BEAT­ING THE BLUES

DE­PRES­SION, IN­FLAM­MA­TION & THE BODY- BRAIN CON­NEC­TION

North & South - - Front Page - Ly­dia Monin is a North & South con­tribut­ing writer.

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.”

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