Episode 36

  • What are benzodiazepines?
  • How are they used?
  • What are the risks?

Benzodiazepines can feel like a miracle for a person with anxiety. Feeling panicked to feeling ok in a matter of minutes. But there’s more to them than that.  Tune in to this week’s episode of All Things Substance.

Transcript

You’re listening to the All Things Substance podcast, the place for therapists to hear about substance abuse from a mental health perspective.  I’m your host, Betsy Byler and I’m a licensed therapist, clinical supervisor, and a substance abuse counselor.  It is my mission to help my fellow therapists gain the skills and competence needed to add substance use to their scope of practice.   So join me each week as we talk about All Things Substance.

Welcome back to the All Things Substance podcast. This is episode 36.  As mental health therapists we talk about medication kind of a lot.  As therapists, we don’t prescribe of course, but a lot of our clients end up on medications and we have to know something about them. Some of us got really good training and grad school. Others had to learn it on the job.  

There’s lots of different kinds of medications like SSRIs, SNRIs, antipsychotics and even the old school MAOIs. Today, we’re going to be talking about benzodiazepines. This is going to be a two part topic. I started making one episode to talk about benzodiazepines and it got really long. As I was editing. I started to get bored just listening to myself.  So I decided to make two shorter episodes and this is the first of those.

The first episode is going to be about the class of benzodiazepines in general, what they’re used for, what the different kinds are, what the risks are and what the withdrawal is like. In the second episode, I’m going to be talking about the three main benzodiazepines that we use in our work: Ativan, Xanax and Klonopin.

Benzodiazepines or benzos as I’m going to call them, mainly because it’s easier, are a class of drugs that are used typically on an as needed basis, or at least that’s how they’re used currently  in the majority of cases I’ve seen them in.

There was a time though when I would run across clients who had been on benzodiazepines for a really long time. I recall having a client who was taking four milligrams of Klonopin every day for the last 10 years. The Klonopin wasn’t actually working anymore. It just had to be taken to maintain the average level of anxiety. It didn’t help for spike anxiety anymore. 

I think of these anxiety spikes the same way I think of breakthrough pain. Let’s say somebody had a surgical procedure and they’re in pain  and given a pain medication regimen they can have what’s called breakthrough pain. Meaning that typically the pain is mostly under control, but that there are spikes that break through the ceiling of the drug. Well, the same is true with anxiety. 

We give people medication that they take on a daily basis to treat anxiety. Could be something like Prozac or Zoloft that tends to have good coverage for both anxiety and depression, or it could be something like Buspar that’s typically used just for anxiety.

There are other drugs that are used more off label, like propranolol, which is a blood pressure medication used for social anxiety or Lamictal, which is used sometimes for bipolar and also for seizure disorders. And is sometimes used off-label for anxiety.

All of these medications do a pretty good job of managing day-to-day anxiety. It’s those spikes that can get to people and cause problems. In some ways we’re able to manage anxiety spikes with using skills. A lot of times these PRN or as needed medications, aren’t necessary. 

There are other times though that skills just aren’t effective. That happens when anxiety gets too high. After a certain point when anxiety hits, there is a moment at which skills no longer seem to work. The person is heading into a panic attack or an anxiety attack as some people call it. There’s really not much that they can do to stop it.

Anxiety is a bitch. One of the worst things about anxiety in my opinion, is that you start getting anxious about being anxious. That is some bullshit. You’re not just anxious about all sorts of things, but now you’re anxious that you might be anxious later.

Another part that I think is complete bullshit is that once you feel better, then you’re anxious about the fact that you’re not anxious and that is so maddening. Once my clients start feeling better and they’re not as anxious, then they’re worried that they’re missing something or that they’re not going to be on guard. It can take a while to get used to the absence of the daily ruminating anxiety that they have. This is where benzodiazepines typically get used. 

So we need to talk about what benzos are, how they work, what the different kinds of them are. And then we’ll focus on the ones that are mainly used in our work. When I started researching it, I realized that there were way more benzos  than I had knew existed.

I knew that Valium was a benzo and I thought that was kind of odd, but I really had only thought about benzos as being Ativan, Klonopin and Xanax. Turns out there’s kind of a lot more

Benzos first entered the U S market in 1960. Librium was the first one to be approved and used in clinical practice.

Benzos became popular because they had a much lower risk of respiratory depression. Respiratory depression is one of the biggest risks with opioids because as your breathing slows down, eventually there’s too many seconds between each breath and that can be really fatal. Benzos. Didn’t have the same risk level as a lot of opiates.

Benzos gained popularity over what had been used before, which would have been barbiturates, which we’ll cover in a different episode because that’s not typically a word we use very much. But I will cover it in the future just so we know what people mean when they say barbiturates. for now,  the point I’m making is that benzos were seen to be safer because they had reduced respiratory depression as compared with older medications, like barbiturates.

It wasn’t until about 20 years later that that researchers began to understand how they work. Benzos promote the binding of GABA, an inhibitory neurotransmitter to the GABA receptor.

According to the things I read, the exact mechanism of  how this works still, isn’t totally known. What they do know though, is that it does work on neurotransmitters in the brain. Neurotransmitters are the chemicals that our nerves release in order to communicate with other nerves.

Gamma aminobutyric acid our GABA  is the chemical that reduces activity in areas of the brain that are responsible for reasoning, memory, emotions, and essential functions such as breathing. GABA  is one of those neurotransmitters that suppresses the activity of the nerves. Scientists believe that the excessive activity  of nerves may be the cause of anxiety and other psychological disorders. Benzodiazepines reduce the activity of the nerves in the brain by enhancing the effects of GABA.

So basically what benzos do is it’s like dropping a nice calming blanket on a bundle of nerves that’s a little too hyperactive. Think of it like a weighted blanket for your nerves that are a little too amped up and the mechanism is the GABA  neuro-transmitter.

Benzos tend to be pretty well tolerated. However, when there are side effects or toxicity, it can be really, really serious and fatal. This is especially true for elderly clients  and certain other patients with lung, liver or kidney dysfunctions.  As well as patients on other kinds of medication.

So most of us know that benzodiazepines are used to treat anxiety and panic, insomnia, or other issues with sleeping.  A lot of times one of the benzodiazepines is used before surgery in order to help the patient relax. Benzos  also  have use in treating seizure disorders and are used in general anesthesia, muscle relaxation, alcohol withdrawal, and drug associated agitation, nausea, and vomiting and depression.

So I’m going to read you the list of names of the different benzodiazepines. I don’t expect you to really remember them. If the brand name is simpler to pronounce than the scientific name, I’m going to go with that.  So the drugs that are included in the benzodiazepine category are Tranxene, Xanax, Librium, Klonopin, Valium, Prosom, Dalmane, Ativan, Versed, Serax,. Restoril, Halcion, and Doral. That is far more than I really ever knew existed. I think I’ve heard of about half of those and they’ve been used in different ways for different clients.

The reason that they’re in this category is because of the way that they. All of these involve the GABA  neuro-transmitter and the GABA receptors. The idea is that if they can calm down the nerves, then they can help deal with whatever is being treated. So it could be seizures, it could be sedation, it could be nausea, it could be anxiety and the idea is that part of the reason that those things are happening is because of the over-excitability of those nerves. 

There are differences between each of those benzos. The main differences are the time they take to kick in, how long the duration of that effect is and what they’re most commonly prescribed for. 

So the fastest to start are Valium and Tranxene. The longest lasting, which might be a day or more are Librium, Klonopin and Valium. So in terms of their uses we know that for anxiety and panic that it tends to be one of the three Ativan Klonopin or Xanax. 

When it comes to seizures or convulsions typically they’ll use things like Klonopin, Tranxene, Ativan and Valium. For insomnia or sleeping issues they’ll use Dalmane  Doral, restoral and Halcyon.

For general anesthesia Versed, Ativan and Valium. I’m sure there’s others, but those are the main three. For sedation prior to surgery Ativan. Valium gets used a lot for muscle relaxation. For alcohol withdrawal and drug associated agitation that typically tends to be in Librium. Remember that was one of the first ones that got approval and that was being widely used.

The most common side effects of benzos are sedation, dizziness, weakness, and feeling unsteady. Other side effects could be transient drowsiness, which happens usually early in taking the medications. Could be a feeling of depression, headache, sleep disturbances, confusion, irritability, aggression, or memory impairment. These aren’t necessarily very common, but  are part of the side effects that would be told to a client.

All of the medications in the benzo category cause sedation in some form or another. So we’ve talked before how downers  have a compounding effect. So when somebody is taking a benzodiazepine on top of alcohol or narcotics or tranquilizers,  that’s going to have an additive or a compounding effect  causing those effects to be magnified.

So the way that benzos work and how fast they work and how long they last depends on a number of factors. They called us pharmacokinetics, which is the absorption, distribution metabolism and excretion of a drug. I E what the body does to the drug. Pharmacodynamics describes the responsiveness of the receptors to a drug and the mechanism by which these effects occur, what the drug does to the body.

So what the body does to the drug is affected by the route of administration. So are they taking it orally or is it being given I.V. The rate of absorption and how much they’re being given of that medication.

Now in a medical setting, benzos could be administered oral or IV, but there are also sublingual, intranasal or rectal gel forms. Now in our clients and on the street typically we’re going to be dealing with oral use in the form of pills.

Each of the benzos I listed all have different profiles in terms of how they’re absorbed, how much you need, how they’re eliminated and what they do in the body.  So there are some drugs that when taken in conjunction can slow the liver’s process of those medications, therefore raising the level of those medications in the bloodstream. One of those interactions happens to be between drugs like Xanax and Valium and the medication Prozac

Reduced elimination means that there could be an increase in blood concentration. Because of that increased blood concentration, it could prolong the side effects from the particular benzo. Another interaction is between antacids and benzos.

Antacids may reduce the rate of absorption of the benzos when they’re in the intestine. Separating the administration of antacids  and benzos by several hours and may prevent this interaction. We know that upset stomachs and heartburn go along with anxiety.  People treat that typically over the counter. So you can imagine that some of our anxious clients are probably taking a handful of antacids at different times.

Well, if they’re taking a benzodiazepine, it may be in their best interests to, to separate taking those medications by a few hours. They should definitely ask their doctor about it to see about the interaction.

There was a time when benzodiazepines were prescribed more freely. That’s not necessarily the case anymore. Every benzodiazepine has the ability to cause dependence. They all have the ability to create tolerance and physiological dependence on them. Abuse of benzodiazepines is absolutely a risk and something that people struggle with. 

Probably 10 to 15 years ago, the clients that I saw were on benzodiazepines far more often than they are now. A lot of them were on them on a daily basis just taking a specific amount, a specific number of times a day. 

Around 2010 in the United States doctors and hospitals began slowing way down  on prescribing opiates. It seems like at the same time the prescriptions of benzos also dropped. You can imagine the problems that this would cause. 

So you have people who are taking benzos on a regular basis, probably taking them as prescribed.  From the time they started on it, their doses would have been increased because nobody’s taking four milligrams of Klonopin in one day and staying awake and functioning. Not unless you have a tolerance. That stuff will knock you on your ass. Over time, taking Klonopin or Ativan or Xanax for that matter, a number of times a day, you build up to that. Because what happens is that the body gets used to the amount of the chemical. Tolerance, just like anything else.

You have to increase the dose, otherwise it doesn’t do much. Going without it however, that gets pretty intense. So here we have people who have been on regular prescribed doses of the benzodiazepines and their doctors are suggesting that they need to go off of them or taper down.

So we think about anxiety and the fact that now someone suggests that the thing that keeps the anxiety in check gets tapered down or taken away. You can imagine how well that would go for most of the people we know who have anxiety and panic disorders. I don’t blame the doctors for wanting to cut back on them. I don’t think benzos are a great choice for daily use  on a long-term basis and the literature backs that up. But at the time, what do you do with all the people who are on them? 

So as benzodiazepine prescriptions got cut down, we had a number of people who still have panic and experienced numerous panic attacks, unable to get access to these medications. That can be really frustrating, both for the client and for those of us who are trying to work with them in therapy.

We know that it can be really hard to work with someone who has chronic panic attacks.on doing anything super therapeutic because their anxiety is just too high for them to focus on anything other than that. Until the anxiety is managed in a way that makes them somewhat functional.

We can’t focus on a lot of other things. I liken it to the whole Maslow’s Hierarchy of Needs thing. When somebody’s anxiety is really high, they feel like they’re in danger and we can’t focus on other tasks until they feel like that danger has receded.

The two main problems with benzo with benzodiazepine use is their potential for abuse and subsequent overdose, which is life-threatening and the development of physical dependence.

So the thing about benzodiazepines is that when they’re being abused, it’s typically not just benzodiazepines,  they’re used often in addition to some other drug. Certainly there are people who only use benzodiazepines and that is their “drug of choice”. But in general, what we find is that people use them in addition to other things. 

A lot of factors go into that such as the fact that they’re just not easily available.  Now, certainly there are pressed pills out there that say that they’re Xanax or Klonopin or Ativan,  and aren’t really those things. And you can’t tell, but it’s just not as common that I find that people use that as their go-to.

So for the benzodiazepine class, the most commonly abused are Valium and Xanax. At a high dose, dependence and subsequent withdrawal can happen actually pretty quickly. I had a client who within a month was using upwards of 20 milligrams a day and the withdrawal from that was extremely intense.

For most people, the use of benzodiazepines for a period of several months doesn’t cause issues of addiction or tolerance or problem stopping the medication when it’s no longer needed. It’s really about the consistent use rather than the sporadic use when, when benzodiazepines are used on an as needed basis. 

Many of my clients who have PTSD have had experience with benzodiazepines:; where they’re able to use them a few times a month only when something really big comes up. In general, I end up working with them on how to manage those spikes and use that as a last case. Oftentimes just having the benzodiazepine in their possession means that they feel more secure because they know that there’s an out. Part of the thing about a panic attack is that you feel like it’s never going to end. And if you know that there’s a thing that will stop it oftentimes you feel a little safer and I have found that my clients are able to manage those without benzodiazepines, more often. 

For benzodiazepine withdrawal, they end up using a lower amount of a benzodiazepine to end up to help them come down. That could be something like Librium that’s used for drug associated agitation. If it’s an overdose, there is an antidote used called Romazicon. Romazicon  is used to reverse the effects of benzodiazepines.  It can also be used to reverse conscious sedation and general anesthesia. It’s an antagonist  much like Naloxone is for opiates. 

One of the ways that benzodiazepines get used is that oftentimes opiate addicts want to drop it on top of an opiate because it increases the euphoric effect. This is especially important when we’re talking about people who are on Suboxone or methadone. Those are opiates in and of themselves and if someone’s dropping a benzodiazepine on that, they’re going to get high. It may not be as high as they might like, but it will definitely give them something even though they’re not taking a dose of opiates that’s supposed to get them high.  Some research studies have found that people who are from prescribed opioids are considerably more likely to be prescribed a benzo also.

Approximately 75 million prescriptions for benzos are written in the United States each year. Usage increases with age and women are often prescribed benzos twice as often as men. Research has shown that the highest number of abuse cases exist in the non-Hispanic white population. Young adults ages 18 to 35 comprise the largest portion of the benzodiazepine abusers. And as would be expected, a lot of the people abusing benzodiazepines also have comorbid psychiatric disorders.

So with benzodiazepines being a secondary drug of abuse, the issue of the compounding nature of depressants is important. If benzos aren’t typically used alone and they’re a downer, they’re probably going to end up being combined with a downer also. I don’t know why you would take a benzo on top of meth. That doesn’t really make any sense. Certainly I could see using a benzo to deal with meth withdrawal, but that’s a different story. 

We’re talking about benzos in use with opiates and alcohol and other things that are depressant in nature. Those effects get compounded. And then what used to be less risky in terms of respiratory depression now increases that risk. Opiates have a huge risk for respiratory depression. A downer on top of a downer, absolutely is a problem.

What’s interesting to me is the research puts benzodiazepine abuse rates at a certain level, but that the rate of diagnosing substance use disorders for benzodiazepines is actually pretty low. A benzodiazepine use disorder is a different story.

What I mean is that the number of people who abused or have abused benzodiazepines in their lifetime have not necessarily met criteria for a benzodiazepine use disorder. I don’t know if that’s because they only have abused them a few times and haven’t done it a lot or if they just aren’t being diagnosed properly. It seems like from the research that most people who have abused them aren’t necessarily abusing them for a long period of time and therefore developing an abuse disorder.

Benzodiazepines have a really specific withdrawal syndrome that’s actually pretty dangerous and it’s not just dangerous it’s incredibly unpleasant and the length is unpredictable. So it’s going to depend on which benzo that you’re taking as to what the withdrawal is like.

The problem from what I’ve seen is that it can feel like panic attacks are either happening or just about to happen all the time. There’s agitation, lack of sleep, restlessness, muscle tension, irritability. There could be some nausea, blurred vision, nightmares, depression, problems with muscle coordination, tremors. There could be hallucinations, delusions, seizures and ringing in the ear. 

So the withdrawal seizure is what the problem is here. The risk of that goes up depending on how high the dose was of the benzo, how long the treatment was and if there were any other drugs on board that lower the seizure threshold. 

It’s important to know that with withdrawal, it doesn’t always happen right away. Typically it begins within 24 hours and may last from a few days to a few months. However, there are some of these that have a longer half-life and so they’re not going to develop withdrawal symptoms right away. There are some places I saw that suggested it could take up to two weeks for the withdrawal symptoms to occur.

Getting off benzos is really complicated and kind of a nightmare.  If you have someone on benzodiazepines who wants to go off of them I would encourage them to talk to their doctor about weaning themselves off of them.

Even if they’re buying them off the street. it’s not going to get them arrested. They need to tell their doctor and ask for help getting off of them. They’re not going to get reported. It’s going to be fine. It can be really dangerous and fatal to just drop them. It’s going to put them in a world of hurt with anxiety, and they’re going to feel like total shit for kind of a while. I’ve had clients who have gone off long-term benzodiazepines, and it’s super hard to watch because it’s terrible.

During that time, we’re kind of not able to make much progress on therapy, but also no major changes in their medication. Even though they feel awful because we don’t know what’s a withdrawal symptom and what’s going to be there when it’s all over. Watching suicidal ideation at that time is  really important too.

In terms of withdrawal, there are three possible phases. Each has an estimated timeline and I want to be clear if I haven’t made it super clear already, no one should detox or taper down on benzos without the guidance of a medical professional.

Early or immediate withdrawal symptoms are sometimes called rebound symptoms and they’ll happen shortly after someone stops taking benzos. So a person’s withdrawal would depend on the half-life of the drug. Withdrawal symptoms from short acting drugs, like Xanax could come on faster than  long acting drugs like Valium.

During the early stages of withdrawal, the person might notice that the symptoms they were originally treating are starting to come back. So for example, for someone who’s being treated for anxiety or insomnia, those symptoms may come back or get worse right away. Drug tapering or using other drugs to get off of benzos might help the withdrawal symptoms  be more mild and manageable. 

Acute withdrawal begins after the initial withdrawal symptoms. It’s usually within a few days and it can last anywhere between from like five days to a whole month. Some of the benzodiazepines can have an even longer withdrawal syndrome that could last several months. During the acute phase of withdrawal, sometimes doctors are going to help with other medications to help manage those symptoms. 

Then there’s protracted withdrawal. So in the British Journal of Clinical Pharmacology, they state that about 10 to 25% of people who use benzos for an extended period of time have withdrawal symptoms that can last for 12 months or longer. Protracted withdrawal, sometimes called PAWS, post acute withdrawal symptoms can be insomnia, anxiety, poor concentration, loss of sex drive, depression and mood swings. Some of these symptoms can appear without warning and can be really hard to manage.

Withdrawal symptoms can begin even when  used as directed. As you would expect, the withdrawal symptoms are typically more mild in people who take the drug for short periods. There are some people who have had severe reactions though, even if they’ve only used it for a short time. Research suggests that 40% of people taking benzos for longer than six months, experience moderate to severe withdrawal symptoms.

In addition to the other ones for post-acute withdrawal syndrome, they can have physical aches and pains, abnormal sensations like the feeling like bugs are crawling on them, muscle spasms, sweating, nausea, vomiting, depersonalization or detachment from reality, hallucinations or delusions, but the most difficult one of course are the grand mal seizures.

As you would expect with a withdrawal syndrome, there can be really intense cravings to use either the benzo or another drug to help calm it down. This can often lead to them using a different kind of drug and potentially trading one for another.

Benzodiazepines are classified as a schedule four controlled substance. According to the classification, these drugs have a low potential for abuse and a low risk of dependence. I haven’t found that to be true though. The research indicates that physical dependence could begin in just a few weeks. 

Most of the time withdrawal can be handled outpatient, where the doctor would meet with the patient and work with them on this taper that they’re going to be doing. In some cases the doctor or medical provider might suggest that someone go inpatient to help them down a little faster. What happens and what they’d like to have happen depends on the conversation between the patient and the doctor.

If you want to know more about how benzodiazepines work in the body, why they become less effective over time and what system is affected, you can head over to the show notes and I’ve included a number of articles there  so that you can take a look if that interests you. 

A lot of the articles are good. It’s just that they get really technical. And I’m trying to stick to what it is that I feel like would be best for us to know. But I know that some of you might have more involvement with people who are on benzodiazepines or potentially work in a medical setting where this is more prevalent and you might want to know more.

So you can head over to betsybyler.com/podcast and find episode 36. and the links will be in the show notes.

One of the risks I haven’t talked about yet  is an increased risk for developing dementia, including Alzheimer’s. Elderly people are susceptible to alterations in the pharmacodynamics and the pharmacokinetics as well as drug interaction to poly-pharmacy.

What they found is that in the elderly population changes in how the body processes the drug,   how the body absorbs the medication, processes it, eliminates it and all of the other medications that tend to be on board as a person gets older, that those things are all having an effect on how the benzodiazepine is being tolerated.

These situations increase the risk of the appearance of  cognitive affectation and the development of things like Alzheimer’s and dementia. From what I could see in the research this is typically from long-term use of benzodiazepines and not someone using them on a short-term limited basis.

Benzodiazepines in general can be used safely in certain situations and with a doctor’s supervision. It’s pretty clear though, that long-term use of benzodiazepines has a lot of risks.

When this class of medication became popular between the 1960s and the 1980s it seemed to be treated like a frontline medication. However, in the eighties and nineties when we started having SSRI’s the role of benzodiazepines started taking a back seat.  Most prescribers prefer to go with SSRIs or SNRIs to treat depression and anxiety rather than using benzodiazepines.

Next week we’re going to talk about the three main benzodiazepines that we use, Klonopin Ativan and Xanax.  While Valium is also a commonly prescribed benzodiazepine it’s not necessarily something that is prescribed often for anxiety or depression. It’s typically given in more medical type situations and less on a regular basis.

We’ll pick up this discussion next week. I hope you join me for that podcast until then have a great week.

Thank you for listening to the All Things Substance podcast. For show notes, links and downloads, please visit betsybyler.com/podcast. If you loved what you heard today, it’d be great if you would share those with your therapist friends and colleagues. If there are topics that you think would be useful and you’d like to hear me cover them, please let me know.  Just send a message to podcast@betsybyler.com. I’ll see you on next week’s podcast. And until then have a great week.

This podcast is designed to provide accurate and authoritative information in regards to the subject matter covered. It is given with the understanding that neither the host, the publisher or the guests are rendering legal, clinical or any other professional information.

Helpful Links

Benzodiazepines Drug Class: List, Uses, Side Effects, Types & Addition

https://www.psychiatrictimes.com/view/benzodiazepine-use-risk-dementia

Risk of Dementia in Long-Term Benzodiazepine Users: Evidence from a Meta-Analysis of Observational Studies

Frontiers | Benzodiazepines and Related Drugs as a Risk Factor in Alzheimer’s Disease Dementia | Frontiers in Aging Neuroscience

Benzodiazepines: Revisiting Clinical Issues in Treating Anxiety Disorders

The epidemiology of benzodiazepine misuse: A systematic review*

High enhancer, downer, withdrawal helper: Multifunctional nonmedical benzodiazepine use among young adult opioid users in New York City

Patterns in Outpatient Benzodiazepine Prescribing in the United States

Antidepressants plus benzodiazepines for adults with major depression

Benzodiazepine Use and Misuse Among Adults in the United States

Benzodiazepine Pharmacology and Central Nervous System–Mediated Effects

Benzodiazepine use, misuse, and abuse: A review

Withdrawal effects of benzodiazepines | Mind, the mental health charity – help for mental health problems

Tolerance to benzodiazepines among long-term users in primary care | Family Practice | Oxford Academic

Research suggests benzodiazepine use is high while use disorder rates are low | National Institute on Drug Abuse (NIDA)

Benzo withdrawal: Timeline and symptoms

Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators?

The hidden phenomenon of high dose benzodiazepine use | Pharmaco Vigilance