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Article, Oct/20: Benzodiazepines: it's time to return to the evidence


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The authors of this article, entitled "Benzodiazepines: it's time to return to the evidence", are members of the International Task Force on Benzodizepines.

 

https://www.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/benzodiazepines-its-time-to-return-to-the-evidence/B4DBF992E78EBCC53DC15930829B79E6

 

Abstract

 

Summary

 

We propose that discussions of benzodiazepines in the current psychiatric literature have become negatively biased and have strayed from the scientific evidence base. We advocate returning to the evidence in discussing benzodiazepines and adhering to clear definitions and conceptual rigour in commentary about them.

 

 

 

    Editorial

 

    The British Journal of Psychiatry , Volume 218 , Issue 3 , March 2021 , pp. 125 - 127

    DOI: https://doi.org/10.1192/bjp.2020.164

 

 

    Copyright © The Author(s), 2020. Published by Cambridge University Press on behalf of the Royal College of Psychiatrists.

 

When benzodiazepine anxiolytics were first introduced in the 1960s they were viewed as a liability-free alternative to barbiturates and meprobamate and were prescribed widely to patients with complaints of anxiety. After a decade of experience, it had become clear that benzodiazepines could be abused, and the pendulum began to swing towards suspicion of them. It is now commonly believed that they are dangerous drugs, prone to abuse and addiction. Treatment guidelines caution against their use as first-line or long-term therapy. It has become almost standard for clinical publications about benzodiazepines to issue warnings about dependence, abuse, addiction, tolerance or dangerousness, even when their central topic is an unrelated matter. Clinicians who advocate use of benzodiazepines may risk opprobrium from peers and institutions.

 

Terminology

 

The literature and diagnostic classifications such as the DSM and ICD use varying terminology when describing substance-use disorders. Here we differentiate between abuse (taking a drug to achieve an appetitive effect, or ‘high') and misuse (any use that deviates from the way a medication has been prescribed).

 

A reminder of what the evidence tells us

 

The bulk of scientific literature on benzodiazepine safety, dependence and misuse tells a different story. Although demonstrating a range of potential liabilities, including cognitive and psychomotor impairment, possible risk in pregnancy and severe and/or prolonged withdrawal syndromes, it does not confirm that these medications are primary drugs of abuse or gateway drugs leading to other substance abuse. The database was scrutinised in the 1980s and 1990s in a series of extensive reviews, including a volume commissioned and published by the American Psychiatric Association. In aggregate, they comprise over 2000 literature citations, dealing with both animal and human studies bearing on abuse, misuse and dangerousness of benzodiazepines.Reference Woods, Katz and Winger1–Reference Woods, Katz and Winger3 Their authors conclude that benzodiazepines ‘do not strongly reinforce their own use and are not widely abused drugs. When abuse does occur, it is almost always among persons who are also abusing alcohol, opiates or other sedative hypnotics’2 and that ‘epidemiological studies of various populations of drug abusers have often found rates of nonmedical use of benzodiazepines that exceed those found in the general population [but] the preponderance of the extensive use of benzodiazepines is directed by physicians for disorders in which these drugs have proven therapeutic effect’.Reference Woods, Katz and Winger3 Although co-abuse of benzodiazepines has risen in the context of the opioid epidemic, there has been no newer evidence suggesting that either benzodiazepine abuse or any other substance abuse has its genesis in prescribed treatment for general (i.e. non-substance-abusing) patients. In his 2005 review of benzodiazepine abuse and dependence, O'Brien states, ‘benzodiazepines are usually a secondary drug of abuse – used mainly to augment the high received from another drug or to offset the adverse effects of other drugs. Few cases of addiction arise from the legitimate use of benzodiazepines’.Reference O'Brien4 Although most of the literature on this topic is not recent, neither is it outdated; it is simply ignored.

 

Reasons for the bias against benzodiazepines

 

Why bias against a safe and useful class of medications has become so entrenched is not entirely clear and is itself a subject worthy of investigation. One factor may be that major pharmaceutical companies long ago abandoned benzodiazepines in favour of antidepressants, which we believe has had a substantial influence on practitioners and has left benzodiazepines with few people to speak up for them. Concern about co-abuse of benzodiazepines by opioid abusers, with potentially lethal consequences, may be another factor motivating physicians to avoid them. In this climate of opinion, discussions about benzodiazepines often blur important distinctions about their clinical pharmacology or describe them in inaccurately pejorative terms. We discuss below five instances of unfounded beliefs about benzodiazepines that we believe have been especially detrimental.

 

    (a) Benzodiazepines prescribed for anxiety disorders are likely to be abused. Benzodiazepines have a short latency of onset to calming or sedating effects, which may make them attractive to people who abuse substances. However, they are not prone to being abused by those with no such history. Conflating risk in these two populations stigmatises people with anxiety disorders and deprives them of treatment that might restore them to more functional lives.

 

    (b) Patients who misuse benzodiazepines are on a spectrum of drug abuse and are at risk of proceeding to frank abuse or addiction. Misuse is defined as any use of a medication that deviates from the way it has been prescribed by a clinician – including taking extra doses or taking less medication than prescribed.Reference Maust, Lin and Blow5 Addiction (called dependence in ICD-10) is defined by a cluster of behaviours that includes drug-taking to achieve appetitive effects (i.e. a high), preoccupation with the substance in question, temporary satiation, loss of control and persistent use despite negative consequences. Misuse of benzodiazepines is common, estimated at 17% of overall use.Reference Maust, Lin and Blow5 However, the great majority of people who deviate from doctors’ prescriptions of them are trying to control symptomatic distress, not to get high,Reference Maust, Lin and Blow5 and there is no evidence that misuse is likely to lead to abuse. Abuse and addiction should be addressed by substance abuse treatment; misuse is a more heterogeneous phenomenon that may involve suboptimal prescribing, poor doctor–patient communication, and patients inappropriately attempting to eradicate all negative affect with medication. However, alarmed clinicians who automatically view patients who deviate from their instructions as medication abusers may demand that they taper off benzodiazepines, with detrimental consequences.

 

    © Patients prescribed benzodiazepines tend to escalate their doses, which should preclude long-term use. There is a common belief that long-term benzodiazepine treatment is associated with tolerance to their anxiolytic effects and consequent dose escalation. The accumulated evidence is to the contrary: long-term treatment is associated with maintenance of therapeutic benefits, and no dose escalation. Tolerance does develop to the sedating and psychomotor effects of benzodiazepines, however.2 Failure to make this distinction may be the basis for withholding benzodiazepines, or for withdrawing them from patients who have been doing well on them during acute treatment.

 

    (d) Benzodiazepines are dangerous in overdose. Benzodiazepines alone are among the safest of psychotropic medications, with lethal dose LD50 estimates for most in the range of thousands of mg/kg. Even alprazolam, which may be more toxic, has an estimated LD50 range of 300–2000 mg/kg. Taken in conjunction with alcohol or opioids, they markedly raise the lethality of these already dangerous substances. That benzodiazepines are safe for the vast majority of people with anxiety disorders for whom they are prescribed is obscured by commonly used phrases such as ‘benzodiazepine-related death’ to describe a lethal combination of opioids and benzodiazepines ingested by a polysubstance-abusing person.

 

    (e) Taking benzodiazepines long-term leads to dependence. The word ‘dependence’ almost invariably has pejorative connotation and may unfairly characterise patients when applied vaguely or inconsistently. As used in ICD-10, ‘drug dependence’ is essentially a syndrome of addiction. ‘Dependence’ may also be used to describe a physiological withdrawal syndrome, an entirely different phenomenon that occurs with many medications, and is not in itself a sign of addiction.Reference O'Brien4 People with anxiety disorders discontinuing chronic benzodiazepines may experience a syndrome that includes rebound anxiety, which clinicians may take as a reason to withhold long-term treatment. Dependence is commonly applied, without clear definition, to patients in long-term treatment with benzodiazepines who lack any of the behavioural characteristics of substance abuse. They may be labelled as dependent (or addicted or hooked) because of the potential for a withdrawal syndrome and told that they must deal with it by getting off their medication. It is not surprising that anxious patients summarily told that they are drug dependent and deprived of an effective medication have difficulty tapering off it. But their doctors may interpret their struggles as evidence that a benzodiazepine prescription was problematic to begin with.

 

A call to clinicians

 

It's time to return to the evidence about benzodiazepines and to conceptual rigour in interpreting it. Benzodiazepines are highly effective for treatment of anxiety disorders, but are not for everyone, have potential liabilities and are best used in conjunction with targeted psychotherapies. That polysubstance abuse often includes benzodiazepines, however, should not blind us to their appropriate use. Distinctions between abuse, addiction/dependence, misuse and physiological dependence may be challenging, but they are supported by the evidence and are clinically important. Conflating these phenomena will perpetuate stigma against benzodiazepines, the clinicians who prescribe them and the patients who take them. We invite colleagues to engage in evidence-based reappraisal of the benefits and risks of these medications and to abandon aspects of conventional wisdom that do not stand up to such scrutiny.

 

Acknowledgement

 

This manuscript arose out of discussions among the members of the International Taskforce on Benzodiazepines, an informal collaborative group of academic clinicians (including the authors) who are interested in disseminating accurate information about and fostering appropriate use of these medications.

 

Author contributions

 

E.S. prepared the first draft and subsequent revisions; all other authors reviewed the drafts, commented, made editorial suggestions, and reviewed and approved the final draft.

 

Declaration of interest

 

The authors are members of the International Taskforce on Benzodiazepines. C.Z. was Chair of the American Psychiatric Association Task Force on Benzodiazepine Dependency and author of its report.

 

ICMJE forms are in the supplementary material, available online at https://doi.org/10.1192/bjp.2020.164.

 

References

1

Woods, JH, Katz, JL, Winger, G. Abuse liability of benzodiazepines. Pharmacol Rev 1987; 39: 251–413.Google ScholarPubMed

2

American Psychiatric Association Task Force on Benzodiazepine Dependency. Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force Report of the American Psychiatric Association. APA, 1990.Google Scholar

3

Woods, JH, Katz, JL, Winger, G. Benzodiazepines: Use, abuse, and consequences. Pharmacol Rev 1992; 44: 151–347.Google ScholarPubMed

4

O'Brien, CP. Benzodiazepine use, abuse, and dependence. J Clin Psychiatry 2005; 66(suppl 2): 28–33.Google ScholarPubMed

5

Maust, DT, Lin, LL, Blow, FC. Benzodiazepine use and misuse among adults in the United States. Psych Services 2019; 70: 97–106.CrossRefGoogle ScholarPubMed

 

 

 

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Its an all out media blitz to get prescribers back into the practice of pushing benzo's at their patients, a practice I haven't seen slow down or we wouldn't have a forum of newly wounded members.  It sure makes me wonder why they're pushing so hard, maybe the members of the task force need a benzo to mellow out a bit, maybe take it for a few months to a year then attempt to withdraw.  I wonder if their tune would change?
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Its an all out media blitz to get prescribers back into the practice of pushing benzo's at their patients, a practice I haven't seen slow down or we wouldn't have a forum of newly wounded members.  It sure makes me wonder why they're pushing so hard, maybe the members of the task force need a benzo to mellow out a bit, maybe take it for a few months to a year then attempt to withdraw.  I wonder if their tune would change?

 

I hope someone over at the Benzo Information Coalition is aware of this and maybe can run some rebuttals against some of these editorials.

 

This is maddening. They are going to put more people through what has been done to us.

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Its an all out media blitz to get prescribers back into the practice of pushing benzo's at their patients, a practice I haven't seen slow down or we wouldn't have a forum of newly wounded members.  It sure makes me wonder why they're pushing so hard, maybe the members of the task force need a benzo to mellow out a bit, maybe take it for a few months to a year then attempt to withdraw.  I wonder if their tune would change?

I hope someone over at the Benzo Information Coalition is aware of this and maybe can run some rebuttals against some of these editorials.

 

This is maddening. They are going to put more people through what has been done to us.

 

Its my understanding they have or will be addressing the Task Force during the comment period which ends Oct 17.  http://www.benzobuddies.org/forum/index.php?topic=271675.0

 

Edit: Grammar

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Hi Pamster and Nathan,

I just wanted to point out that this article is from 2020, and I only posted it now because I just came across it when I was trying to find that background document on the Benzodiazepines Task Force from 2018 (which I also re-posted in the News section here). I don't recall ever seeing this 2020 article, but I do absolutely know that I saw and posted the 2018 article. Many BBs and I had quite an intense discussion about it at that time.

 

The individual authors/doctors/scientists may well have written other articles on this topic since 2018, but someone would have to take the time to do that in-depth research and go author-by-author.

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I guess one question I have is this - what incentive is there to encourage benzo use?  Aren't all the benzos long since available in generic form?  I can't see some manufacturer slipping money under the table to get favorable articles on benzos given their low profit margin. 

 

I do see why doctors may be incentivized to prescribe benzos.  I mean, it quickly takes care of the patient, and the patient (initially) feels it solved their problem.  Much easier and quicker than getting to the root of the problem.  Still, I don't think that would cause a doctor to necessarily push for favorable articles - they are just being expedient.

 

So what group I wonder is behind a push for more benzo use, and why?  How do they benefit from more benzo use?

 

 

 

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I guess one question I have is this - what incentive is there to encourage benzo use?  Aren't all the benzos long since available in generic form?  I can't see some manufacturer slipping money under the table to get favorable articles on benzos given their low profit margin. 

 

I do see why doctors may be incentivized to prescribe benzos.  I mean, it quickly takes care of the patient, and the patient (initially) feels it solved their problem.  Much easier and quicker than getting to the root of the problem.  Still, I don't think that would cause a doctor to necessarily push for favorable articles - they are just being expedient.

 

So what group I wonder is behind a push for more benzo use, and why?  How do they benefit from more benzo use?

 

You basically hit on the answer in your question.

 

Anxiety is a rampant problem in the world today. And practicing doctors have a multitude of patients coming to them looking for a solution to their anxiety issues.

 

And the fact of the matter is, when it comes to anxiety ... benzos work. At least for a while. In fact for most people with significant anxiety, when they get that prescription for that first benzo they find their anxiety is shut off like flicking off a light switch. Now long term we know that the picture is not so rosy, but if you're a doctor with an anxiety riddled patient nothing is going to make that patient happy like getting that first benzo. And a happy patient is a happy customer. And medicine is a business and businesses like happy customers.

 

If you take benzos off the table and you're looking for a pharmacological solution to anxiety - doctors really don't have much in their arsenal.

 

SSRIs and SNRIs were originally created to address depression, not anxiety. And those drugs don't really work very well for the aliment they were created for (if they work at all). Whatever little they do for depression, they do less for anxiety.

 

What else have they got? Antipsychotics? They aren't that great for anxiety either and they have a terrible side effects profile. A patient sitting in your waiting room twisted up like a pretzel with tardive dystonia or pacing and shaking with akathisia because of the antipsychotic meds you gave him isn't the best advertisement for your business.

 

No, if you're a modern general practitioner or a psychiatrist who's essentially been trained to address every issue by whipping out your prescription pad and you want to treat patients with anxiety, you're going to feel really crippled if benzos are taken off the menu. You just aren't going to have much to offer to your customers.

 

Besides, if in a few years your patient has unimaginable anxiety, DP/DR, dizziness, muscle spasms, headaches, etc. etc. the list goes on and on because he tried to quit taking the benzos you gave him - well the bastard has anxiety so what the hell do you expect? Really it's the patient's fault if you think about it.

 

So I agree with you, I don't think this recent push to cast benzos in a positive light is coming from the pharmaceutical industry so much as it's coming from rank and file doctors.

 

To the extent that the pharmaceutical industry cares about the public perception of benzos, it's mainly that there aren't any major studies that implicate these drugs as causing some patients such devastating harm as that would expose them to legal liability. Even though these drugs have been off patent and generic for many years, the recent spat of lawsuits over cancer causing impurities found in Ranitidine shows that the original patent holders and marketers of a drug can be held liable years after the drug goes generic.

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I do think these doctors really believe that benzodiazepines are the best options out there for anxiety. I just find it so strange that they feel the need to band together and write articles in defence of these medications.
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I think that many doctors do believe that benzos are the best option for treating anxiety, but they arrive at that conclusion by ignoring all contrary evidence.

 

When you attribute every patient report of negative consequence to the patient’s own anxiety (in essence blaming the patient) then of course you’re going to view benzos favorably.

 

What they’ve done is to decide a priori that any negative report of adverse effects of benzo use is due to something other than the drug itself. Given that bias they can reach only one conclusion. Many simply can’t bear to have these drugs taken off the table since they know they don’t really have an alternative that works. Also, given that most doctors have written more than a few prescriptions for benzos they are extremely reluctant to accept that they might have caused harm to a patient. So doctors carry these biases that they may not even be consciously aware of, but they are significantly driving their evaluation of the evidence.

 

Whatever this is it’s not science. And it’s certainly not returning to the evidence. You don’t return to evidence you’ve never acknowledged.

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True. If you just look at the number of studies done that show falls, fractures and motor vehicle accidents in people taking benzodiazepines -- especially in seniors -- then you already have irrefutable evidence of harm done. I can't tell you how many of those I've come across over the years of looking at PubMed studies. They almost all conclude with a suggestion to deprescribe benzodiazepines or to review the Beers list of medications that should be avoided in seniors, which includes benzodiazepines.
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