Guest: Dr. Lara Pizzetti Fernandes

View the recording from our Migraine Clinician Masterclass, developed in partnership with IVPN Neuropsychiatry. In this webinar, we hear from Dr. Lara Pizzetti Fernandes, who talks about Medication Overuse Headache. Please note that this video is intended for healthcare providers.

TRANSCRIPT

Dr. Lara Pizzetti: This is a really important subject. We could spend like maybe two days talking about medication overuse headache. But I know we have a short time, so I will try to be objective and clear and to use some practical tips that I can give you.

But first, we need some introduction. So medication overuse headache, which I will refer as MOH, only happens in patients with a preexisting headache disorder, which is usually a primary headache. Analgesic overuse can be caused by other painful conditions, such as low back pain, neck pain, and arthritis. And the diagnosis of MOH implies that overuse medication is the cause of the frequent headache. 

The most commonly used drugs are triptans, simple analgesics, and combination analgesics, as well as opioids. And depending on which country you live at, you’ll also find some patients that use a lot of barbiturates and ergotamine. But most of these patients with MOH, they take more than one drug class. 

And since MOH is, in principle, preventable, we need to talk about it. Like many, many cases are iatrogenic, especially those that the overuse medication requires medical prescription to be bought. And I’m sure it is exacerbated by poor medical advice. So talking about epidemiology, we know up to 2% of adults have MOH, and the most part of its population is female. And that makes a lot of sense since the most common headaches have a female prevalence.

It tends to develop years after the onset of the underlying headache disorder, and it accompanies the prevalence rates of migraine and tension-type headache. And that also makes sense because these are the most common two headaches that are the underlying problem. And so prevalence will increase with age until middle age. And though MOH is not as prevalent as migraine or TTH, it is the most prevalent chronic headache type. 

70% of patients with chronic migraine have MOH, and migraine is the underlying headache disorder in 80% of patients with MOH. And it is among the costliest headache disorders, and 92% of its cost is attributed to presenteeism and absenteeism.

We are not sure if the risk factors are directly or indirectly associated with MOH, but we know there are a lot of patients with psychiatric comorbidities, especially depression and anxiety. And these both are also independent risk factors for chronification and for MOH. And they’re also predictors of worst prognosis.

And among the genetic risk factors, we see mostly ones involved with serotonergic and dopaminergic transmission, as well as these polymorphisms. And you will find that many of the probable risk factors are shared with other chronic headache conditions. It’s pathophysiology seems to be headache specific as patients with episodic headaches may develop MOH if they use analgesics for other painful condition, but the other painful condition does not get worse.

And it is hypothesized that MOH influences neural pathways of the underlying headache disorder. And this is why it looks like the headache is getting worse along the years, but it looks like the same headache that is progressive among a long time. And we have evidence of functional and structural changes in neuroimaging studies. And curiously, some of the state of these alterations normalized after MOH is resolved, and it is better studied in association with migraine. 

So I will try to summarize the pathophysiology into figures cause it’s long and I don’t want to like be writing the slides for you.

So what you have here is that C and A-delta fibers become pro-nociceptive and they transmit peripheral input from painful headache and neck structures to higher dorsal cervical roots and the trigeminal ganglia, leading to sensitization of second-order neurons in the trigeminal nucleus caudalis.

And this in association with noradrenergic and serotonergic inputs from the dorsal raphe nucleus and the locus coeruleus will be transmitted to third order neurons in the thalamus and in the somatosensory cortex for sensory integration and central sensitization. And we will also have the pulmonergic boot from the VTA, which is the ventral tegmental area, which is here, to the basal ganglia.

And it will be involved in maintaining the habit to overuse medication. And we all know that the amygdala is involved in dependency behavior. And the periaqueductal gray and the rostral ventromedial medulla will show decreased inhibition and increased facilitation of pain transmission. 

And here, what you have from the peripheral sides is that the use of triptans and opioids will sensitize the trigeminal ganglion neurons, and it will result in the increased expression of CGRP and neuronal nitric acid synthase.

Here, you will have neuroendocrine mechanisms as well as prolactin. They will contribute to pain sensitization. Here on number three, we have increased transmission from the trigeminal ganglion neurons will promote sensitization of secondary neurons in the trigeminal nucleus caudalis. And this will involve long-term potentiation and NMDA receptor. 

In here on number four, we will find that medication overuse will promote adaptations in the descending pain modulatory pathways that involve serotonergic and noradrenergic signaling in favoring pain facilitation and diminishing pain inhibition. And we cannot address MOH without noticing that these patients they have a behavioral phenotype.

And so the most frequent comorbidities of MOH are anxiety and depression. They also commonly show dependence-type behavior. And it’s very common that they show ritualized drug intake and psychological drug attachment. And that happens because they are afraid of missing out important life events.

And they also have worse response to acute medication, which leads them into taking even more medication. Actually, it is very common that these patients, they have aggravation of pain when they try to pause or to terminate the use of the acute medication. And when we talk about MOH, we have to address cephalalgiaphobia and avoidance behavior.

So what are the things? Cephalalgiaphobia is the fear of getting a headache or of worsening of the pain while it still is mild. It could be a form of anxiety disorder. It is linked to the progression of episodic to chronic migraine and to medication overuse headache. And it decreases the threshold for consuming analgesics. 

And what is avoidance behavior? Avoidance behavior is a conduct that the patient acts in order to avoid a potential trigger for a headache attack. And when you put it in these words, like avoiding bright lights, loud noises, or certain foods, it doesn’t seem to be so hard.

But when you translate this to real life, you have a patient that no longer engages in conversations with their parents because they have a little bit of hearing impairment, and they have to speak a little louder. They don’t do outdoor activities when the sun is bright, and they cannot go to places with live music with their friends. So they will skip social and professional events.

And this is a very cruel disease because the patient is already deprived of so many things, of the joy, at least, when they’re in pain, but they also have a lot of complications on painless days. And it will also lead them to refrain from physical activity, which is something that helps us along the way in the treatment. And it is very common for them, again, to show pain catastrophizing.

And I think we all see this very commonly in the office. They have anticipatory anxiety and they have obsessional drug-taking behavior. And even though they’re aware that they’re taking medication so often, like what other choice do they have if they don’t have good medical advice available, right? And it is very common for them to overuse other types of medication, like eye drops, decongestants, laxatives and sedatives.

I think that what we see mostly, in Brazil, it’s zolpidem and clonazepam, which curiously are medications that don’t even help with the pain. They just make you sleep. And they also use a lot of muscle relaxants, which are inefficient drugs in most of the headaches, so it makes no sense. This is all due to poor medical advice. 

And since most of our population here is women, we cannot avoid talking about gender-specific factors, right? So we know that menstruation is a trigger for about 80% of women, and this is due to rapid falls in estrogen levels that decrease serotonergic tone.

And we also know that perimenstrual migraine attacks are more severe and more refractory, so they lead patients into taking more acute medication. Another difficult phase in a woman’s life is the perimenopausal phase, because again, migraine tends to get worse, again, because of the escalated levels of estrogen.

And we have evidence that estrogen modulates vulnerability to cortical spreading depression in female mice. And we hypothesize that this can happen as well with women, with human women. And so what is the clinical presentation of MOH? So what you find is a patient with gradually worsening of headache, despite the frequent use of painkillers.

They always come saying that medication that previously worked no longer help, and they have to take more and more medication. And everything trying to relieve the headache only seems to make it worse, but still they feel that they need to take something. And the phenotype of the pain will be determined by the preexisting headache and the type of medication that is being overused.

And you can find that sometimes the characteristics change over time as MOH develops. And this might make it difficult to give the diagnosis of the underlying headache disorder in the first encounter. So don’t worry if you cannot do it in the first time.

And what we see is that frequent users of triptans will develop daily migraine-like pain in the morning that disappears after triptan use and comes back again, maybe in a couple of hours or in the following day. And this is easily confounded with red flags that are pain that wakens the patient up from their sleep and pain that is worse when you wake up in the morning. And we see that patients who mix medication classes report more frequent drug use and fewer crystal-clear days in those who just use triptans.

And this is a personal tip that was told too late in life – that when you have a patient with frequent headache, you don’t ask them how often do they have headache. But instead you should ask them how often they’d have crystal clear days, because patients tend to underestimate the days where they don’t have severe pain. So we’re reaching diagnosis. So what you have is a patient with a previous headache condition and they had an episodic pattern that evolves over time, usually takes some years to get to MOH. And medication use is taken into account, even when it is used for other painful conditions.

And it might not be easy to determine the temporal relationship, so what came first, the frequent pain or the overuse of medication. Especially because these patients have an average of 20 years of headache and 6 years of medication overuse, they might not remember. So you have to treat it anyway.

And as other headache conditions, you should search for red flags to assess the need for complimentary exams. And the diary here will be indispensable both for diagnosis but also for monitoring outcomes. And it’s very good for the patient like to see how often do they have headache and how often they’re taking medication and then to see how it improves afterwards.

And here it is, the diagnosis criteria. So you will have headache occurring on 15 or more days per month in a patient with a preexisting headache disorder, which is in regular overuse for over three months of one or more drugs that can be taken for acute treatment of headache. And it should not better be accounted by any other headache condition.

And before we reach treatment, we need to talk about prevention because at least most cases of MOH only happen because healthcare providers and patients are not aware about it. And it might seem contradictory to many people and doctors in this case as well, that taking painkillers for headache will only induce its worsening. Everybody has heard of some colleague advising a patient that they should take the medication when there’s a trigger, sometimes when they don’t even have pain yet.

And a fun fact is that now the FDA requires companies to add facts about MOH on the labels of their counter drugs that are sold to treat headaches. And now we reached management and something you cannot forget is that this whole treatment revolves around the patient. We cannot do this by ourselves.

So the most important step is to prepare the patient. You need to be patient and available. You need to spend time explaining to the patient their importance in this treatment strategy.

They need to understand their role in this. You need to explain the reasons for withdrawal. And these patients already feel so much blame because they miss everything, like they miss encounters, they miss their social life.

And they’re already so stigmatized by their families and colleagues. Many people just think they’re just not trying hard enough. So please do it, use it gentle language with no guilt. You should give them detailed information about the nature of MOH.

And you need to directly ask the patient if they think they can stop overusing medication. Because if they cannot, they just will never show up again. Like if you were a doctor they just met, you cannot just tell the patient that the only thing that seems to help them needs to be stopped. It just sounds like torture. So you need to tell them how it works. And in the first encounter, you should also teach them how to make a headache calendar.

And as it will happen for other headache types, the choice of the prophylactic drug will be based on the pain phenotype and the patient’s characteristics. We have clinical evidence that the majority of patients with this disorder will improve after the discontinuation of the acute medication. And you can propose both early discontinuation with or without preventive medication and/or early preventive medication with stepwise drug discontinuation.

About 70% of patients will revert to the exotic form. And this should be taught to patients because they need to have real expectations. You’re not promising them they will be cured of headache.

But once you put this in the appropriate words, it will be enough to convince them that just their life is going to improve. And in simple cases where patients only overuse triptans or simple analgesics and did not have major psychiatric issues, you can just try advice alone. Sometimes it’s enough.

So the overuse medications should be discontinued or their frequency of use limited to up to two days a week. It is proven that complete discontinuation is more effective than restricted use, that discontinuation was superior to no treatment, and that discontinuation plus preventive treatment was superior to discontinuation alone and to preventive treatment without discontinuation. 

So you need to inform the patient about potential withdrawal symptoms. And the most common are headaches or [inaudible], hypertension, tachycardia, restlessness, anxiety, and sleep disturbances. It tends to be shorter to patients that only overuse triptans. And many patients will experience initial worsening of the headache so be prepared. I advise that you should do this while you’re available. So maybe if you’re just getting a vacation the next week, you can propose to the patient to do it when you come back so you are there for them. 

You need to be available. But mostly it will get better in maybe two or three weeks. And since you cannot take a step further in this treatment without passing through withdrawal, and this is really energy consuming for the patient, you should consider giving them a sick leave, because this is really important.

When you have available, you should offer nursing and psychological support. And we all know that opioids and barbiturates should be tapered down. You cannot take it all at once and probably as inpatient care, just to be more careful. And as an exception, in difficult cases, you can change the acute medication that is being overused for something from a different class. But of course we limit the use.

And once MOH is resolved, you can even bring back the drug that was being overused but with limited use. And there’s no strong evidence for this, but the drugs we use to go around withdrawal symptoms are usually the same we do for status migrainosus. And also about the withdrawal phase, when you have patients with serious psychiatric issues, when they overuse medication from different classes and who have previously failed to attempt to withdraw, you should consider inpatient care.

And this is more of a personal tip – I think it works a lot – I really like to use occipital nerve blocks as a bridging for prophylaxis, as it is really safe. It is available everywhere once you know how to do it. And it has a fast onset of response. The prophylactic treatment if you do it, of course, it will help reducing the pain intensity, the frequency, and the intake of the acute medication.

And again, there’s not strong evidence. It’s only weak and moderate evidence. And you can see most of these drugs are used for migraine, but you can use topiramate, Botox, all the CGRP monoclonal antibodies, and the gepants. And [inaudible] use gepants both for acute and prophylactic treatment, in theory, they don’t cause MOH. So it might be a good choice if you have them available.

And of course, if you feel it’s appropriate, you can also use beta-blockers, flunarizine, or amitriptyline. And I know it takes a lot of time, but it is really important that you talk about everything with the patient. And you should also address subjects like pain coping methods.

This is really important. It’s very nice to work along with psychologists to help with this. You should ask them about their anxiety and depression symptoms and also suicidal ideation, obvious in chronic pain conditions.

You should encourage for lifestyle changes. And there’s, again, weak evidence for this, but it is always good to have a card up your sleeve in these cases. You should advise for behavioral interventions, acupuncture, and neuromodulations in cases of MOH associated with migraine.

And what is the prognosis of this patient? So up to 41% will relapse, and most of them in the first year, but relapsing rates tend to be lower in patients who keep in touch. So offer close follow-up, ideally every three or six months. And success in the first year will be associated with a good long-term prognosis. And you should keep a close eye to patients that have risk factors for relapse.

And the most important ones are opioid overuse, greater number of previous preventive treatments, longer duration of MOH, patients who have the association of migraine and tension-type headache when the patient is admitted to the hospital after discharge, and when they have important behavioral symptoms. 

And I think I’m sorry if I went really fast, but I will leave you to this last slide, which is a resume of everything I talked about, and I hope I could give you some personal tips and practical tips for your daily practice. That’s all. Thank you very much.

*The contents of this video are intended for general informational purposes only and does not constitute professional medical advice, diagnosis, or treatment. Always seek the advice of a physician or other qualified health provider with any questions you may have regarding a medical condition. AMD and the speaker do not recommend or endorse any specific course of treatment, products, procedures, opinions, or other information that may be mentioned. Reliance on any information provided by this content is solely at your own risk.