Cluster headache

The pain of cluster headache is amongst the worst pains that anybody seems to be able to experience, be it other types of headaches, broken bones, renal stones or anything else. So it is amongst the most disabling pain which has been described.

[Music] Welcome to the Australian Prescriber podcast. Australian Prescriber, independent, peer-reviewed and free.

I'm Dhineli Perera, your host for this episode. It's a pleasure to be speaking to Dr Jason Ray. Jason is a consultant neurologist and headache fellow at the Alfred and Austin Hospitals in Melbourne, as well as the Department of Neurosciences at Monash University. Jason describes the characteristics of cluster headaches and updates us on the most current approaches in its management. Jason, welcome to the program.

Thank you so much for having me.

I know very little about cluster headaches, except that they sound really awful. In comparison to other headache types, where does this sit on the scale of severity?

Yeah, up at a 10. There's no great way of trying to compare two different types of pain. For the patients who suffer more than one headache type or have had cluster headaches and then have a different type of pain, the response we get is almost universal that the pain of cluster headache is amongst the worst pains that anybody seems to be able to experience, be it other types of headaches, broken bones, renal stones or anything else. So it is amongst the most disabling pain which has been described.

In your article, you touch on the fact that there can be significant delay in diagnosis of up to eight years. What are some of the points of difference that set cluster headaches apart from other types of headaches that could potentially help prescribers identify that and reduce that delay?

Unfortunately, there just hasn't been funding in Australia for headache research, and so we really don't know what the Australian experience is in terms of delay of diagnosis or how many people suffer from the condition in Australia. The pain which a patient experiences with a cluster headache is strictly on one side of the head, whereas most other headache types could start on one side but then migrate or not always be on that one side. And the duration of pain is different from the more common headache type such as migraine, which is characterised as a headache which lasts for more than four hours and has sensitivity to light, sound or nausea and is itself moderate or severely disabling.

In the case of cluster headache, it's a shorter period of time, but that pain is just maximal at onset so the duration of the pain is between 15 minutes and four hours and typically sits around the 90-minute mark, but it's also associated with autonomic activation on one side of the head and on the same side as the pain where you get tearing from the eye, you can get flushing at the face, changes in the pupil or discharge from the nose. Patients also can describe this sense of internal agitation and restlessness where you just can't stay still because of the pain, which again puts it in contrast to a headache such as migraine where, due to the sensitivity to light and the fact that it gets worse when you exercise or do anything physical, patients tend to retreat to a dark room.

Your article touches on the genetic component of cluster headaches. Can you tell us a bit more about that?

We know that if you or I were to have cluster headache, then our first-degree relatives are somewhere between five and 18 times more likely to have it than that of the general population. So there is a genetic component, but exactly which genes they are has been quite difficult to pin down. And so there's been some recent research out of the UK that has identified a couple of genes, but exactly what the genetic component is and how it plays into putting somebody at risk is complex.

You've mentioned in your paper that there are three key structures involved in the pathophysiology of the disease. What would you say would be the most critical parts of that that both prescribers and other health professionals need to know about them?

It's an interplay between the trigeminovascular system, the parasympathetic system and the hypothalamus, which are likely responsible for the clinical features of cluster headache. Activating or inhibiting any one of those systems doesn't seem to be sufficient to control the disease. So the trigeminovascular system from the brain stem out into the peripheral branches of the thalamic division of the trigeminal nerve is responsible for that quintessential pain sitting on that temple on one side, but removing it, as people have done in very early trials of trying to control the disease, didn't seem to adjust the pain which patients experienced. So there's a central process at play as well.

And the parasympathetic system is what gives us the autonomic symptoms that we were describing earlier. While the hypothalamus, which is responsible for your circadian rhythm, presents with the patients having pain often with a diurnal variation. So it's quite typical to get this pain at 10:00 at night and also with a seasonal variation. So patients will often, if they have an episodic version of the disease, have it in the springtime or sometimes towards the summer. And understanding that those systems are involved really can give you some insights into identifying the disease and that kind of rhythm of the disease, which can be a clue that it's cluster headache as opposed to something else.

Before launching into the treatment options. I wanted to find out more about their accessibility via the PBS. You mentioned that many of them are off label, and I think that's important to highlight, but they are supported by evidence. For the more expensive treatments, I assume these need to be prescribed through a specialist in the public hospital sector as they are not available in the PBS. Is that correct?

For the more specialist treatments that aren't on the PBS, unfortunately they're just not at the moment available to people. So even within the hospital setting, we don't have any more or greater access to some of the more expensive treatments. And we really need to see greater research and funding into cluster headache and headache disorders, both to train up more doctors so that we can start to meet the demand but also so we can have access to some of these treatments. Galcanezumab, for example, is a new medication which inhibits calcitonin gene-related peptide and has been shown to be efficacious both in migraine and episodic cluster headache, but at the moment it's only on the PBS for migraine. So the patients with episodic cluster unfortunately are missing out, or can access it via a private script, which is not the type of healthcare we like to see practised in Australia where some people can access something and some can't.

When it comes to therapies, you divide the options into acute abortive, preventative and bridging therapy. The triptans are considered first line in abortive therapy. I found it interesting that they had such high placebo response rates. Can you tell us exactly what these percentages mean in your table?

High placebo response rates is slightly ubiquitous for all headache trials in that you see a higher placebo response in not just the acute abortive treatments for cluster headache but in the trials for both acute and preventative treatments in the migraine setting as well. And the exact reason as to why you see a slightly higher placebo rate than you would expect is something that's debated in the literature. But the medications do work, the response rate for the medication is still far greater than you’d see when the patients are given placebo. In the setting of acute pain that's horrible and maximal at its onset, we want something which works really quickly. So the subcutaneous or intranasal versions of sumatriptan are favoured over tablets. And in the setting that you can take a patient from being in severe, horrible pain to having mild or no pain in 15 minutes, about three quarters of the time, so for 75% of patients who get subcutaneous sumatriptan, you can abort that pain.

How have you found patients to be with self-administering that kind of injection? Because obviously, when you're in that kind of pain, it can be hard to do anything at all, let alone administer a subcut injection.

In my experience, we generally start with the intranasal option, partly because it's a little bit easier than managing with a needle, but also again, because of cost and access. The intranasal option is on the PBS. The subcutaneous one for whatever reason is not. But the patients are generally very well educated. And when it's the difference between having something at home which works or needing to present to the emergency department because you don't have any other option, it's generally a very good motivator for working out how to manage it.

Just doing it, getting there somehow and just sorting it out.

Yes.

High-flow oxygen is also an abortive treatment that you discussed. Patients may be drawn to this if they perceive this to be safer, I guess if it's not an actual drug as such, but what are some of the risks and adverse effects of using high-flow oxygen in this setting?

It's a very useful treatment to have given somebody even if just as a diagnostic test because cluster headache responds to high-flow oxygen in a way that other headache disorders don't. And it seems to have a very similar efficacy to the subcutaneous sumatriptan. So after 15 minutes, about 75%, 78% of people will have a significant reduction in their pain. The downside of it is, again, issues of access. So in order to have that sort of a thing at home, you need a prescription, you need to go to a medical gas company and then arrange for it to have it at home. So it's nice to know beforehand that you expect this therapy to work for you because you're having to go out and buy a bit of equipment and rent a machine. So having tried it in the emergency department or at a GP surgery beforehand and knowing that this is going to be an effective treatment for you gives you that confidence that you're outlying a little bit of money for a good reason, but it also gives you that treatment, that access to something which you can't get at home otherwise.

In terms of dangers, if somebody had type two respiratory failure, then obviously it wouldn't be safe to give them oxygen in an unsupervised environment. Similarly, if somebody was an active smoker then having oxygen in the house isn't necessarily safe. Conversely, triptans have their own concerns, if somebody had ischaemic heart disease due to their vasoconstrictive properties.

When and how is bridging therapy used? Can patients ever go directly from acute abortive therapy to prevention?

If a patient was to have a bad cluster bout, you've started them on an acute therapy but you very quickly want to stop them from having that pain at all. A lot of the preventative medications, they require time both to titrate up and to work, and so the bridging therapy kind of sits in that gap in between. So when somebody is having a current cluster bout, it gives you time to have the preventative treatments work. If, conversely, you have a patient who's got a well-established pattern in terms of their cluster headaches and you know that it's going to be coming along every spring, you can start a preventative medication at late winter, titrate it up, and they go through spring without any problems, and you'll never need to reach for the bridging therapies potentially.

Do you use them concurrently if it is something that you are using, so bridging together with preventative?

Yeah, that's correct. Just giving you time for the preventative therapies to work.

So with regards to the up titration of verapamil, if it is being used in the setting of prevention, does the prescriber assume that a dose is effective until the next cluster headache occurs? Is that how you increase it?

When we're starting verapamil, we start it at the lowest dose that we hope to be effective, so we'll generally start a patient at up to 80 mg three times a day and then increasing it again every two weeks, as long as we're watching the ECG and making sure that there's no arrhythmias or any concerns from that perspective until you have control of the disease. So if you're up-titrating it in the context of the current cluster, then you're doing that until the cluster settles, and then leaving them on that dose for a period of time, at which point you can start judiciously yet decrease it slightly.

And the patient’s either ended the cluster, in which case, great, and we no longer need the verapamil, or verapamil was controlling the disease and, as we start to decrease it, we start to see the attacks come back again. At which point, we can just leave them on that as a maintenance dose.

If you see that the cluster has passed and a patient who generally has that kind of seasonal variation, then you may be able to just wean straight back off again down to zero and plan to go back up to the last dose that you found effective the year before in the lead up to the next expected bout.

Do you ever find that those very low initial doses, say the 80 mg three times a day, are ever effective or do you find that you do have to push it up most of the time, at least once or twice?

I've had a few patients where they've seen some benefit at even 40 mg three times a day, but it's not uncommon that you need to get up a little bit higher than that before you start to see real control of the disease. So unfortunately, it's different for different patients. I guess once you're starting to increase it and getting to particularly moderate and high doses, it's worth being confident that you know what you're doing and you're confident in the diagnosis and whether or not you need to be adding in a second medication as well. Sometimes we'll find patients respond better to a modest dose of verapamil with a second agent such as topiramate.

And in your experience, which long-term adverse effects of lithium have limited its use in your patients?

Lithium has evidence as a preventative medication for cluster headache. I personally don't have any patients who take the medication, and it's largely because we are scared of the long-term side effects. It, in the long term, reduces glomerular filtration rate and thereby there's a risk of kidney impairment, there's risk of hypothyroidism and also reducing the kidney's ability to concentrate urine. So with subsequent polyuria, polydipsia and the risk of nephrogenic diabetes insipidus. So where at all possible, we look towards other agents which don't carry the same long-term side effects because this is a disease which people can suffer for many years, unfortunately.

So it sounds like it's something that may have been reached for in the past but just less now that we've got other alternatives available.

Absolutely.

Finally, from both the diagnosis and management of cluster headaches, it sounds like it needs to be quite a collaborative approach between GPs and neurologists. Have you had any success stories of such collaborations that you can tell us about?

It remains some of my happier interactions with GPs and even with patients in taking a patient who's had this sort of pain for three, four, five years and themselves not thought to have a discussion about it to taking it through to a GP and a GP posing the question and sending them on to us, and finally getting control of the disease. And I find that an incredibly rewarding experience personally, but equally rewarding is the converse where you have a GP who poses the question and say, "Look, I think it may be cluster because of this," and you're able to sit there and see the patient and have a conversation, correspond back with a general practitioner or specialist and say, "Look, it's a great thought, but because of these reasons, I think in this case, it may be migraine and this is what helped me decide," and still making a difference in terms of getting the patient on the right treatment for them.

And even with the titration of the doses and the bridging therapy, is that usually something that is managed by the neurologist alone or can it be done together with the GP? I'm thinking of patients that may not have access to neurologists as readily as some of us in the city. Is this something you've seen in your experience?

It is. I'm lucky in that I work in a couple of tertiary institutions in Melbourne, so we have ready access to services for patients both on the general practice side but also on the neurologists’ end. We have access through neurology in providing a few extra treatments that the general practitioners don't have in terms of performing greater occipital nerve blocks, for example, which are an excellent bridging therapy.

But we do have patients who we are managing remotely as well, and that very much is a partnership with the GP. We help with setting up towards a bit of a plan and seeing what we can tie them in with locally and really being called when there's an issue rather than being primarily responsible for their care.

Thank you so much for joining us today, Jason. It was really interesting.

Thank you for having me.

Jason's full article is available online at nps.org.au/australian-prescriber.

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Jason Ray has received compensation from the Pharmaceutical Society of Australia, sponsored by Viatris for educational material.

The views of the hosts and guests on the podcasts are their own and may not represent Australian Prescriber or NPS MedicineWise. I'm Dhineli Perera, and thanks for joining us on the Australian Prescriber Podcast.