In Part I of Making headaches history, Niki Bezzant spoke with Tom Zeller about game-changing medications that are offering sufferers new hope. Here, in this extract from The Headache, Tom Zeller outlines his encounters with a drug billed as the first preventer for migraine and cluster attacks in 60 years.
About 35 years ago, drugs known as the triptans hit the market and sparked a revolution. For a significant percentage of patients, they can quell the grinding pain of a migraine in a couple of hours – and even faster for cluster patients, if taken by injection rather than in pill form. In keeping with the notion that migraine and similar headache disorders were a disorder of the vasculature, scientists have long presumed these drugs worked because they trigger the constriction of engorged blood vessels in certain pain-sensitive tissues between the skull and brain, known as the meninges. For many clinicians, the idea that dilated meningeal blood vessels are somehow irritating or activating surrounding pain-sensitive tissue remains the default explanation for why headaches hurt – and for why the triptans, which selectively target and constrict those engorged blood vessels, are so good at shutting down the pain. Others question that, and regard vasoconstriction and vasodilation as mere epiphenomena – extras milling about in the background of headache’s key dramatis personae.
Whatever their salient mechanism, the triptans have always been imperfect remedies. For starters, the efficacy rate of the triptans in relieving migraine pain varies widely, from as low as 30% in some analyses to as high as 70% in others. The truth is likely somewhere in between, but it’s clear that they don’t work for everyone. Further, the vascular action of the triptans can make them unsuitable for patients with heart-related comorbidities like hypertension – a sizable population. They are also what’s known as an abortive medication – specifically designed to stop an individual headache that’s already under way, rather than preventing the process that results in head pain from unfolding at all. In most cases, the triptans should be taken sparingly, lest they start to cause terrible headaches. And yet, because migraines and clusters are often typified by repeated attacks, sometimes occurring day after day in the former, and even multiple times per day in the latter, many patients overuse the triptans out of desperation, becoming ensnared in a vicious cycle.
The elusive thing, the Holy Grail for patients, doctors, and scientists invested in this space, has always been a safe and effective preventive drug – something that would, for a high percentage of patients, stop whatever it is that’s causing these cyclic storms from starting in the first place. For most of human history, that’s proven elusive – and from one angle, it’s not surprising. If scientists can’t be sure what bits of anatomy are drivers and which are supporting players; which activated neurons are pointing toward the root of the disease, and which are merely downstream participants in an attack already under way, it can be very difficult to develop effective drugs. What part of the anatomy, after all, should be targeted?
Peptide blocker
A promising and recent candidate [for intervention] is called calcitonin gene-related peptide, or CGRP – a neuropeptide first described in the 1980s. Among other things, it is a key chemical messenger in the nervous system’s pain communication pathway. It took three decades for that discovery to wend its way through animal testing, pre-clinical human experiments, and pharmaceutical company drug development and trials, but in September 2018, an injectable solution designed to prevent CGRP from binding to its neural receptors – a monoclonal antibody called erenumab and sold under the brand name Aimovig – was first approved by the US Food and Drug Administration.
It had been nearly 60 years since a drug had been purpose-built to prevent migraines – the last being methysergide, an effective but ultimately noxious migraine drug first marketed in the late 1950s under the brand names Deseril and Sansert. Because long-term use was linked to a litany of risky side effects, including hallucinations, vision problems, and most seriously, scarring of kidney, heart, and other tissues, methysergide was ultimately discontinued in many countries, including the US.
By June 2019, the FDA had approved drug company Eli Lilly’s CGRP inhibitor – which binds to CGRP itself to prevent uptake – for the prevention of cluster headache, too. Mere months later, after weeks of imperfectly managing excruciating headache pain with lousy drugs and haggling with insurance carriers, I stood in my kitchen – then in Western Massachusetts – hiked down my trousers, and administered three separate injections of the CGRP inhibitor, as prescribed, into my right butt cheek. Alongside a slight burning sensation, I felt a rush of hope and a measure of gratitude that some 200 years after Erasmus Darwin dreamed of spinning people like me on a millstone, things were finally getting a bit more sophisticated.
Can I say that the CGRP therapy worked for me that first go around? I think so. My attacks abated shortly after – though it’s characteristic of cluster headache to go into periods of remission anyway.
In 2020, my wife and I relocated to Montana, and during the 2021 bout that had me tripping on mushrooms and desperately pedalling up a mountainside, the injections seemed to have no effect – perhaps, I reasoned at the time, because I’d taken them too late in the cycle. In 2023, however, I’m quite sure I stopped an oncoming period of clusters before it ever got off the ground by relying on ageing CGRP syringes that I have kept in my refrigerator long past their expiry date. Indisputably, applying brakes on a bout has never happened for me in 30 years of battling these attacks, and given early tussles with a new doctor in nearby Missoula who didn’t want to prescribe the expensive remedy, I have hoarded the syringes whenever I can. Headache people hoard meds.
Effectiveness may wane
Three years after the CGRP inhibitors hit pharmacy shelves, the most coveted prize in neuroscience, the $1.5 million Brain Prize, went to four scientists who, often working independently of one another, helped to usher in this new class of CGRP medications. The innovation has helped to nudge a more nuanced understanding of migraines and clusters as true neurobiological disorders – byproducts of a still uncertain signalling malfunction in the brain and/or surrounding anatomy. “I’m humbled by the emails that we get from patients whose lives have been changed by these medicines,” one of those researchers, Peter Goadsby, told The Guardian at the time.
All of this said, these are not miracle cures. While there’s every indication so far that the new treatments are safe, the long-term side effects of repeated, prolonged CGRP inhibition are still unknown. More pointedly, some patients have begun to note that, as with so many other drugs that have come before, the effectiveness of the CGRP cocktails can wane over time – their bodies and brains adapting and realising some spirited will to pain.
And even while the CGRP blockers continue to prove effective for large numbers of people, for others they have simply been another in a long line of pharmaceutical heartbreaks. Perhaps these disorders are so complex, so multifactorial and so idiosyncratic, that no perfect remedy will ever be found.
Perhaps advanced genomic studies will help doctors better identify which patients will respond to which medications, so that therapies can be more tailored to our individuated anatomies. Or maybe there is some more fundamental, more universally effective molecular target still hiding in the darkness of our skulls.
The Headache: The Science of a Most Confounding Affliction – and a Search for Relief by Tom Zeller (HarperCollins, $37.99).