The Experts Guide to Treating Agitation 

Treating agitation is a big part of inpatient and emergency psychiatric treatment. In the emergency department agitation accounts for 2.6% of total patient encounters. Knowing which medications to use and how to use them is critically important. Today I’m going to discuss all the options for the treatment of acute agitation in clinical practice. 

What is Agitation?

Agitation is an extreme form of arousal that is associated with increased verbal and motor activity that poses a threat to themselves and others. Agitation needs to be recognized immediately and addressed due to the risk of harm to the patient and others. 

Verbal De-escalation is Always The First Step

Engaging the patient and attempting to elicit a reason for the agitation should always be attempted first. In many cases patients are hungry, tired, or overly stimulated by the busy inpatient or ED setting. If these interventions are unsuccessful and the patient remains agitated security staff lead by the physician should inform the patient that if the behavior continues medication will be administered for safety purposes.

Thinking About Medication

Sometimes using medication is unavoidable and is required to facilitate a medical evaluation. We need to be mindful of the potential adverse events associated with sedating medication. The most common adverse effects are hypoxia, airway obstruction, QTc prolongation, bradycardia, and hypotension. Patients over the age of 65, alcohol intoxication, and multiple medication administrations in a short period of time increases the risk of adverse events.

Routes of Administration

It’s always best to offer PO (oral) medication prior to using IM or IV medications. In the inpatient setting we do not allow IVs due to the potential risk of self-harm; IM medication is second route of administration commonly used. I will usually use risperidone 2 mg or olanzapine zydis 10 mg because it begins dissolving immediately once the person puts it in their mouth in both cases. Oral medications can be “cheeked” and will also take longer to start working. In general, it’s important to note the onset of PO medication will be slower. Antipsychotic medications and benzodiazepines are commonly used for sedation in acute agitation. 

First Generation Dopamine Blocking Medications

These medications have been around for a long time and have a good safety profile when used to treat acute agitation. Some antipsychotics have the risk for more side effects due to their ability to lower seizure threshold, cause hypotension, and have an increased anticholinergic burden. 

Haloperidol

This is the go-to antipsychotic for acute agitation. It works by blocking D2 receptors and can be given PO, IM, or IV. Typical dosing is 2.5 to 10 mg with a recommended maximum dose of 20 mg/day. The average time to sedation is 25-28 minutes and the mean total time sedated is 84-126 minutes. The main risk for haloperidol is EPS such as acute dystonic reactions. To avoid this situation, we usually combine Haldol with lorazepam or benztropine/diphenhydramine. Haldol is also well studied and relatively staff for those who are acutely intoxicated with alcohol. 

Chlorpromazine

I will usually go to chlorpromazine when I need someone to sleep such as cases of mania with acute agitation. I find it to be a little more sedating and it can be combined with diphenhydramine. Doses can range from 25 mg to 200 mg depending on the level of severity. The maximum dose is 400 mg/day. 

Second Generation Dopamine Blocking Medication

Second generation medications have the added advantage of lower risk for QTc prolongation, less sedation, and fewer extrapyramidal symptoms compared to the first-generation options. 

Olanzapine

Olanzapine comes in PO, IM, and IV forms, and the typical starting dose is 10 mg. Olanzapine reaches peak concentration in 15-45 minutes and its half-life is 2-4 hours. The incidence of EPS is much lower than injectable haloperidol. There is very rare incidence of QTc prolongation. There is some evidence that 10 mg of olanzapine is more effective than 5 mg of haloperidol for sedation and that most patients are adequately sedated at 15 minutes after administration of 10 mg olanzapine compared to 5 mg and 10 mg of haloperidol. 

It’s important to note that multiple studies have demonstrated adverse events when olanzapine is combined with benzodiazepines. Although the risk may be overstated it’s best to avoid this combination unless necessary. Olanzapine is highly anticholinergic and should be avoided in cases where anticholinergic overdose is suspected. 

Ziprasidone

Ziprasidone is a second-generation medication that is available in either PO or IM formulations. The PO form of the medication has little utility in acute agitation, but the IM version can be useful. Time to onset of effect is usually 15-20 minutes and it reaches peak concentrations in 30-45 minutes. The duration of sedation is at least 4 hours. Ziprasidone carriers the highest risk of second-generation medications for QTc prolongation

Risperidone

Data for risperidone in acute agitation is limitted. It does have the advantage of coming as an oral disintegrating tablet. In most cases I would administer 2-4 mg depending on the severity of symptoms. It can be a good option for patients with psychotic agitation due to paranoid delusions. It’s a good option for elderly patients and pregnant patients who can take PO medication. 

Benzodiazepines 

Benzodiazepines are another good choice when it comes to rapid treatment of acute agitation. Benzodiazepines do carry the risk of creating a paradoxical reaction in the elderly, but it’s relatively rare and seen in only 1% of cases. Flumazenil (benzodiazepine blocker) can be used to counteract this paradoxical reaction if needed. There is risk for respiratory depression especially in those who are already on central nervous system depressants. If withdrawal is suspected from benzodiazepines or alcohol, this is the first line option for treatment. 

Lorazepam

Lorazepam is available in IV, IM, and PO formulations. The typical dosing is 0.5-2 mg IM or PO. This medication can be given every 30 minutes up to a maximum dose of 12 mg/day. Lorazepam is longer acting than midazolam and has an average time to adequate sedation of 32 minutes. 

Midazolam

Midazolam is available in IM formulation and the typical dosing begins at 2-5 mg. The average time to sedation is 13-18 minutes for the IM formulation. When given IM the total time of sedation is between 82-105 minutes. Midazolam offers the advantage over lorazepam because it’s onset of action is faster. Midazolam also works faster than haloperidol or ziprasidone. The duration of sedation is also shorter. 

Medication Combinations

In most cases these medications will be used in combination to maximize their effects. The most well-known is the so called B52 which consists of Haloperidol 5 mg, Lorazepam 2 mg, and diphenhydramine 50 mg. The idea here being 50, 5, and 2 are the doses and B52 because it’s like the B52 bombers when it comes to sedation. I also often combine chlorpromazine and olanzapine with 50 mg of diphenhydramine in the IM formulations. For PO risperidone you can combine it with PO lorazepam and diphenhydramine if needed. With ziprasidone I will usually give this one alone without lorazepam or diphenhydramine. 

Physical Restraints

The utilization of physical restraints may be necessary when safety is a major concern. In some cases, verbal de-escalation, and medication are not enough. The problem is physical restraints can lead to injury for both the patient and staff. Patients who continue to fight against the restraints can have a complication known as rhabdomyolysis where the muscles are literally breaking down from the person fighting against the restraints. Sedation should always be provided when physical restraints are used. What happens if a person is given high doses of sedating medications and placed in psychical restraints but remains agitated?

Special Cases

It’s rare but I have had two clinical scenarios where an individual was placed in restraints given multiple doses of medications and remained severely agitated. Due to concern for the patient’s safety and risk of rhabdomyolysis I had to transfer each of these cases to the medical floor for IV dexmedetomidine (Precedex) which is commonly used to sedate patients in the intensive care unit who are intubated. After a short course of Precedex treatment each patient’s agitation resolved. There is now a rapidly dissolving film of dexmedetomidine available for acute agitation in bipolar disorder and schizophrenia, so I guess I was ahead of the times when I made these clinical decisions. 

Conclusion

Agitation is a complicated and multifactorial process that requires quick action. To maintain safety, agitation needs to be quickly identified and managed. Verbal de-escalation and comfort measures should always be the starting point. If medications are required there are several individual and combinations that can be selected based on the clinical situation. When all else fails physical restraints remain a possibility until medications have had time to reach peak concentrations and effectiveness. 

Take Your Pills: Xanax What They Got Right 

As many might know there is a new Netflix documentary called Take Your Pills: Xanax and it combines interview footage from physicians, patients, and journalists about anxiety and the use of Xanax. For the most part I thought there were a lot of reasonable discussions about anxiety, its treatment, and the role of medication. I feel like this is an appropriate way to cap off our recent discussions about anxiety disorders and treatment. 

Fear and Anxiety: Are They the Same Thing? 

The documentary made it seem like anxiety and fear are the same thing and that the exact same neurobiology is involved in each case. I think about anxiety and fear as two separate things that require different approaches. 

Anxiety is what an individual feels when they are worried about something that could potentially happen in the future. If you watched my other videos on generalized anxiety disorder (GAD) then you know the Diagnostic and statistical manual (DSM) has made excessive worry the hallmark of GAD.

Fear is a core emotion along with sadness, anger, joy, excitement, and disgust. It’s different than anxiety, which is a fear of some future event happening. Fear is triggered in the moment. When you see that bear walking on the hiking trail or hear the rattle of a snake the fear centers of our brain are activated immediately in that moment. It’s not that we are obsessing about some future outcome, there is something present in the environment that is threatening and demands immediate action.

The Fear Center of The Brain

In humans the fear center of the brain is called the amygdala which stands for almond and that’s because they taste like almonds. No, wait that isn’t right, it’s because they are shaped like an almond. The amygdala is what fires when you see that bear in the woods. This triggers the fight or flight response which leads to things like increase blood flow to the muscles, and increased energy. It prepares the body to run away or fight if necessary. 

Benzodiazepines MOA

Benzodiazepines enhance GABA activity by acting as allosteric modulators of the GABA-A receptors. This is the major inhibitory neurotransmitter in the body, and it acts to dampen everything down. Benzodiazepines increase the frequency of opening of chloride ion channels which in turn inhibits the cell and prevents the neuron from firing. 

Anxiety Is a Part of Life

As I’ve said before we all have anxiety under certain circumstances. It’s not always a bad thing to have anxiety. In many ways anxiety reminds us that this situation is important, and we need to be appropriately prepared. A healthy amount of anxiety is a good thing overall. 

Things go sideways when the anxiety is chronic, persistent, and severe. As I’ve stated in the previous videos some people are just more prone to anxiety. These individuals are high in the big 5 personality trait of neuroticism. While most of us will fall somewhere in the middle there will be outliers on either side with some having significantly less anxiety and others having significantly more.  

The one thing that made this documentary hard to follow is that they combined all the anxiety disorders together, at one point they were describing panic attacks, social anxiety, and GAD as if they are all part of the same disease process. While there is significant overlap, the course of illness, and treatment plans will vary greatly which is why proper diagnosis is so important. 

Xanax Works great for Physical Symptoms of Panic Attacks 

When the interviewees start talking about Xanax it’s in the context of people experiencing panic attack. This is an important distinction to note as most of the symptoms of panic attacks are physical and thus will have a greater response to benzodiazepines. If we are talking about GAD, or social anxiety the anxious thoughts will still be there, and the benzodiazepine may be less effective. 

Why Temperament and Environment Deserves More Attention 

Much of our baseline temperament is genetic and will be part of the story that determines if you will have more or less anxiety. The other part of the story is environment. The experiences we have matter a lot too. In child psychiatry, there has been this huge focus on minimizing adverse childhood events (ACES). We discovered that things like sexual abuse, physical abuse, and loss of a parent can result in significant risk for poor health outcomes in the future. Baseline temperament that predisposes someone to anxiety combined with significant lifetime trauma could set the table for a future anxiety disorder. 

The Prevalence of Benzodiazepine Use 

In this documentary they make it seem like benzodiazepine prescriptions have skyrocketed over the last several decades. These prescriptions have increased but we need to explore why. One thing I see all the time is primary care providers prescribing benzodiazepines for patients early in treatment for depression and anxiety. Before exploring psychotherapy or other medication options the person walks out with a Xanax prescription. There is a reason the research tells us most people who see a primary care provider for depression and anxiety do not get better. In fact, as few as 20% of those started on antidepressants by primary care will show significant clinical improvement. This is not a knock on primary care, it’s more that they have been thrown into a mental health crisis and are usually the first person to encounter a patient with anxiety. 

The important trends I would like people to pay more attention to is the risk of prescribing opioids and benzodiazepines in combination. This can result in increased risk for overdose death and a significant risk for severe respiratory depression. In addiction treatment people often feel very anxious when stopping opioids and it’s common to want to address that anxiety as a doctor. What ends up happening is people are on medication treatment for opioid use disorder, a benzodiazepine for anxiety, and gabapentin for that little extra relief. All these medications in combination put the patient at risk for adverse outcomes. Another thing to pay attention to is where all the opioid prescriptions are coming from. The highest rates are in many southern states and in places like West Virginia where the opioid epidemic hit the hardest. The final item to discuss is the increased rates of benzodiazepine prescribing in the elderly. There seems to be an increase in benzodiazepine use in this population which is more dangerous due to the risk of falls, altered mental status, and possibly dementia. 

There has been a lot of talk over the years about the increased risk of dementia associated with benzodiazepine use. There data has been mixed, but I would say it’s largely in favor of using caution when prescribing benzodiazepines in older populations and avoiding the long-term use of benzodiazepines in all populations.

Social Media and Anxiety 

I think social media has done as much harm as it has good for people’s mental health. If you believe everything you see on social media, the impression is everyone you know, or follow is winning, and you are losing. In the past you only had to compare your life to people in your community. Now, we get to compare our lives to the world. Not only are we comparing our lives to large pool of people, but we are also comparing them to people who have created online personas under false pretenses. These are individuals rent house for photo shoots to make you believe that is where they live, or people taking steroids then asking you to buy some supplement that does not provide the results it promises. We all like to think we are immune to these types of schemes, but we are not. In our minds we are comparing our worst moments to other people’s best moments and assuming that this is reality. This is clearly a recipe for anxiety and depression. 

Dangerous Coping Strategies for Anxiety 

I do not think using alcohol or drugs to alter one’s state of consciousness is exclusive to the past. People have been doing this forever, and it remains a poor way to cope with anxiety. I think one of our problems is attempting to cure the stresses of life. In my practice I do not believe that taking a medication or using alcohol are ways to “cure” anxiety. Most individuals need to take a long hard look at their life and see where the anxiety is coming from and where life changes can be implemented to reduce the tension. When someone takes time to systematically dissect the cause of their anxiety, they often already know what they should do. Take more time off work, practice better self-care, exercise, eat healthy, and sleep better these examples all come to mind for most patients. Most people feel trapped and do not believe they can carve out the time to do these things and that is part of the reason they turn to medication or drugs/alcohol to cope. 

While I still believe benzodiazepines can be useful in the right context, they are designed to be used short term. I set limits with my patients early in the process letting them know up front that we are not using this as a long-term solution for their anxiety. 

Potential Side Effects of Benzodiazepine use 

They did a nice job of describing the changes in memory that occur because of benzodiazepine use. The ability to laydown new memories is impaired when using benzodiazepines that is why I caution anyone with PTSD who is in trauma-based psychotherapy to avoid the use of benzodiazepines. They also focused on the disinhibition caused by increased GABA-A activity. This is less a side effect and more a response that should be expected from the medication. Most individuals with anxiety are wound too tight and have trouble relaxing. The problem with this response occurs when that disinhibition is excessive resulting in embarrassment or inability to work for example. 

Withdrawal from these medications can be deadly. There is risk for seizure, rebound anxiety, rebound insomnia all of which can be very distressing. The problem with benzodiazepine withdrawal is the variability in terms of patient’s tolerance to dose reductions. Some patients can tapper off very quickly and have no issue, others need to be tapered slowly over months to years. While I would say it’s rare to have someone who is very sensitive to dose adjustments it can happen and tapering slowly while watching for withdrawal symptoms is important. The example of the guy pipetting a liquid microdose of alprazolam would not be a normal situation, and if you just watch this documentary, you may think everyone who tries to come off these medications must go through a similar process. Benzodiazepines can be safely reduced under the guidance of doctor. 

Conclusion

What we see in the end is more of the same recommendations most of my patients would tell “doc I already know this.” They talked about using complementary and alternative medicine which I am a big fan of, diet, exercise, mindfulness, and psychotherapy to find the underlying causes of the excessive worry. They introduce the idea at the end that the world is broken and defective and we should not have to accept the world as it is. This is fine but significant change on a massive scale takes time and it still leaves people asking the question “what do I do right now.” I’m personally active in advocacy work at the local and state level, which is one approach, but it takes a lot of time and resources to affect policy changes and not every patient will have the time or desire to engage in such activities. The only true way out of anxiety is through it. Daily life is painful, and we need to accept that to some degree. Medicating away feelings that are part of life is certainly not the solution and can be the reason we find ourselves in trouble. 

Can Benzodiazepines be Prescribed Ethically?

Benzodiazepines are quickly gaining a reputation as the new opioids in terms of risk for abuse and potential for adverse events. The question remains, is there a way to ethically prescribe these medications to patients while reducing the risk of abuse? 

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