The Cacophony of Cluster Headache
My first experience of cluster headache was when I was 25 and working at Oxford University. I was just going back to the lab after lunch and as the lift door closed, I caught sight of a student I would later find out was called Rachel, sitting hunched on a chair at a table, and literally banging her head against the wall with the ‘Encapsulated Asbestos’ sign on it. I hit the button to open the doors again and approached her cautiously. There is always that part of you that thinks if somebody is upset they probably just wish to be left alone, but there was something about the involuntary nature of her movements that alerted me. Besides, if she didn’t want me to be there, she’d tell me to go away and this was the only course of action I could live with.
I sat down next to her and at this point her forehead was on the table; I couldn’t see her face as her hair was all over the place. The gentle touch of my hand on her shoulder only elicited a groan, as if I had made things worse. Eventually, she raised her head and began a rocking motion; she was clearly very upset. It was when I looked more closely that I realised Rachel had a droopy left eye, that was watery and very bloodshot, and she was extremely flushed and her nose was all stuffed up. She also appeared panicked when I looked into her eyes. I jumped to the conclusion that she had been attacked and at least punched in the face, or had fallen down the stairs. None of this was true. ‘I have a headache, it feels like it is going to explode. It’s the worst I’ve ever had. Nothing helps,’ she whispered, clutching the left side of her skull as if trying to keep its contents in. Welcome to the world of cluster headache.
What is cluster headache?
There are several common descriptors of cluster headache, which was relatively ill-defined and unknown back when I encountered Rachel in the lab (we are talking 20 years ago). 1 One of my favourite of its many monikers is Erythroprosopalgia of Bing. It sounds very sci-fi, but I am not sure Paul Robert Bing, the titular German/Swiss neurologist active in the early 1900s, would be very impressed with my categorisation. It really just means redness (erythro-) of the face (prosopo-) with pain (-algia). Then, in 1926, Willfred Harris, a neurologist based in London, called it migrainous neuralgia, further confusing it with the migraine experience. This was followed by Horton’s Cephalalgia, or the catchier Horton’s Headache after Bayard Taylor Horton, who described its pathogenesis (development of a disease) in 1939. I find it hard to believe that anybody would want something so unpleasant to be named after them, but whatever twists your biscuit, I suppose. 2
The most anatomically descriptive moniker for cluster headache is sphenopalatine (a group of nerve cells that are connected to the trigeminal nerve) neuralgia, but that doesn’t do it for me either because it is too narrow in its focus. By 1953, however, Edward Charles Kunkle had coined the term ‘cluster headache’, since they tend to ‘cluster’ together over time, both within a day and at certain times of the year, and this is the term I use. Eventually, this led to the formation of the Cluster Club 3 in 1974, led by Norwegian neurologist Ottar Sjaasted and of which academic and clinical researchers were members. It was very clear that interest in headaches had been exploding since 1960 with societies and associations springing up on both sides of the Atlantic. Ottar would later go on to navigate a political storm to unite global headache researchers under the International Headache Society in 1983.
Over the years, our understanding of cluster headaches has changed radically. Many factors are now considered when it comes to working out what causes them. Back in Horton’s day in the 1930s and 1940s, histamine was identified as a culprit, reflected by the seasonal nature of the onset of a cluster of headaches (they tend to be more common in the spring) and the specific symptoms they display. But over the years, genetic abnormalities, activation of the autonomic nervous system, hypothalamic function and other factors have all been brought into the explanatory mix. There are some lifestyle factors, too, the main offender being smoking, but also alcohol. So, first of all, let’s think about how the cluster headache presents itself and how people experience them, so that we can decide what effect each cause has and what we can do about it.
What cluster headache looks like
Headaches have to have particular symptoms to be considered as belonging within the ‘cluster’ class. Rachel, the girl I met in Oxford, was a pretty classic presentation, except for the fact that cluster headache is four times more common in men than women. You have to have reddening and watering of the eye, a runny or blocked nostril, a drooping or swollen eyelid, constriction of the pupil, flushing and facial sweating. In addition, the patient will be restless and often be rocking or pacing up and down. They will describe the pain over one of their eyes and towards their temple as excruciating and as if somebody is either trying to push their eye in or out of their socket. This only happens on one side or the other but has been known to switch sides within an attack. Of course, given its name, when, how and how often the headache presents is also a key distinguisher from migraine. Attacks have to happen between one every other day and up to eight a day, and there have to be at least five attacks with the symptoms described above at any stage before a diagnosis can be made.
These symptoms have been defined as cluster headache since 1998, when the International Classification of Headache Disorders (ICHD-I) first recognised it as a disorder in its own right. Since then there have been two ICHDs, with the most recent ICHD-III in 2018 recognising two variants according to whether it is episodic (at least two cluster periods lasting from seven days to one year, separated by a pain-free period of greater than one month) or chronic (which occurs without a remission period, or when pain-free periods last less than a month and this has gone on for at least a year) in nature. But what is happening in the body to cause all of these effects?
The causes of cluster headache
The first clue lies in our genes, for it is by the action of these that proteins are created – the building blocks not just of how we look but also our bodily functions. The reason we suspect genetics is because 5–10 per cent of cluster headache patients have a family history of cluster headache. It is likely, though, that there are many genes that have a part to play.
A quick bit of biology background: we have 46 chromosomes in each of our cells (23 pairs), but only 23 single, unpaired chromosomes in each of our ‘gametes’ – the ovum or egg cell for females and the spermatozoa for males. When the male and female gametes fuse, we get a merging of these chromosomes into 23 pairs (so 46 chromosomes in total) and this is how we end up with half of our chromosomes coming from our male parent and half from our female parent. Twenty-two pairs of chromosomes are autosomal (non-sex). The other pair is the sex chromosomes; you have two chromosomes that look like Xs if you are genetically female and one shaped like an X and one like a Y if you are a genetically male. And sometimes, as in the case of cluster headache, genetic abnormalities can be passed on with all the other traits (see here in Chapter 7 for more about traits).
Now, some traits are dominant, which means that you only need to have the gene from one parent in order for it to be expressed in the resultant child. If a trait is recessive, though, you need that gene to be passed on by both parents in order for the child to develop the trait.
However, although it’s true that the traits that are coded by the 100,000 genes on each chromosome make us who we are, there are other factors at play, too. The biggest factor is known as epigenetics, or factors that affect whether genes are turned on or off without affecting the DNA sequence. This is why cloning rarely results in genetically identical organisms that look exactly the same, completely nixing the plot of many B-movies – a plot device that always makes me throw my popcorn at the screen. The prenatal and postnatal environment and even how parents interact with their offspring can change how proteins are made through gene expression without changing the DNA structure of the chromosome. So we, and our actions, are created every day by an intimate interaction between our genes and our environment. Patrick Bateson, a zoologist from Cambridge, has a lovely way of putting this. We all start our lives with the capacity to develop in any number of ways; we have the ability to play any number of developmental tunes. Patrick calls it the ‘developmental jukebox’. Crucially, though, it is our environment that picks out the tune. This doesn’t mean that genetics don’t have a part to play, they do –it is your genes that determine what kind of developmental tunes you have stored in your jukebox from which the environment can select – but epigenetics takes care of the rest.
So, we mustn’t have tunnel vision about genetic causes. Yes, an abnormality may indicate a propensity to a particular trait or disorder, but we also need to think about under what circumstances that trait is expressed and if there is anything we can do through our environment or behaviour to stop that. In the case of cluster headache, the gene that has the most evidence for involvement is the one that creates a receptor for orexin, also known as hypocretin. This means that orexin has more of an opportunity to influence what is going on in the brain. Catchily called the HCRTR2, it is an autosomal dominant gene (meaning it is not on the sex chromosomes and you only need it to be passed from one parent), and it is also polymorphic, meaning there are different variants of what this gene looks like. Some of these variants may alter how the receptor that is made acts, by changing how receptive it is or what the receptor will accept. The science is ill-defined as yet and not constricted to HCRTR2, but let’s follow this particular rabbit down its hole a little further.
The orexin gene has a role that is mainly played out in the hypothalamus, where it helps to regulate feeding behaviours but also lots of other things, such as sleep–wake regulation, mating and maternal behaviour. 4 Orexin is released in higher concentrations after a period of food deprivation but it also responds to the taste incentives of a particular food. Let’s say you are in a restaurant and have had a lovely meal and then the waiter brings you the dessert menu. Given that waiting staff work so hard, it would be rude not to look, of course. And then you spot the chocolate fudge cake served with Madagascan vanilla ice cream. Orexin has the power to override any satiety indicators that are reaching your hypothalamus, allowing you to ‘find room’ (presumably in the separate compartment in your stomach reserved for dessert) even though you are completely stuffed.
Orexin also has a major role in the reward system for substances other than food, such as alcohol, nicotine and drugs like cocaine. Jessica Barson from Drexel University in Philadelphia and Sarah Leibowitz from the Rockefeller University in New York believe that orexin production is kicked into gear by exposure to such substances in early life, and so the environment has a role. Perhaps, then, it is no surprise that the incidence of smoking in those with cluster headache is about 90 per cent in males and 70 per cent in females, which is much higher than the rest of the population. Even exposure to second-hand smoke as a child has been linked to cluster headache prevalence. But instead of thinking of nicotine as a cause of cluster headache, it may merely be correlative due to the action of a more sensitive HCRTR2 receptor for orexin. This idea seems to be validated by smokers themselves. Anna Ferrari and colleagues from the University of Modena, Italy, admit that even though smokers seem to have a more severe experience of cluster headache, stopping smoking does not prevent it from happening.
And, as it turns out, those who suffer from cluster headache and those who treat them believe that alcohol is a trigger for cluster headaches. The early research indicated that not only were you more likely to be a heavy smoker but also a ‘hard drinker’ too. But instead of alcohol being a trigger, one way of looking at it is that through the abnormal action of the orexin gene, it is easier for these individuals to become addicted to, say, nicotine or alcohol, but neither of these substances is actually driving the bus to cluster county – orexin is.
Smoking and alcohol can have negative effects on any headache, though, and so it is possible that they may induce even more negative effects in cluster headache. Nicotine, the psychoactive drug contained in cigarettes and the more modern vapes, 5 acts to constrict blood vessels in the cerebrovascular system. Blood pressure increases, meaning the heart has to pump harder. With long-term use, carbon monoxide levels build up in the blood to exceed those of people who live in the most industrialised cities in the world. Both of these factors have the effect of starving the brain of optimal amounts of oxygen. This can lead to migraine, as we will see in the next chapter, but for all other types of headache, the rebound vasodilation triggers the pain effect, just like we saw in sinus and tension headache.
The light link
The way our body and brain reacts to light is another clue. Our natural circadian rhythm would actually dictate a 26-hour day, but this happens only if we live in a bunker with no natural light at all, and who wants that? Light acts via the non-image forming cells of the retina, which signals the suprachiasmatic nucleus (SCN) that lives in the hypothalamus (the centre of our hormonal system) to conform to a 24-hour cycle, roughly related to the amount of day and night that exists on earth. The presence, or absence, of light therefore constrains this cycle and so is termed a ‘Zeitgeber’ German for ‘time’ (Zeit) ‘giver’ (geber). The SCN isn’t just a clock, it’s also a pacemaker for many other biological rhythms happening in the body. One of the biggest of these is our sleep/wake cycle. When light levels decrease, serotonin is converted into melatonin in the pineal gland and is released into the bloodstream. This acts on the inhibitory mechanisms in the brain, promoting sleep. In high-light-level conditions, serotonin is not converted into melatonin and so wakefulness continues.
In the winter, when there is less light, particularly at higher latitudes, there is the tendency for more melatonin to be released. This is an evolutionary trigger – winter means hibernation and conservation of resources. In humans, however, this can be counterproductive to modern life, and the greater production of melatonin and therefore lesser concentration of serotonin (the happy hormone) can lead to Seasonal Affective Disorder (SAD). You could therefore reasonably assume that the darker the season the higher the incidence of SAD, but this is not always so. While the prevalence of SAD in Finland is 9.5 per cent, there are few reports of SAD in Iceland, which is at the same latitude. Dietary differences may explain this phenomenon; Icelandics eat much more fish than the Finns and so their diet is richer in vitamin D. Vitamin D regulates our absorption of calcium, which is critical in how well our neurons communicate both with each other and with our muscles, and it seems to have a protective effect against SAD. So, a better diet can fix part of the problem, although we also need to increase the amount of light entering our eyes. If you are not in a position to visit sunnier climes twice a year then exposing your eyes to a light that is a tenth as bright as the sun for 15 minutes a day in the morning using a light box will help kick your SCN into gear.
In cluster headache sufferers, fluctuating light levels over the year might explain the periodicity of clusters that sufferers experience as they may find it difficult to regulate their hormones in response to light. Such rhythmicity also explains why cluster headache often occurs while sufferers are asleep. We have different phases of sleep, ranging from Stage 1 to 4, during which our brain activity gets slower and slower. In between we have periods when our brain shows the same activity as if it were awake, and this is called rapid eye movement sleep or REM. All the other stages are non-REM. Towards the end of the night our sleep becomes dominated by REM sleep, which is why we can often find ourselves dreaming as we wake up. We do dream in non-REM sleep, too, but they tend to be more methodical and even nightmarish. With REM sleep, the frontal lobe isn’t active at all, and so nothing makes much sense; it’s also harder to remember the dreams. The onset of cluster headache is often reported to occur during REM sleep when the brain is more wakeful, and towards the end of the sleep cycle when circadian hormones released to wake the body up are at their peak.
There is another curiosity here: if we tie in the fact that four times the number of males experience cluster headaches than females, you might think that this is related to some kind of sex-linking of genetics, that the trait is mostly passed down to male offspring. However, there is little evidence for this. A more tantalising link is how sex hormones interact with the SCN, particularly testosterone, which is released in much greater concentrations in males than females. Even though the male and female SCN has the same volume, it is more elongated in females than in males, where it is more spherical. The interaction of sex hormones and the activity of the SCN and the knock-on effect on our behaviour is most apparent in teenagers of both sexes – puberty being a veritable hormonal hurricane. It resets the body clock of your average teenager forward by about two hours, which means that their biological day starts at 9am rather than the more usual 7am for adults. 6
Post-puberty, females release hormones cyclically while males release theirs in a more constant way. Bayard Horton back in the 1930s and 1940s and others since have identified that there is a decrease in testosterone release in males who suffer from cluster headaches. Testosterone concentration is ultimately controlled by the hypothalamus by an area called the preoptic nucleus, which happens to be twice the size in males as it is in females. This is an area that is active in sexual behaviour but also body temperature regulation when we are ill. (I once got into bother by joining these dots and speculating that this may be why many males of our species experience ‘man flu’, but I digress.) A malfunctioning hypothalamus might explain lower secretions of testosterone but also how that then affects the SCN, as testosterone has the ability to organise and change the function of this central biological clock. A lack of testosterone may disrupt our normal rhythms, causing non-typical bodily changes for the time of day/year we find ourselves in – explaining the clustering of the headache.
You might therefore think that the answer is to administer additional testosterone to bring levels more in line with ‘normal’, but this doesn’t seem to have an effect on cluster headache prevalence. However, in this small study involving seven patients in 1993, Maria Nicolodi from Florence University, Italy, and colleagues showed that the top-up testosterone did increase patient sexual excitement when compared with that of patients in the control group who didn’t have any additional testosterone, so there are hints here that it is involved in some part of the pathway. (So perhaps you can just self-medicate through sex; more on that later.) Of course, the level of testosterone depletion is key, and as with many drugs, so is the timing of the administration in relation to the body clock; there is no one-size-fits-all solution here. Work needs to be done to tie all of these threads together.
The histamine alliteration
Another clue comes from histamine, the molecule that we discussed with respect to allergy and sinus headache. Since the time of Bayard Horton’s research back in 1939 histamine has been thought to have a role in cluster headache. The increased temperature on the painful side of the forehead and the coincidence of flushing led him to implicate histamine as a vasodilator, and to use the term histaminic cephalalgia (from the Latin cephalo- (‘head’) and algia (‘pain’)) when describing it. Somehow, Horton’s Headache is more catchy, and Horton’s Histaminic Headache has a nice ring to it even if the alliterative police are probably now rolling their eyes. Whatever the name, Horton realised that his patients may have an extreme sensitivity to histamine. In support of this conclusion, he noticed that many also suffered from stomach ulcers, a condition in which histamine has a big role, as ulcers are inflammatory responses to the Helicobacter pylori germ. 7
So, histamine is a by-product of the stomach ulcer, but what Horton had realised was that raised histamine was also coincident with headache. Just to be sure, he also injected histamine just below the skin in his patients and caused many of the symptoms of cluster headache in some of them. What’s more, he had also noticed in his male patients that gastric acid secretion was higher, which is controlled ultimately by the hypothalamus, and testosterone release was depressed, also controlled by the hypothalamus, particularly during an attack.
We also know that histamine controls wakefulness through the hypothalamus working in concert with orexin/hypocretin and the serotonin–melatonin balance described earlier. What controls the action of all of this? The answer: light, entering the eye and being processed by non-image forming retinal ganglion cells reaching the suprachiasmatic nucleus (SCN) of the hypothalamus. And so we have come full circle.
Further still, Marcello Fanciullacci from Florence University noticed a difference in pupillary responses in sufferers back in 1979, with the pupil on the headache side in his cluster headache cohort being smaller than the other pupil. Pupillary response is an automatic reaction controlled by the autonomic nervous system and its malfunction can be seen in other aspects of the cluster headache symptom suite; activation of the parasympathetic system causes the teary eye and the runny or blocked nose, and deactivation of the sympathetic nervous system causes the droopy eye and the smaller pupil. And what controls the autonomic nervous system? The hypothalamus! While we have been occupied with investigating different aspects of the problem, we have been pretty blind to the entire picture. Such is the way of science.
In conclusion, each of these aspects, in particular the vasodilation that results in activation of the trigeminal pain pathways and the influence that each of these hypothalamic functions (histamine, autonomic involvement, serotonin imbalance, orexin sensitivity) has can be persistent and colossal in magnitude.
The hypothalamus hypothesis
So, what is the evidence of hypothalamic dysfunction being a cause of cluster headache (as opposed to the sub-components above)? What do we already know? The hypothalamus can affect things that are happening on the same part of the brain (usually, everything is crossed over with the right side of your brain controlling the left and vice versa). In addition, we know that the hypothalamus has a fast-track connection with the trigeminal pathways responsible for the pain and also that the hypothalamus has a big role to play in dampening down pain signals – if it is working properly. In 1998, Arne May and colleagues from the Institute of Neuroscience at University College London induced cluster headache in people who suffered episodic cluster headache using nitroglycerine (remember, nitric oxide is a powerful inducer of headache through the rapid vasodilation it causes) and put them in a Positron Emission Tomography (PET) scanner, which tracks the flow of radioactive water that has been injected into the patient prior to the scan. They compared the activity seen in this group with that of a group of cluster headache sufferers who were not currently in pain. They could see an increase in functional activity in the hypothalamus during pain periods but also structural changes in the hypothalamus, particularly in the bit where the SCN lives.
Others have debunked this idea, however. More modern imaging like functional Magnetic Resonance Imaging (fMRI) does not rely on the injection of radioactive water but instead works by analysing what water molecules in our bodies do when a radio wave is applied, having first pointed them all in the same direction using a magnetic field. What results is a picture that is much clearer than one we could achieve with PET. Steffan Naegel and his colleagues from Essen, Germany, didn’t see any difference in size of the hypothalamus in cluster headache sufferers in 2014, but did see differences in other areas of the brain, such as the temporal lobe, hippocampus (important for memory), insular cortex (part of our emotion system) and the cerebellum (important in eye movements and balance) – all of which can have roles in the behaviour of cluster headache sufferers, such as rocking, restlessness and irritability.
What is critical about this much bigger study, which involved patients at different stages in the disease and also within and outside of pain bouts, is the finding that brain structure is dynamic and reactive to the environment in which we find ourselves. Many parts of our brain will react to pain strengthening the response of some areas over others to allow us to try to control this abnormal activity that is causing pain in our body. It is this dynamic that has made it hard to define a causal link with the hypothalamus. We need to know more about how these different areas of the brain talk to each other, why and how they get so chummy. But if there is a way to control the symptoms that are tugging on all of these different networks throughout the brain, we need to go to the puppet master, and all accusatory fingers right now still point to the hypothalamus.
You might have been wondering what happened to Rachel, the girl last seen banging her head off the wall. Well, I managed to take her up one floor to my office and sit her down with something cold against her face. Thankfully, she was registered with a GP practice (you would be stunned by how many students who are living away from home don’t do this). I looked up their number and gave them a call, describing her symptoms and asking if she should go to the hospital or to the doctor’s surgery. They told me to send her to them. In the end, I had to put her in a taxi for two reasons. The first was that I rode a motorbike at the time, and even though she had recovered somewhat, I really didn’t think she could cling on behind me properly, so I couldn’t take her that way. The second was that I had a participant coming to see me in the lab so that I could run an experiment on him. Given that I was planning to send magnetic pulses into his head, I didn’t want to muck him around too much by cancelling. Besides, by then Rachel was feeling a bit better; the droopiness in her eye had gone away, though it was still a bit bloodshot and she was flushed, and she was happy to go by herself. I wrote a note describing her symptoms for her GP because there was no physical evidence any more, and mentioned that I thought it could potentially be a cluster headache (many GPs at the time didn’t know they were a separate form of headache).
Rachel came back in to see me a couple of days later. She seemed much brighter, if a bit tired. Her doctor had seen her immediately and checked for other nefarious causes, such as stroke, and he had also arranged for her to have an MRI to rule out severe neck damage or an aneurysm (see here).
How cluster headaches are treated
Treatment of cluster headaches since their acceptance as a headache distinct from migraine has been haphazard, and mainly applied through the myopia of which aspect of the body’s physiology was thought to cause it. For example, Horton (of Horton’s Histamine Headache fame) thought that if the histamine response, whatever the trigger, was excessive, he should be able to desensitise the patient through discrete exposure to histamine and that this would have clinical benefits. We see this as a treatment for people with allergies today in which small amounts of the trigger are given to the patient over time to retrain the immune response to something more proportional. However, Horton’s trials of desensitising patients to histamine proved ineffective on the whole. He also tried ergotamine, a substance extracted from fungi that has vasoconstrictor effects, but was faced with the issue that it also results in some side effects, including muscle weakness or vision problems. Marcello Fanciullacci had some success with a hospitalised patient who in addition to histamine was administered a cocktail of antihistamines (which seems counterintuitive) and ergotamine to prevent the vasodilatory response of the histamine. Marcello tacitly admits that his desensitisation methodology ‘effected by a physician in whom [the patient] had complete confidence and reassurance … may have had the same effect in alleviating his headache for some time.’ Sounds like a placebo effect to me, and indeed did not stand up to later controlled trials involving multiple patients. Antihistamine drugs also proved ineffective as a treatment over a number of controlled trials. So, it is fair to say that mitigating the effects of cluster headache through histamine alone doesn’t work.
When Rachel visited the GP surgery on the afternoon she had the headache, the practice nurse administered oxygen as she was by this point feeling the pain come on again. Oxygen has long been used as a treatment for cluster headache; it was first reported in scientific journals in 1981 by Californian Lee Kudrow, father of actress Lisa Kudrow 8 (who played Phoebe in Friends), both of whom are sufferers of cluster headache. A further study in support of the use of oxygen was reported by polymath Lance Fogan in 1985, also working out of California. 9 Nowadays, the accepted treatment is to deliver 12–15 litres (around 3–4 liquid gallons) of pure oxygen gas per minute by mask for 20 minutes. It really wasn’t known why this had such a remarkable, restorative and instant effect until 10 years ago, when Simon Ackerman and colleagues from the University of California in San Francisco found that oxygen acts to regulate the parasympathetic facial nerves, which in turn lessens the activation of the trigeminal pathway, calming down the cascade of symptoms out of our control that happen in cluster headache.
Of course, we can’t go lugging around oxygen tanks on the off-chance we’ll get a headache but thankfully there is a more pharmaceutical approach than was prescribed to Rachel. She was told to take sumatriptan at the first sign of the headache and if it reoccurred within two hours, she was to take it again. This treatment was first developed in the 1990s as a subcutaneous injection but has since been developed into pill form, although this doesn’t work for everyone. Steve, the husband of a friend, for example, has experienced three cluster headache episodes in eight years, always in February so far. He always carries a sumatriptan injection with him wherever he goes, except for once on a quick trip to London. As he felt the telltale signs of the headache starting, he realised in horror that he didn’t have his injection with him. He could have tried to get an emergency appointment with a doctor or gone to a local hospital emergency room but he knew it would take as much time to do that as it would to get the next train for the two-and-a-half-hour journey home. His instincts screamed at him that this was the thing to do. ‘Do not pass Go, do not collect £200,’ as he put it, instead heading home to his family and his standby oxygen tank and his injection. But he didn’t get there fast enough. Steve’s window of opportunity to stop a cluster headache is very small, which is probably why oral tablets don’t work for him as even they take too long to break down in his system. On the way home the whole shebang hit him, leaving him for two weeks in a dark room waiting for the storm to pass.
The soothing powers of serotonin
Sumatriptan is a serotonin agonist, which means it acts just like serotonin in the brain. It is vasoactive (affects the diameter of the blood vessels) and works to constrict blood vessels (remember, it is the dilated blood vessels that are a major trigger to the trigeminal nerve pain pathways) and decrease the inflammatory response. It works just like ergotamine in this respect but ergotamine is an agonist not just for serotonin but also dopamine and noradrenalin, so its effects are less specific and therefore more prone to causing widespread side effects. Relief can be experienced within 10 minutes of ingesting sumatriptan, and is often accompanied by a sensory wave of well-being, thanks to the activation of the happy hormone network. The use of sumatriptan is therefore tightly controlled to ward off addiction and although it is available over the counter, it is only sold in small quantities.
We know that serotonin and melatonin work in balance with each other: as we get sleepy, serotonin is converted into melatonin by the pineal gland. Melatonin production is decreased in cluster headache sufferers both during active cluster periods and in remission, but this is particularly marked during a cluster bout. It may be that there is a problem converting serotonin into melatonin, but it is more likely, given the rhythmicity of the onset of the headache, that the fault lies with serotonin. If there is not enough serotonin, it will have a negative knock-on effect on concentrations of melatonin. There is simply not enough serotonin to convert to change the melatonin concentration. However, using sumatriptan as a pre-emptive strike does not seem to affect the number of headaches people experience. As the drug only acts on one serotonin receptor (there are many) it may be that its effects are too narrow to engender systemic change.
How can we increase the serotonin in our systems?
• Happiness is the key for long-term regulation of serotonin. Without serotonin, we are not happy, and a lack of it is the biggest indicator of depression. The more joyful and happy experiences we have in our lives, the greater the amount of serotonin we produce. Unless we are very depleted, serotonin is quite regulated by our behaviour.
• Light therapy may also be used to increase serotonin levels in the long term (although that would be quite uncomfortable during a headache).
The option to medicate
Taking lithium has widespread effects in the brain, but it has also been proven to be effective in the treatment of cluster headache. In experiments conducted by Lee Kudrow, lithium showed dramatic effects in the recurrence of cluster headaches in 27 of 28 patients, meaning it could be used as a preventative measure. We could link this to the now known effects of lithium on the hypothalamus, particularly in the sleep–wake centre, on boosting serotonin concentrations and indeed its action in the preoptic nucleus (see here) for sex hormone release. The problem with lithium, however, is that patients often adapt to their doses and require increased amounts to prevent headache episodes, thus leading to undesirable side effects ranging from blurred vision, through balance problems, to full-on convulsions.
Another possible treatment comes from using a cardiac drug called Verapamil, which acts by reducing vasodilation in blood vessels but also affects the hypothalamus itself. Although there are side effects, including constipation and dizziness, Verapamil is better tolerated than lithium and has been shown to be effective in clinical trials for cluster headache. However, careful attention must be paid to patients prescribed this drug due to its effects on the heart. Such monitoring should never end; our life circumstances never stop changing and our physiology is bound up in that so why would we expect the action of drugs we are taking to be constant? Effective treatment of the acute phase of the cluster headache is therefore preferable in most cases.
Chocolate, sex and coffee
For swift serotonin shots, chocolate, which is full of tryptophan, which is then broken down into serotonin, is a good treatment. Sex also results in an injection of serotonin. The case of two male episodic cluster headache sufferers, one of whom was 61 and the other of whom was 47, was reported by Marc Gotkine and colleagues in Israel in 2006. At the point of orgasm with their respective partners, the men reported that their headaches suddenly disappeared. This is somewhat at odds with an earlier report in 1989 by Michael Maliszewski, from Diamond Headache Clinic in Chicago, USA, that sex can bring on a cluster headache. However, it should be noted that numbers in this study were very small. Sex headaches in general happen in 1 per cent of people and in more men than women. They occur mainly due to spikes in blood pressure and vasodilation in the head and neck.
Sex is a huge neuroendocrine undertaking. A lot happens – and it is all controlled ultimately by the hypothalamus. So, rebalancing hormonal concentrations through our behaviours can help with the function of these crucial yet unsung regions, and can certainly induce restorative vasoconstriction when in the midst of a headache.
Caffeine is also a vasoconstrictor, which, as we’ve already learned, is why it is packaged in the same pill as paracetamol, for example. All of this leads us to the conclusion that when in the throes of a cluster headache, the simplest approach to self-medication would be sex with a post-coital snack of coffee and chocolate. Maybe tonight then, dear … but only if there is testosterone to spare.