BEATING THE BLUES
DEPRESSION, INFLAMMATION & THE BODY- BRAIN CONNECTION
The van was driving along a road lined with landmines where an Irish priest had been ambushed and killed a fortnight earlier. I was the producer in a documentary film crew crossing into war- torn Angola and I really should have been thinking about roadside bandits and booby traps, but uppermost in my mind were migraines, or more specifically, migraine avoidance.
The first- aid kit was armed with drugs for all manner of exotic diseases and there was even a pack to deal with bullet wounds, but there was nothing in there to stop that slow but sure descent into three days of debilitating, bed- confining, nauseating pain.
Seventeen years later and my local pharmacy, or any other pharmacy for that matter, still has nothing that really takes that pain away. But this is about to change. The biggest advance in migraine treatment in a generation, maybe ever, is upon us. The drug companies aren’t just talking pain relief, but pain avoidance. A quick preventative jab and we migraineurs could be cast free. And it’s all about calcitonin gene-related peptide, CGRP, a hormone we all have but migraine sufferers seem to carry in greater abundance. So the idea is to shut down the hormone to shut down migraines.
The race to market for this impending wonder drug could be very lucrative.
Up to one in five women and one in 10 men gets anything from an occasional attack to 15 headache days a month. Severe migraine is so disabling the World Health Organisation has compared it to dementia, quadriplegia and active psychosis. I live on the more severe end of this spectrum; a new migraine drug has life- changing potential. So I track down Dr Danny BarZohar at his office in Basel, Switzerland. Bar-zohar is the head of neuroscience development at Novartis, which collaborated with another pharmaceutical company, Amgen, to be the first to get their drug erenumab to market.
“Patients tell us they are desperate because they’re losing pieces of their lives to this,” says Bar-zohar. The population of the United States is roughly similar to the five biggest EU countries, around 330 million people, and in both cases it’s estimated 10 million get migraines so often or so severely it impacts on their daily activities. “So we have a high potential of patients who are seeking safe, effective, simple-to-use therapy they can benefit from and stay on.”
Erenumab is not yet available in New Zealand, but Novartis plans to submit it for approval here by October.
It’s almost 30 years since the last breakthrough in migraine medication – around the same time scientists started honing in on the role of CGRP in migraine. An early CGRP treatment looked promising, but there were significant side effects. Scientists had to go back to the drawing board.
One of the reasons a migraine cure has proved so elusive is because a migraine test isn’t possible. Even during an attack, neurological examinations and scans are normal. The pain is often on one side of the head; the French word migraine comes from the Greek hemicrania, or half-skull. There’s nausea and sometimes vomiting, sensitivity to light and sound. About a third of migraine sufferers get what’s known as aura, when they see flashing lights and lose vision as a warning that the pain is coming.
“People who haven’t had migraine don’t appreciate that it’s not just a pain in the head,” says Dr Jon Simcock. He’s the recently retired medical adviser to the Neurological Foundation of New Zealand. “A person with a heart attack thinks they’re going to die, and a person with a bad migraine wants to die.”
Most migraines are triggered by everyday things: sleep deprivation, strong smells, food allergies, alcohol,
glare or flickering lights. Some people react only to white wine, some only to red, while for others almost any sort of alcohol can bring on an attack. Stress is a trigger – but so is relaxing after stress. For women, hormonal changes play a big part. Sometimes it’s just an accumulation of different triggers.
There was the GP who’d get a migraine from yellow jellybeans but not other coloured ones, says Simcock, delving into his extensive catalogue of anecdotes about patients and their triggers. “I had a medical student who thought he was having a stroke when he lost vision on one side, but it was really a migraine triggered by a flickering X-ray screen.”
As a shy teenager, stress was an obvious trigger for me. But it took many years to discover that grass pollen and sulphites in food and wine were best avoided. Perfume wasn’t a problem; now it is. One old trigger has since been outlawed: smoke-filled bars. Every discovery leads to lifestyle changes. I block supermarket aisles as I forensically analyse ingredient lists, but at least I don’t have to mow the lawns anymore.
WE’VE KNOWN about migraines for millennia. Mesopotamian poets in 3000BC wrote of headaches as demons to be cast out, while Hippocrates – who else? – took a more clinical approach 2500 years later, prescribing hellebore plants to expel all manner of bodily fluids. Migraines have confounded medics ever since.
Until fairly recently, the accepted wisdom was that migraine was a vascular disorder, caused by the contraction and expansion of blood vessels in the head. Now it’s seen as a neurovascular disorder. Electrical activity in the trigeminal nerve, which starts in the brain stem and wraps around parts of the face and head, releases chemicals that cause pain through inflammation and dilating blood vessels.
“Our understanding of what exactly is happening in the brains of people with migraine has evolved tremendously over the past two decades,” says Bar-zohar. At medical school, he was taught that, “for some peculiar reason”, blood vessels in the tissue surrounding the brain dilate, causing pain. “It’s true they do dilate and this dilation of the blood vessels surrounding the brain is painful – but it’s approximately 10% of the truth of what migraine is.”
You had to be a four- day- a- month migraineur to qualify for the clinical trials of erenumab – and there was no shortage of volunteers. “We found it extremely easy to enrol patients,” says Bar-zohar, who reports that in the clinical trial programme, involving more than 3000 patients across the migraine spectrum, up to 50% of patients had their migraine days cut by half or more. The other good news is that for those the drug does help, the longer they take it the better the results. One study showed that by the 15th month of therapy, more than 25% of the patients were migraine-free.
Now that the prospect of a simple preventative injection seems tantalisingly close, it’s worth remembering some of the weird and wonderful ways humans have tried to deal with migraines. Legend has it that our ancient ancestors used to drill holes in each other’s skulls to release evil headache-causing spirits. This surgical procedure, known as trepanation, was recommended as a migraine treatment as late as the 17th century. Blood- letting and mercury were also prescribed before modern drugs came along.
George Bernard Shaw turned to vegetarianism for a migraine cure. During a groggy, post-migraine conversation with the neuroscientist and Arctic explorer Fridtjof Nansen, Shaw said, “You have spent your life in trying to discover the North Pole, which nobody on Earth cares tuppence about, and you
“People who haven’t had migraine don’t appreciate that it’s not just a pain in the head.” DR JON SIMCOCK, FORMER MEDICAL ADVISER TO THE NEUROLOGICAL FOUNDATION OF NEW ZEALAND
have never attempted to discover a cure for the headache, which every living person is crying aloud for.”
My grandmother’s remedy for what she called a “sick headache” was a combination of the decongestant Friars’ Balsam in a steaming bowl of water, aspirin and milk of magnesia. Her sister lived on sweet jelly during a bad head week. When a debilitating migraine struck, she’d retreat into a darkened room for two to three days. Children had to avoid even walking past her door in case they made too much noise.
Natural and alternative therapies have flourished: physiotherapy, chiropractic treatment, acupuncture, vitamins and minerals – all have their advocates in the migraine community. Then, in the early 1990s, there was a major breakthrough with the advent of a class of medications called triptans, which fight migraines by narrowing blood vessels.
At first, I thought triptans were miraculous. A quick jab with a self-injecting pen and I could remain pain-free throughout even the most stressful of days. But gradually my migraines became more resistant to triptans.
There have also been some accidental migraine treatments “borrowed” from other conditions. Beta blockers, epilepsy drugs, antidepressants and even Botox may have some migraine prevention potential, but they don’t work for all sufferers, and there are side effects.
Every few years, I’d check in with a doctor, more for compassion than in the expectation of a breakthrough. Then last summer, I saw a neurologist in Dublin, where I was living at the time. “Actually, there is something new on the way,” he told me. “The drug companies are pushing it quite hard.” He paused. “We’ll see.”
Intrigued, I continued to read the constant stream of newspaper and magazine articles featuring the latest miracle cure, from magnetic zappers, herbs and ear piercings to electric armbands. But then there were tentative reports about promising clinical trials for a new drug. And, for the first time, I read about the hormone that might just be the bane of my life.
TO FIND OUT MORE, I decide to risk dilating blood vessels and navigate my way through the building works around Professor Debbie Hay’s office at Auckland University’s School of Biological Sciences. Hay is a pharmacology research fellow with particular expertise in migraine. Researchers had found a link between higher levels of CGRP and migraine. “And coupled with that, she explains, “if you inject a migraine sufferer with that hormone, it can trigger a migraine-like headache in them, but not in someone who is not a migraine sufferer, suggesting that people with migraine are more sensitised to how that hormone works.”
The new, 21st-century treatments for migraine are the beginning, not the end, says Hay. Researchers need to find out which groups of patients respond better than others. A combination of drugs might be better than one. And as the intricacies of the brain come into ever sharper focus, the causes of migraine will be become clearer.
“The underlying neurological causes remain poorly understood,” she says. “The brain is so hard to study… Many conditions are studied in some way, shape or form, in translation of models in animals, and the reality is you cannot model migraine easily at all in anything other than a human, because it’s not just pain, it’s not just a headache; there’s far more to migraine than that.”
As I’m ushered out of the biological sciences block and back into the sunlight, it seems clear to me that migraine is too complex and diverse for a onesize-fits-all treatment.
Hormones attach themselves to certain types of cell. A particular hormone needs a particular receptor to bind onto a target cell. Then it can change the way that cell functions. In migraines, CGRP triggers a chain of events within nerve cells; break the chain, break the migraine. Researchers have taken two different approaches, either binding to the CGRP molecule itself, or binding to the nerve cell receptors CGRP targets. These drugs can be antibodies, which have to be injected, or small-molecule drugs, which are swallowed. But ultimately they all work by blocking CGRP.
Erenumab, administered as a monthly antibody injection, blocks the CGRP receptor. It has already been approved for use by health officials in the US, Europe and Australia. Other CGRP blockers are expected to follow shortly.
Whether the new drugs can be sold in New Zealand will be decided by the government’s medical regulatory body Medsafe. Then Pharmac decides whether to subsidise the drugs approved by Medsafe. And now we’re into economics.
Migraine always appears in any published top-10 list of chronic disabilities.
Missing work and underperforming at work because of migraine is estimated to cost American employers $US11 billion a year. Clearly, I have a vested interest, but wouldn’t erenumab and/or any of the new drugs set to follow, be a good investment? All those productive hours thrust back into the New Zealand economy. Next stop, Pharmac. These are the people who make the tough calls on which drugs to subsidise, and now my head is in their hands.
Pharmac’s director of operations is Lisa Williams and from the outset she’s clear they are not guided by lost wages or productivity. “We’re particularly interested in whether or not a medicine can help enable people to return to their usual daily activities, whether that’s paid employment or not.” That includes the elderly, children, and people who are chronically ill or disabled; Williams says Pharmac isn’t in the business of disadvantaging people who aren’t in paid employment.
My economic argument has been blown; now the guilt kicks in. Migraine isn’t life-threatening, so wouldn’t it be better for Pharmac to save 10 people who might otherwise die without subsided treatment than to give 10,000 people a better quality of life? “We don’t weight one over the other,” says Williams. They analyse the potential improvement in both quality of life and length of life when looking at new drugs.
Now I fear this holy grail might be as expensive and elusive as the original. Monthly injections of erenumab will cost American patients $US6900 per year. Williams says Pharmac doesn’t shy away from funding expensive medicines – even as high as $50,000 per patient per year – if they’re going to offer the best health outcomes to New Zealanders. It’s about driving a hard bargain. Pharmac can bring the price down. Williams says they recently negotiated a confidential discount on new-generation hepatitis C medicines that cost $1000 per pill at the list price but have cure rates of around 95%.
Pills for pain, pills for nausea, pills to help the absorption of other pills or, if all else fails, pills to induce sleep. It’s the migraine sufferer’s survival kit. When the storm clouds gather, I revert to war-room thinking: what to deploy, when and how much.
Plan A, do nothing. Drugs like triptans work best if taken early, before nausea sets in. But we migraineurs can still get a mild headache that doesn’t evolve into a full-blown migraine. Plan B, risk the counter-offensive. If the blister packets start popping too frequently, you can be drawn into a vicious cycle. This is the medication- overuse headache, where taking drugs causes a headache, for which you take another drug that causes another headache.
The panacea of migraine prevention won’t usher in a period of survival-kit disarmament, however. Bar-zohar says acute medication may still be needed, but “significantly less of it”. It’s also
Drilling holes in the skull was still seen as a migraine treatment as late as the 17th century.
good news on the side-effects front: the drug companies are yet to find anything significant in the trials, although side effects can appear after a drug makes its way into the general population.
“These drugs have gone into thousands of patients and they look really quite safe, but that’s not to say there won’t be something we’re not aware of,” says Hay. “The drug companies have spent a lot of time and money developing these and it’s fantastic, but they don’t understand all the details of how they actually work,” she says, arguing that academic research holds the key to unlocking these secrets.
“What we do is really important for plugging those gaps – making sure we have all the knowledge we need to truly understand how effective and safe these drugs will be, and whether there are more opportunities for the future.”
THE ONLY TRULY effective treatment for migraine that’s ever worked for me is motherhood. Three-and-ahalf years of around three broken hours of sleep a night (thanks to a raging-insomniac first child and a second baby in the mix) with barely a migraine. Some migraineurs get relief during the second and third trimesters of pregnancy and during breastfeeding.
But continuous baby production isn’t an officially recommended migraine therapy. When the magic spell of motherhood wore off, the migraines came back with a vengeance.
In women, migraine generally begins with puberty, improves in the teens and 20s, gets worse after having children and better again with menopause. Nature giveth and nature taketh away. Migraines are replaced by old age. By which time, one of my daughters might be in the middle of this migraine life- cycle. It runs in families, with statistics showing migraineurs are more likely than not to have a fellow sufferer as a close relative.
But now there’s a realistic chance the migraine curse can be broken for a significant percentage of chronic sufferers. CGRP- blockers are at the forefront but other treatments are on the way. An advance on triptans is close to approval and several companies are developing blockers against another hormone found in nerve cells that can also trigger migraine.
There was no minefield migraine in Angola for me; the vessels remained undilated and the ordnance unexploded, although a near-miss with a local puff adder could have rendered a terminal solution to all my health issues.
But in a world with the prevailing threat of two or three days a month written off in a darkened, throbbing haze, the lure of the snake oil salesman is strong indeed. Cure-all elixirs promising a quick exit have been a migraineur’s curse. Now it seems we have a potion that might very well be magic for some, and I’ll be there when this medicine show comes to town. +
The new, 21st- century treatments for migraine are the beginning, not the end, says Hay.
The author, migraine-free, on location in post-war Croatia.
Among the earliest known migraine sufferers is thought to be Hildegard von Bingen, a 12th-century German abbess, philosopher and composer who saw her migraine-related visions and auras as divine.
George Bernard Shaw turned to vegetarianism for a migraine cure.
Professor Debbie Hay, at Auckland University’s School of Biological Sciences. “You cannot model migraine easily at all in anything other than a human.”