The Problem With Benzodiazepines.....

I want to thank David Allen for the inspiration for this post when he commented that as an addiction psychiatrist, I was probably seeing a skewed sample of people addicted to benzodiazepines and that might be why I have such a jaundiced view of them.  I use the above bubble diagram to illustrate how benzodiazepines are prescribed by docs like me with a strong bias toward preventing addiction compared with physicians who have no such bias.  To make sure that we are on the same page, benzodiazepines are all technically tranquilizers or sedatives.  They marked a therapeutic advance from the earlier barbiturate class  in that their therapeutic index (ratio of the drug that produces toxicity in 50% of patients to the dose that produces a therapeutic response in 50% of patients) is much greater than earlier tranquilizers like barbiturates.  The practical measure is that it takes much higher doses to produce respiratory arrest and death.  Despite the increased safety these drugs are addictive.  People can develop a tolerance and in some people they produce a euphorigenic effect, very similar to the effect of alcohol.  Some people describe benzodiazepines as "alcohol in a pill."  Unfortunately we do not know the percentage of people where that occurs or how to detect them. There are many common clinical situations where the safety margin of benzodiazepines is cancelled out by other factors.  Mixing them with alcohol and opiates are two of the most common dangerous situations and if you are treating addiction - you see that happen all of the time.

Rather than list the entire table of benzodiazepines, I am going to list the commonest ones that I see being abused.  In order from the most frequently abuse that group would include alprazolam (Xanax), lorazepam (Ativan), clonazepam (Klonopin), and diazepam (Valium).  Of those compounds Xanax Bars or 2 mg alprazolam tablets seem to be the most commonly abused by far.  The maximum recommended dose of alprazolam is 4 mg/day and I frequently have seen people taking 8-20 mg/day in combination with other street drugs.  Benzodiazepines have all been generic for a long time so they are very inexpensive to purchase if you have a prescription.  If you don't have a prescription and acquire them illegally the "street value" of a drug is a sign of abusability.  The average street value of alprazolam is about $5 for a 2 mg bar.  The immediate risk of using benzodiazepines excessively is accidentally overdosing on the single drug or in combination with alcohol and other drugs of abuse.  There is also a significant seizure risk from abrupt withdrawal when the supply of medications have been used.  The abuse of benzodiazepine like compounds that are more typically used for sleep like zolpidem (Ambien) or eszopiclone (Lunesta) does happen but it is more likely to occur in combination with alcohol for alcohol related insomnia.  A common example would be a person with alcohol dependence who takes zolpidem at night so that they can sleep through the entire night.  Without it they would predictably wake up at 2 or 3 AM from the withdrawal effects of alcohol.  Chronic use of benzodiazepines whether by prescription or acquisition from illegal sources can lead to tolerance and chronic withdrawal symptoms that can last for months if the drug or medication is stopped.  That fact alone should be considered as part of the risk of taking benzodiazepines - even in the situation where the person does not have an addiction and has anxiety that they do not believe can be treated by any other means.  In my experience, I am not sure that kind of anxiety exists.

Another common problem with benzodiazepines is that they can be psychologically debilitating, even if the person affected never takes the pill.  It is all part of the behavioral pharmacology of addicting drugs.  It usually starts out with a panic attack.  That panic attack can result in people going to the emergency department once or twice because they believe they are having a heart attack.  Somewhere along the line a physician prescribes alprazolam to take "in case of a panic attack."  That starts to happen and even if the panic attacks are rare, brief, and situational - the person affected starts to believe they need to carry alprazolam around with them wherever they go "in case" of another panic attack.  They may not have had a panic attack in years, but they are more anxious about whether they are carrying a pill when they get on a plane, cross a bridge, etc.  The pill have taken on Talisman-like features based on their using it for a condition that for most people fades away over time.  Some  who don't know the sequence of events might suggest "what's the harm" if somebody develops such a belief system around a pill.  In my estimation the harm is that the person's normal conscious state has been transformed and they have exchanged one form of anxiety for another.  The debilitating effects of anxiety depend on the illusion that your life needs to be modified in a certain way to accommodate it.  Proving to yourself that is not true is one of the best ways to adapt.        

Despite those reservations, I have prescribed a lot of benzodiazepines in my career.  They are very good medications to use in controlled environments for acute alcohol and sedative hypnotic withdrawal, acute seizures, catatonia,  akathisia, and various agitation syndromes associated with acute psychosis and mania.  The goal is typically to get the patient off the medication before they are discharged and to avoid treating patients with addiction with benzodiazepines.  Benzodiazepines are also useful for the first month in treating panic attacks, but that typically takes a lot of work.  The work involved is convincing the patient that a medication that seems to work rapidly is not a good one to take for the long haul.  The other dimension that is operating here that is rarely commented on and never explicit is whether the person receiving the benzodiazepine enjoys taking it.  Medications that are potentially addictive lead to an array of problems that are not there with drugs than are not addicting.  The main one is that they tend to be viewed as solutions for everything.  Instead of just anxiety or panic people will take them for insomnia, stress, or just to wind down at the end of the day.  Medications that reinforce their own use have the problem of inventing new uses that they were never prescribed for and that can lead to escalating doses of the medication.  In some complicated situations benzodiazepines are added to treat anxiety.  They have been used in psychiatric patients with multiple problems and been shown to add no benefit.  They are commonly added to multiple medications including opioids in patients with chronic pain with no additional benefit.

Benzodiazepines are a big problem in primary care.  The NSDUH survey illustrates that most people with an addiction are not aware of it and further that only a small minority seek treatment and find it.  That same survey suggests that about 1.5 million Americans start using tranquilizers and sedatives (they do not have a unique benzodiazepine category) for non-medical use very year.  Even if it is apparent to a primary care physician and their patient that an addiction to benzodiazepines exits, there are significant obstacles to reversing the process.  Although there are protocols for slowly tapering the medication on the Internet, it takes a very highly motivated person and ideal circumstances to accomplish this.  Outpatient detox from urgent care, the emergency department or an outpatient clinic is problematic because the same medication that the patient is not able to control is being given to them to self administer at home.  It is common that the detox medications are all taken the same day or in some cases at once.  Structured detoxification in the American health care system is practically impossible to find, especially in the case of benzodiazepines that require careful attention to seizure prevention, the prevent of withdrawal delirium, and adequate treatment of chronic withdrawal symptoms when they emerge.  Some primary care clinics are taking the preventive approach of not starting benzodiazepines in the first place.

Substance Abuse and Mental Health Services Administration, Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013.

There is a lot of resistance to the ideas of addiction docs when benzodiazepines and their long term effects are discussed among physicians.  There is always a physician who claims that they have successfully treated a person with an alcohol use disorder with benzodiazepines or they have people who have stayed on low doses for decades in order to treat their anxiety.  I see the failures.  It leads to the question of how many people are capable of staying sober, not developing a tolerance to benzodiazepines, and not experiencing a negative impact on their life.

As far as I know there are no good studies that address that question and I would not expect that there will be.  Any study that allowed subjects to mix alcohol, opiates, and benzodiazepines would be unethical and should not be approved by any Human Subjects Committee.


George Dawson, MD, DFAPA


Supplementary:

This article was subsequently edited and modified for the Psychiatric Times.  The edited version reads better.

Clozapine As A Fictional Murder Weapon On The Walking Dead

clozapine (Clozaril)

clonazepam (Klonopin)

When something doesn't fit my typical hypothesis testing interview style, I start to think that there are other things going on.  Things that might not be obvious and things that I will need to piece together with further evidence gathering and collateral information.  That is what happened when I was watching television last weekend.  It happens all of the time in real life.  I remember the day when I was a second year resident and my attending asked my: "Suppose that you are at a party and this person comes up to you and starts to act in a certain way.  Do you tell yourself: "I am off the clock" and try to react in a way other than a psychiatrist might act or do your think about that interaction like a psychiatrist would?"  There was some uncertainty there as a rookie, but not after 3 decades of practice.   You see the world as a psychiatrist.  That is why I suddenly became much more attentive when I heard the words clozapine and clonazepam mentioned in a very popular television drama last weekend.

Before any further consideration, this is about the implications of a purely fictional scenario.  This post is more about the motivations of the author or authors than psychiatric treatment.  At that level it is probably more about individual or cultural perceptions than reality.  I was watching the highly popular television series the The Walking Dead  last weekend.  This series is all about surviving a zombie apocalypse.  In this scene, a group of survivors is providing some kind of emergency medical care.  They are in a large hospital building.  I was surprised when the ragged physician gave the order to give a patient "75 mg of IM clozapine".  Any psychiatrist or psychiatric nurse knows that there is no IM form of clozapine and that according to the standard titration that dose is probably too high in any clozapine naive patient on day 1.  Apparently the writers of the show knew at least some of that because the actress who was working on the doctors orders had to take clozapine tablets out of a standard large pharmacy bottle and grind them up with a mortar and pestle so that they could be dissolved and injected.  She proceeded to inject the fictional patient with clozapine.  In a few minutes, the treated patient developed tonic-clonic seizures and dies.  She goes back to confront the original physician who gave her the order and is told: "No I said clonazepam and not clozapine."  Interestingly this combination is not on the list of look-alike, sound-alike or confused drug names by ISMP , but it is in this document about using TALL MAN font conventions to prevent mistakes among drugs that look alike.  On page three we learn that clonazePAM- cloZAPine-KlonoPIN are confused medications.  I think that anyone without experience in these medications might make that mistake.  Of course for the purpose of drama, we learn later that the physician giving the order actually knew that the deceased man was a physician.  They previously worked together in a hospital setting.  In the dog-eat-dog world of the zombie apocalypse, the ordering physician did not want any competition for his medical position.  He did not want to risk elimination by his more ruthless leader.  He intentionally ordered his assistant to give a clozapine injection and then lied and told her that he said clonazepam and not clozapine.

I posted the structures here to illustrate that before there were administrators focused on the confusion between names there were chemists to show that each of these compounds is unique.   Studying pharmacology and those technical details adds another layer of appreciation.  Psychiatry adds another layer of meaning on top of that.  I have seen the benzodiazepine trends and concluded like many psychiatrists after years of practice that clonazepam and other benzodiazepines might be useful for the first months of treating anxiety or panic.  As an add-on for anxiety in people with severe problems they don't add much.  In the end there are still the same problems and an additional addictive medication.  When I think about clonazepam, I am also reminded that even the professionals can be confused.  I used to work at a place where it was not considered a benzodiazepine and not subject to the same security precautions - even after I pointed that out.  Clozapine on the other hand can be a life changing medication.  People with refractory psychosis and mood symptoms become clear and function at a much better level.   If clozapine did not have significant limitations from toxicity, I doubt than there would be a need for any other antipsychotic.  It is the only one with clear advantages in terms of symptoms relief, improved function, protection against suicide, and it even treats tardive dyskinesia and other movement disorders.  But the way it stands there are significant side effect limitations and  it is the antipsychotic that psychiatrists worry about the most.  

We have a case of homicide by injection of 75 mg clozapine.  Does that hang together as being plausible?  It also triggers an entire series of question about: "Why clozapine?"  Clozapine is a fairly esoteric second generation antipsychotic.  It is indicated for treatment refractory schizophrenia and a lot of experts believe it is underutilized because of its superior efficacy in this population.  It also is the only medication that has been shown to have anti-suicide properties in a double-blind clinical trial.  Those superior effects occur in the context of a wide range of toxicities that require close monitoring including weekly to monthly complete blood counts with differentials (depending on the time course of treatment)  for the length of treatment with the drug.  In addition to hematological side effects the drug can cause seizures and a number of other organ specific toxicities like myocarditis.  It should only be prescribed by experts familiar with its use and registered to prescribe it and follow the white blood cell counts.  If the white blood cell counts fall below a certain parameter, the clozapine must be discontinued and not restarted.  Clozapine can cause fatal agranulocytosis.  I view clozapine as one of the most beneficial drugs in psychiatry and one of the most toxic.  Clonazepam on the other hand is a benzodiazepine.  It can be used to treat anxiety and panic attacks.  It can also be used to treat seizures, but I have rarely seen it used for that purpose.  The main toxicity is excessive sedation and the main clinical problem is that it can be addicting.  But in terms of toxicity, it is generally well tolerated.

My first question is why clozapine would be available in the post apocalyptic pharmacy?   In any shorter term situation the medications that run out first are maintenance medications for chronic conditions.  In this case, the survivors are supposed to be in Grady Memorial Hospital, one of the largest hospitals in Atlanta.  I suppose it is possible that they would have a larger supply of clozapine since they are a metro hospital and if psychiatric services were as bad before the apocalypse as they currently are they would typically have a significant number of people in the emergency department that may be taking clozapine.  The second question is - can it be given intramuscularly?  It turns out it can be.  A 1999 reference from Lokshin, et al describes their use of parenteral clozapine in 59 patients.  They are using the drug for acute stabilization of inpatients and they do not describe whether or not their patients are taking other medications or are medication naive.  They do not specify dosing but in one case described the problems with giving large intramuscular injections of up to 300 mg in injectable clozapine when  patient refused the same oral dose.  They had surprisingly few side effects, no fatalities, and no seizures.   Unless I missed a reference somewhere this may suggest that the author of The Walking Dead episode believed that clozapine is a lot more toxic (and lethal) than it really is.   Or do they have access to other information?  That also brings up the question, if you were a physician with access to the post-apocalyptic pharmacy would there be more toxic and more lethal medication that could be used for that purpose.  Most probably, but I will not be speculating about that here.

There are a large number of questions that come up if you think about the possible intentions or biases here that involve the use of clozapine in a fictional plot.  In situations like this, I prefer to contact the author directly and ask them what they were thinking.  After a significant amount of time searching, I learned that there may have been some controversy with the writers of this series, but I could not find a single e-mail or snail mail address where I could send them that question.  I would certainly prefer to get an answer from the author or authors.  How did they first hear about clozapine?  Why did they decide to use it in this case?  Do they have a medical advisor who suggested it?  Do they have a personal relationship with anyone who takes clozapine?  Do they have an opinion about the medical treatment of psychiatric disorders in general?  There is really a long list of questions.

And finally there are also the practical treatment implications.  Up to 17.3 million people watch The Walking Dead, a large percentage of them 18-49 year olds.  I am sure that  has implications for informed consent conversations between psychiatrists and patients and their families.  We live in a country where 21% of 18-29 year olds get their news about Presidential campaigns from The Daily Show.  After hearing the name from a psychiatrist somebody is bound to say:  "Wasn't that the medication that we heard about on The Walking Dead?"  The standard reply is that medical conventions and treatments are not immune to artistic interpretation and all areas of medicine are similarly affected.

I may be missing something but it just seems like an unusual choice for this medication in this plot to me.


George Dawson, MD, DFAPA



Ref:

1: Lokshin P, Lerner V, Miodownik C, Dobrusin M, Belmaker RH. Parenteral clozapine: five years of experience. J Clin Psychopharmacol. 1999 Oct;19(5):479-80. PubMed PMID: 10505595.