COMMENTARY

Using Propofol for Difficult-to-Treat Headaches in the ED

Robert D. Glatter, MD; Sergey M. Motov, MD; Richard M. Pescatore, DO

Disclosures

March 22, 2018

Robert D. Glatter, MD: Welcome. I am Dr Robert Glatter, assistant professor of emergency medicine at Northville Health in New York City and adviser for Medscape Emergency Medicine. Today, we will be discussing the use of propofol for difficult-to-treat headaches in the emergency department (ED).

I recently came across an article by Dr Rick Pescatore in Emergency Medicine News [1] related to the use of low-dose propofol to treat headache in the ED. It immediately caught my attention because treating migraine and other types of headache is a common part of emergency medicine practice. The article led me to a June 2017 post of Dr Pescatore's on the blog R.E.B.E.L. EM[2] that also described the use of propofol for treating headache.

Emergency physicians are not only tasked with determining which headaches may be the most life-threatening, but also with figuring out the most effective ways to treat them. The standard headache cocktail—a neuroleptic agent, ketorolac, diphenhydramine, and dexamethasone—is ingrained as the most effective first-line approach for alleviating migraine and tension headaches in the majority of patients. We often use this approach in the ED, and although it is certainly effective, another novel strategy that deserves discussion is propofol.

Joining us to discuss this interesting tactic is Dr Rick Pescatore, assistant director of emergency medicine and research at Inspira Health Network in Vineland, New Jersey, and Dr Sergey Motov, associate research director at Maimonides Medical Center in Brooklyn, New York, and assistant clinical professor of emergency medicine at SUNY Downstate. Welcome, gentlemen.

Propofol Makes Its Way Into the Headache Armamentarium

Dr Glatter: Rick, I applaud your efforts championing the use of propofol for managing headache in the ED. It is certainly a novel approach. Can you review the basic pharmacology of propofol? Why is this an ideal medication to treat headaches?

Richard M. Pescatore, DO: Propofol is a safe drug. I believe there is no emergency medicine physician alive who is not abundantly familiar with propofol, its capabilities, and its qualities.

Why does propofol work in headache? The first answer is that we don't 100% know for sure, just as we don't 100% know for sure know why people get headaches. It probably works multifactorially. Propofol has GABA potentiation, which probably provides a certain amount of direct analgesia. It reduces that central sensitization and cortical spreading depression that we associate with primary headaches and migraine disorder. And at low doses, it provides a certain amount of NMDA inhibition, similar to ketamine. That is probably why it is so effective.

Finally, it crosses the blood/brain barrier incredibly quickly. If there's one thing we know about treating headache, it is that the speed with which these medications cross the blood/brain barrier is directly correlated with their effectiveness in treating it.

Dr Glatter: How is it that propofol worked its way into the headache armamentarium? Are there any studies or did this come about by accident?

Dr Pescatore: This has evolved over the past 5 or 10 years. A growing body of literature supports its use for headache.[3,4,5,6,7,8,9,10] I would argue that we have more literature supporting the use of propofol in primary headache disorders than we have for a lot that we do in emergency medicine.

It started with case reports and case series.[3,4,5] Since then, we have seen retrospective reviews,[6,7] prospective, observational studies,[8] and even relatively strong randomized controlled clinical trials[9,10] that demonstrate that propofol is a safe and effective treatment for treatment of primary headache in the ED.

Dr Glatter: Sergey, what are your thoughts on this? You are a specialist in pain management. You have written extensively about ketorolac, ceiling dosing, and so forth, and recently published on this topic in the Annals of Emergency Medicine. [11] Do you see propofol as something that could replace our standard headache cocktail, or something that may be an adjunct for the difficult-to-treat?

Sergey M. Motov, MD: Before we start, I want to thank Rick for pushing the agenda and putting together these amazing publications. Thank you for doing this.

At present, I think propofol is not ready for prime-time, first-line treatment, but we should definitely consider using it. In my practice, I resort to propofol when traditional treatment modalities, as you mentioned—the neuroleptic cocktail, nonsteroidal anti-inflammatory drugs—fail to achieve appropriate analgesia after two or three doses. I resort to propofol as a rescue analgesia.

Deciding on Which Patients to Treat With Propofol

Dr Glatter: Do you find it to be appropriate for certain kinds of patients?

Dr Pescatore: That is a great question. I would flip that around a bit. There is certainly a cohort of patients for whom the neuroleptic agent has a bit of a necessary secondary effect. There also is a patient population for whom propofol is more effective. We have yet to parse out that patient population.

I have had a lot of success with propofol in patients with complex migraines, specifically patients with ocular migraines who are temporarily blinded by the severity of their headaches. It is amazing to watch them regain their sight after a low dose of propofol. I do not yet know who the population is that benefits from this. For now, I use a taste-test approach.

Reserving [propofol] for rescue analgesia is certainly a reasonable and laudable way to use this. As we gain greater clinical experience with propofol, as we are more comfortable with it, and as we begin to identify patient populations for whom it is particularly effective, I do see it becoming more of a first-line agent.

Dr Glatter: Sergey, what are your thoughts on this?

Dr Motov: Obviously, those with resistant headache would be a subgroup of patients who would be eligible for this type of analgesia, and my favorite group of patients, pregnant women in their third trimester. Let's look at this while considering the US Food and Drug Administration's ABCD classifications of drugs for pregnant women.

I saw a patient recently, a 35-year-old pregnant patient who came to me with intractable headache. It was not a gestational headache. It was just a headache, a migraine headache. She did not have preeclampsia. She had gotten metoclopramide, which is a category B drug—no risks have been found in humans. She got magnesium, which was classified as a B drug but now is a D—indicating the potential for adverse events in humans. Then she got a second dose of metoclopramide, but nothing worked.

If I go by the classification categories, propofol is in category B. The patient comes to me from labor and delivery because of intractable headache. I used 10 mg of propofol every 5 minutes; I broke her headache at 60 mg. She was absolutely the happiest woman alive. She was headache-free, and she went home. For pregnant women in the third trimester, propofol is safe. Use it.

Dr Glatter: I can imagine the pushback from other providers just thinking about pregnancy, and especially the obstetrician in how they would approach this. Certainly, with its categorization, I believe it is safe. I guess the issue is monitoring the patient.

Hospital Administration of Propofol

Dr Glatter: A lot of nurses and administrators are concerned about the problems this drug has had in the past. Here we are trying to push propofol in small aliquots. How do we approach the hospital administration? What is the best plan?

Dr Pescatore: That is the key question that comes up when we talk about using propofol for headache. The first thing to get across here is that it is not the drug that causes sedation. It is the dosage and the intent behind giving the drug. As Sergey said, the small doses we're administering are incredibly similar in effect to low-dose or subdissociative ketamine use.

There is no need to use standard conscious sedation or moderate sedation protocols when we administer propofol in the manner we are discussing. Are we going to be reckless with it? Absolutely not, and certainly we will take into account the fact that this drug has a history associated with it.

There is no emergency physician alive who is not comfortable with this drug, who does not understand how to use it. We will monitor the patient for respiratory depression as we would for any opioid analgesic, for example. But this is an incredibly safe drug.

Dr Glatter: Do you have a specific, written protocol at your hospital that you refer to?

Dr Pescatore: I have been lucky enough to work at quite a few hospitals. One or two of these hospitals required a written protocol, but the vast majority of my use of this drug is similar to my use of any other drug in the ED.

Dr Motov: I agree with Rick and with you, Robert. In our traditional thinking, the doctor and nurse are the champions of the patients, and everything fits into the place. But I would bring a bit of caution: I believe to protect ED personnel, you have to protocolize it.

You have to clearly say that this is a subanesthetic dose of propofol. It does not require monitoring. Propofol does not require any interventions beyond the usual, similar to what we do with morphine. I believe it needs to be protocolized and vetted by the department of nursing, other department chairs, and everyone else. I would push for getting it protocolized and then roll it out.

Propofol Over Ketamine: What Are the Advantages?

Dr Glatter: Why not use low-dose ketamine rather than propofol? What is the advantage or disadvantage?

Dr Pescatore: I would defer to Sergey for this. He is clearly the expert. But propofol may add something that ketamine lacks; you get a bit of GABA action from propofol. There is a bit of inhibition of cortical spreading depression that you won't get from the ketamine. That is not to say that ketamine can't be effective. This is just another tool to place in our toolbox, and it adds to that versatility.

Dr Glatter: What will make you select propofol over ketamine when you look at a given patient? Can you point to anything specific?

Dr Pescatore: I can't say that there is anything I have been able to parse out. I believe we all have had enough experience with ketamine now that we can look at a patient and say this is probably not the best patient for ketamine.

Dr Glatter: If the patient has a psychiatric history and a history of agitation, is that something you will consider when you're looking at ketamine versus propofol?

Dr Pescatore: Without question, that goes into it. I also look at the blood pressure. Patients who are profoundly hypertensive may be more amenable to propofol than ketamine, for example. Then overall, I look at the severity of their symptoms.

Dr Motov: I have been using a stepwise approach to just about all headaches. If propofol fails, I resort to ketamine. I resort to ketamine to double the NMDA blockade. I use ketamine if propofol fails, and as Rick said, in the patients with schizophrenia or excessive weight, and perhaps pregnant women, I avoid ketamine because it is not entirely safe. I am also not going to give it to young children.

Ketamine is essentially a very safe medication. The hemodynamic compromise, which happens with certain doses of ketamine, is negligible. But I start with propofol. If propofol fails, at least I have something else to rely on and use before I go to general anesthesia and total sleep.

Treating Pediatric Migraine in the ED

Dr Glatter: What about pediatric migraine? Have either of you used this approach in that population?

Dr Pescatore: I have, absolutely. In fact, I find propofol to be particularly effective in the pediatric population. One of the studies that planted the seed in my mind was in a pediatric population.[7] Propofol is even safer in this population than in patients who have any possibility of respiratory compromise, and it is very effective.

Dr Motov: I have not used it in pediatric patients because I primarily see adults. But I agree with Rick. One of the first trials that evaluated a subanesthetic dose of propofol used it in pediatric patients.

Propofol Versus Subcutaneous Sumatriptan

Dr Glatter: I want to talk about a randomized 2014 trial[12] that compared subcutaneous sumatriptan versus intravenous propofol. The study found no significant difference at 1 and 2 hours, although there was more improvement in the propofol group at 30 minutes.

Propofol reduced the side effects that you often would see with sumatriptan—the nausea, the vomiting, maybe some chest pain, things of that nature. What are your thoughts on this trial?

Dr Pescatore: I believe the side effects, in the administration of all these drugs, are truly the crux of this issue. They are all going to be effective. If we are couching that in a setting of a whole bunch of side effects and a whole bunch of prolonged ED stays, whatever we can do to minimize that is a target for me.

Dr Motov: I always have an issue when a titratable medication is compared with a nontitratable medication. Also, the route of administration is different. Remember, sumatriptan has a fairly narrow indication, for migraine headache only. In contrast to that, propofol can be used for any type of headache, as long as the headache is multidrug-resistant. Side effects are side effects. I personally believe that propofol is safer than sumatriptan. If it is a young patient with a complicated migraine and propofol helps, go ahead and use it.

Final Thoughts on Propofol

Dr Glatter: Rick, you brought up the length of stay in the ED, and that is a key issue. Earlier, we were saying that 15-20 minutes could be the total duration of the ED stay, with pain relief and subsequent discharge. But do you have to monitor these patients for any significant time afterward?

Dr Pescatore: Absolutely not. There is no reason to continue observing these patients after they have endorsed that the propofol's effects are gone. Propofol has an incredibly short half-life. Patients' headaches are relieved almost immediately. Then they get a Tylenol®, and they go out the door. In my experience, it is a rapid discharge. There is a very low rate of headache recurrence, it is incredibly successful, and it leaves the bed empty for the next patient with a headache.

Dr Glatter: Are you finding the same, Sergey? A very quick discharge after you administer propofol?

Dr Motov: Yes. I completely agree with Rick.

Dr Glatter: Why shouldn't we be using this drug for headache throughout the United States? What are the issues that prevent this from being adopted?

Dr Pescatore: The biggest issue is the stigma. People are afraid to administer this medication because of the Michael Jackson stigma and the stigma of conscious sedation. I believe we will get there; I really do.

Dr Motov: I agree 100%. People need to understand that we are not sedating patients; we are just taking care of their pain.

Dr Glatter: Is there any risk for physical or psychological addiction? Will people be returning to the ED to get a euphoric effect?

Dr Pescatore: I would love to hear what Sergey has to say about this. I am not aware of any literature that has looked at the addiction potential or dependence level of propofol. In my own experience, I have not seen that happen. Contrary to the warnings of my colleagues that patients will be bouncing back for their fix, I have not seen that.

Dr Motov: I have yet to see a patient come back to the ED and ask for propofol.

Dr Glatter: I believe we need a larger, randomized study to really flesh out and validate the results of these smaller trials. Do either of you have any other ideas you wanted to bring up or thoughts about propofol?

Dr Pescatore: My parting message is that we do many things in the ED that have little, if any, knowledge base surrounding them. If there is a drug that emergency physicians are more than comfortable with, it is propofol. If there is a drug with as wide a therapeutic window as propofol, I would like to see it. Propofol is incredibly effective, with a rapid onset of effectiveness, and with only limited danger associated with it. I believe it offers a good option for many of our patients.

Dr Motov: I agree. I will just add this: The key to the success of using propofol for headaches is to use it for properly selected patients at a properly selected dose, understanding that we are not sedating patients but taking care of pain by using a protocolized approach that is vetted by nurses and doctors in the ED.

Dr Glatter: I believe that brings home the message. We are trying to spare opioids. We are trying to help patients. This is a valid approach that has been validated by research and is something we can reach into our toolbox and use.

Thank you both. This has been a very informative discussion.

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