. Meyer and Linda F. Quenzer, Psychopharmacology: Drugs, the Brain, and Behavior, 2005: “Although tolerance [of benzodiazepines] and physical dependence are less than with barbiturates, rebound withdrawal insomnia often occurs after chronic use. p. 426.

5. CRITICISM OF TWO SOURCES THAT ADMINISTRATORS/EVALUATORS OF THIS XANAX PAGE EMPHASIZE AND RELY UPON. We have cited above only a few of the recent references attesting to the substantial dependency and abuse risks of Xanax. Now, it is true that there are other studies attesting to the innocuous character of the benzodiazepines. On the Wikipedia discussion page for Xanax, we read:

“Please consider following ref http://www.psychiatryonline.com/pracGuide/PracticePDFs/PanicDisorder_2e_PracticeGuideline.pdf Major concerns about benzodiazepine tolerance and withdrawal have been raised. However, according to the report of the APA Task Force on Benzodiazepine Dependence, Toxicity, and Abuse, ‘There are no data to suggest that long-term therapeutic use of benzodiazepines by patients commonly leads to dose escalation or to recreational abuse’ (294). The studies of long-term alprazolam treatment for panic disorder show that the doses patients use at 32 weeks of treatment are similar to those used at 8 weeks, indicating that, as a group, patients with panic disorder do not escalate alprazolam doses or display tolerance to alprazolam’s therapeutic effects, at least in the first 8 months of treatment. Furthermore, data in the more severely ill Medicaid population with a mix of mostly mood and anxiety disorder diagnoses show that long-term use of benzodiazepines (at least 2 years) does not typically result in dose escalation, with the incidence of escalation to a high dose being 1.6% (346).”

Note first of all that the APA Task Force report cited here was published in 1990, over 20 years ago. The dependence/abuse potential of BZDs has become more evident since that time.

Second, the claim in the report that “There are no data to suggest that long-term therapeutic use of benzodiazepines by patients commonly [our emphasis] leads to dose escalation or to recreational abuse” is not only very imprecise but also weaker than the current Wikipedia Xanax claim that “The potential for abuse is low and is similar to that of other benzodiazepine drugs.” If we divide risk into three degrees: common, moderate, and low, then the qualification “not commonly” suggests a higher risk, including “moderate” incidence of dependency/abuse, than does the Wikipedia qualification “low.”

Third, “the report of the APA Task Force on Benzodiazepine Dependence, Toxicity, and Abuse” that is referenced above does not unequivocally support the claim that “The potential for abuse is low and is similar to that of other benzodiazepine drugs.” Carl Salzman, MD, who chaired his task force, concludes his editorial about the task force report with an appraisal that is at odds with the Wikipedia affirmation that we are contesting:

“… benzodiazepines are important therapeutic drugs when carefully prescribed for appropriate patients. At standard therapeutic doses, short-term treatment is usually without substantial toxicity or development of dependence. At high doses or for prolonged periods of use, toxicity and dependence may increase in frequency and severity. Benzodiazepines are not drugs of abuse, although benzodiazepine abuse is common among people who are actively abusing alcohol, opiates, cocaine, or sedative hypnotics. Clinical evidence suggests that abuse is also more likely among patients with a history of alcoholism. It is important for clinicians to feel comfortable prescribing benzodiazepines for appropriate patients, but the potential for toxicity and dependence must be considered before prescribing. Patients who may receive benzodiazepines for long periods or at high doses should be also informed of these risks.”

We believe that Salzman’s evaluation is more positive than the evidence warrants; he has been an enthusiastic advocate of benzodiazepine use for decades. Nevertheless, even Salzman’s running commentary on benzodiazepines over the years isn’t as unequivocal and broadly endorsing as the sweeping Wikipedia affirmation, “The potential for abuse is low and is similar to that of other benzodiazepine drugs.”

We turn now to an additional piece of evidence emphasized by Doc James:

“… data in the more severely ill Medicaid population with a mix of mostly mood and anxiety disorder diagnoses show that long-term use of benzodiazepines (at least 2 years) does not typically result in dose escalation, with the incidence of escalation to a high dose being 1.6% (346).” This data comes from the study done by Stephen B Soumerai et al.: ”Lack of relationship between long-term use of benzodiazepines and escalation to high dosages.” Psychiatric Services 2003; 54:1006–1011

This research is well-conducted with good statistical measures. However, this study uses data from a very atypical patient population, and for additional reasons as well does not adequately support the broad claim that the risk of Xanax abuse and dependence is low. Please consider:

A. The authors themselves acknowledge the limitations of their research: "First, we are uncertain about the generalizability of these findings from a low-income Medicaid population to other groups of long-term benzodiazepine recipients."

B. A confounding factor in this study – and it is one that is nowhere acknowledged or addressed by the investigators in their write-up – is whether patients’ use of a benzodiazepine was constrained by inability to obtain more of the drug. The study does not provide us with a crucial piece of information: if a patient returned to his/her medical provider and said “I’d like to take more than I’m taking now – will you increase my dose?” how often did the provider comply with this request? Low income populations are exposed to both Medicaid prescribing limitations, and to inability to pay for a drug.

C. For this study 2,440 subjects were selected out of a total population of 26860 patients who had received benzodiazepine medications. These 9% of the total were judged to be long-term users, as indicated by the history of their benzodiazepine prescriptions; they had received prescriptions “for at least two years without interruption.” But what do we know about the other 91%, those who had not received prescriptions uninterruptedly for two years? Was their use of the BZD as even-keeled as that of longer-term users? Might they have escalated their use by finding other sources for the drug? Do we know that the selection criteria for acceptance into the study did not inadvertently screen out those patients whose drug use profile did not follow the long-term, temperate pattern that the researchers found?

D. According to the study, "At least a quarter of the patients had a diagnosis for a specific chronic illness for which benzodiazepines are often prescribed - for example, schizophrenia or depression". But Xanax’s prescribing guidelines mainly target problems outside this range, including panic disorder, insomnia, and certain kinds of anxiety, and it is typically for these problems that the drug carries substantial dependence and abuse risk. Schizophrenics have a low incidence of BZD dependence because their kind of anxiety is not affected by the drug. The study reports that, in the patient population, “About a quarter were treated with an antidepressant agent, and another quarter received an antipsychotic agent…. These longitudinal data on 2,440 long-term recipients of benzodiazepines suggest that the great majority of such patients have serious physical and mental illnesses.” However, the research literature on Xanax focuses almost entirely on healthier populations with a diagnosis of minor mental illness and overall good physical health outside of the diagnoses for which the BZDs are typically prescribed.

E. The study looks only at prescribed medication, "not actual ingestion." We do not know whether the patients in this study had access to sources of their BZD outside the channel of prescription that provides all the data used in the study. When BDZ supplies run out, users sometimes obtain drugs "on the street" or from people they know, sometimes at discounted cost; such use is not captured by the data in this study.

F. Although the National Institute on Drug Abuse (NIDA) funded this study published in 2003, that organization was not assured by the findings in this study that the BDZs are safe. On the contrary, NIDA has concluded that the risk of dependence, tolerance, and abuse of BDZs is substantial; we will elaborate this point below.

G. The study found that "Regular use of the short-acting, high-potency benzodiazepine lorazepam was associated with dose escalation among new and continuing benzodiazepine recipients." Among the agents considered in this study, lorazepam is most like Xanax in regard to its high potency and short half life, and least like the other BZD agents included in the study. Hence Xanax, like lorazepam, could be expected to exhibited dose escalation too.

H. The national use of BDZs has increased a great deal since 2003, when this study came out. Alprazolam is now the 8th largest prescribed drug in America. And its use beyond the boundaries of prescribed instructions has increased as well. Hence the study is dated, and carries diminished weight with regard to current dependency/abuse rates of the drug.

Taken together, these considerations show that this study does not contravene the conclusion that so much other evidence points to, namely that the use of Xanax carries a substantial risk of abuse.

6. PRESENTATION OF ADDITIONAL AUTHORITATIVE SOURCES THAT ATTEST TO THE SUBSTANTIAL RISKS OF XANAX DEPENDENCE AND ABUSE: CHARLES PFIZER AND NATIONAL INSTITUTE ON DRUG ABUSE (NIDA). The view that “The potential for [Xanax] abuse is low and is similar to that of other benzodiazepine drugs.” is contradicted not only by almost every pharmacology textbook published over the past decade, but also by the labeling instructions of the agent's manufacturer (Pfizer) and by the National Institute on Drug Abuse:

A. Pfizer, the US manufacturer of Xanax, publishes a description of the drug on the company’s web site: http://labeling.pfizer.com/ShowLabeling.aspx?id=547. On page 5 this description states that “Certain adverse clinical events, some life-threatening are a direct consequence of physical dependence to XANAX. These include a spectrum of withdrawal symptoms. Even after relatively short term use and doses recommended for treatment of transient anxiety and anxiety disorders, there is some risk of dependence.”

Note Pfizer’s acknowledgement that withdrawal symptoms are closely affiliated to substance dependency. Indeed, the DSM IV-R definition of substance dependence lists withdrawal as one of the criteria for dependence. On page 7 it is stated that “Withdrawal reactions may occur when dosage reduction occurs for any reason.” On page 18 it is stated that “While the severity and incidence of withdrawal phenomena appear to be related to dose and duration of treatment, withdrawal symptoms, including seizures, have been reported after only brief therapy with XANAX at doses within the recommended range for the treatment of anxiety (eg, 0.75 to 4 mg/day).… Psychological dependence is a risk with all benzodiazepines, including XANAX. The risk of psychological dependence may also be increased at doses greater than 4 mg/day and with longer term use, and this risk is further increased in patients with a history of alcohol or drug abuse.” Pfizer, with an explicit interest in increasing sales, would be unlikely to publicize adverse addictive qualities (dependency and withdrawal symptoms) of a popular drug it manufactures unless these qualities really do characterize the drug.

B. National Institute on Drug Abuse: http://www.nida.nih.gov/researchreports/prescription/prescription3.html . This website was updated in 2005, as confirmed by our phone call to NIDA on Aug. 27, 2011. The NIDA states that “Despite their many beneficial effects, barbiturates and benzodiazepines have the potential for abuse and should be used only as prescribed…. If one uses these drugs long term, the body will develop tolerance for the drugs, and larger doses will be needed to achieve the same initial effects. Continued use can lead to physical dependence and - when use is reduced or stopped - withdrawal.”

In conclusion, given the abundant, very strong evidence that exists on the risk potential of Xanax, we ask that the entire Wikipedia entry be reviewed in the light of this evidence. Specifically, we request removal of the Wikipedia Xanax sentence: “The potential for abuse is low and is similar to that of other benzodiazepine drugs.” We suggest the following as a replacement: “Many scientific authorities and medical experts have concluded that the use of this drug carries a substantial risk for dependence, abuse, and misuse.”

Thank you,

Peter Barglow, M.D., Berkeley Raymond Barglow, Ph.D., Berkeley

Rbarglow (talk) 23:21, 3 October 2011 (UTC) Rbarglow (talk) 22:17, 3 October 2011 (UTC)

Hey Guys To keep things manageable we must address one issue at a time. What one sentence do you wish to change / add? And what refs do you propose to support it?Doc James (talk · contribs · email) 00:32, 4 October 2011 (UTC)

This ref, the APA guidelines, may cite dated material, as you say. But we are citing this ref, not the references they cited, and this ref is recent, published 2009, and it has been revised 2008. If you think they made a mistake, you should discuss it with them. We cannot contribute our opinion here, but we have to take the APA guidelines as an authoritative source, which represents the majority opinion of the profession in this matter.

http://www.psychiatryonline.com/pracGuide/PracticePDFs/PanicDisorder_2e_PracticeGuideline.pdf

The DEA also states "Given the millions of prescriptions written for benzodiazepines (about 100 million in 1999), relatively few individuals increase their dose on their own initiative or engage in drug-seeking behavior."

This is an article about alprazolam, as used by the majority of patients, not an anti-abuse and warning pamphlet for the relatively few who abuse it. It is also not intended to translate the article to such common language, as it is maybe understood by the abusers, if at the same time the common scientific meaning of the terms as cited from the references is lost. "the reference says white, but the commoner should understand that they in fact mean black and the term white is just an euphemism scientists use among themselves." Wikipedia is not investigative journalism. Please provide recent review articles to support your statements. 70.137.133.93 (talk) 03:29, 4 October 2011 (UTC)

Furthermore, you cite again the discontinuation symptoms and rebound symptoms as well as tolerance as evidence for abuse potential. This connection does not exist as such. The discontinuation and withdrawal symptoms and tolerance have been cited in the article as it is now. 70.137.133.93 (talk) 03:35, 4 October 2011 (UTC)

You do not seriously propose, to use Michael Jackson as evidence for any claims, do you? 70.137.133.93 (talk) 04:37, 4 October 2011 (UTC)

On a related note we have also removed the anecdotal evidence in another benzodiazepine article, that a man injected benzodiazepines successively into his leg arteries, until both legs had to be amputated, after which he proceeded to inject the drug into his eyeballs. He is now hanging in a basket from a wall in some institution, as a so called basket case. The reason for removal (from the article) was that anecdotal evidence and single but sensational case reports in particular are not regarded as reliable evidence to be included as reference. 70.137.133.93 (talk) 05:59, 4 October 2011 (UTC) 70.137.133.93 (talk) 05:59, 4 October 2011 (UTC)

Concluding, in wikipedia we cannot change technical terms to a meaning, which does not reflect the sources any more, but in your opinion would reflect the understanding of commoners of this matter, without redefining the article into some newspeak of drug abuse. This would be doubleplusungood (ungood++), even if you propose it for the doublepluscommongood. There is already no lack of such publications. Actually the creation of a wiki in newspeak as ns.wikipedia would be a fun project and as we can see would fill a niche, with finally all language redefined to new meanings and simplified to unmistakeable authoritative sense by recursive application of the Sapir–Whorf hypothesis. 70.137.133.93 (talk) 06:18, 4 October 2011 (UTC)

Regarding your reference to the harm scales of Dr. David Nutt I am not sure if his combined scales of individual harm and societal harm are an attempt to quantify a scientific framework for a regulatory system as well as cost optimization algorithm for a tax-run state health system in the UK, insofar being a hybrid of medical and political/economic research. At least does it seem to be so controversial that it is not to be seen as scientific consensus, in particular in the US. Maybe he comes to different results if he factors the savings in pension costs in, suddenly making smoking and drinking after the age of 65 highly societally useful and beneficial. With the widespread preference for a young and inexpensive workforce these weights may shift towards an age of 35 in the future, like in the movie "Logans Run". It is not yet to be seen how the scales would shift then, and what drugs would then become societally useful or harmful. 70.137.133.93 (talk) 08:33, 4 October 2011 (UTC) 70.137.155.195 (talk) 23:46, 4 October 2011 (UTC)