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Headaches are quite a headache for researchers. Because although science has uncovered several biochemical mechanisms underlying aching or throbbing pain in the head, it has not yet mapped the mechanisms that trigger headache. 

Haidar M. Al-Khazali, PhD student in neuroscience at the Danish Headache Center, under Rigshospitalet, Denmark’s leading hospital, is now well on the way to discovering how headaches arise.

“We know that a headache has a beginning and an end. And I’m fascinated by the fact that headaches have this kind of on/off switch. My aim is to locate it,” he says.

And he has already made an important discovery. In studies of volunteer headache patients, Al-Khazali has discovered that the same substances can trigger headache across three types: migraine, cluster headache and the post-traumatic headache that occurs after concussion. Studies involving healthy volunteers reveal that the substances in healthy individuals only cause mild and transient headache.

“When these substances are administered to the patients they get a bout of their ‘usual’ headache. This indicates that there are common molecular mechanisms behind the three types of headache. And that means it may be possible to identify a common solution to the problem,” he explains.

Discovery of common headache triggers is one of the reasons why Al-Khazali received the Lundbeck Foundation's Talent Prize. 

Other reasons are his persistence, his collaboration and mentorship, and his dedication to this field of research. He has been and still is a supervisor to a large number of students, and serves as a member of the board of the Danish Headache Society. 

Provoking headaches experimentally

Much of Al-Khazali’s research involves deliberately inducing headache in study volunteers. It may sound strange, but it makes sense because it has proved to have great potential in identifying new treatments for headache. 

“The method employed by Al-Khazali and other headache researchers is known as ‘human provocation modelling’ He has provoked 250 such experimental headaches during his PhD fellowship alone. 

The experiments involve the volunteers being given a substance by mouth or by IV drip, and then resting on a medical couch, waiting for the headache to come on. 

“We monitor the volunteers during headache onset, and they tick boxes on a questionnaire to tell us where their headache is located and the nature and severity of pain experienced. We use this procedure to test a large number of different substances,” Al-Khazali explains.

He emphasises that the patients can opt to break off the experiment at any time, and then be treated with pain-relievers.

The study involves a large number of diverse substances, including the signalling substances known as neurotransmitters and other medical substances. 

One substance tested by Al-Khazali is a medication for treating high blood pressure, which in an earlier study at the Danish Headache Center was shown to induce migraine in migraine patients. He has now tested it on patients with cluster headache and patients with post-traumatic headache, and has discovered that the substance triggers cluster headache in those affected by cluster headache and migraine-like headache in individuals with post-traumatic headache. Again, this suggests that there is a common trigger mechanism. 

Vasodilation and potassium are key

The substances discovered by Al-Khazali as common triggers for the three types of headache are so-called vasoactive substances, which either widen blood vessels (vasodilation) or narrow them (vasoconstriction).

The research theory is that the key to headache is in the vasodilation that occurs when the substances cause the potassium channels in the smooth muscle cells of the blood vessels to widen. Potassium channels have gates that control the cell’s electrical activity by opening and shutting, to allow or prevent the flow of electrically charged particles known as potassium ions. This is a critical mechanism in many cell processes. 

“We believe that the combined effect of potassium release from the smooth muscle cells of the blood vessels and vasodilation causes activation of nerve endings in the meningeal brain membranes and sends signals via the brain stem to the pain centre inside the brain.” 

Discovering novel drugs

In daily clinical practice Al-Khazali meets patients plagued by headache disorders. His hope is  consequently that the research will pave the way for new drugs to treat headache.

“These might be targeted therapeutics that block a specific substance, a special receptor or the specific potassium channels that are involved,” he explains. 

There is still a large unmet need for treatment, despite the biological therapeutics introduced since 2018 that prevent migraine in a large proportion of migraine patients. 

These biologicals, as they are called, are based on monoclonal antibodies, which are laboratory-made antibodies. Unlike the body’s many different natural antibodies, which the immune system uses for combating harmful substances like bacteria, the monoclonal antibodies are identical and target a specific substance.

“The new therapies are effective, but only work for half of the patients. And that’s because many roads lead to Rome; many substances affect the processes that cause headache,” he says.

Al-Khazali’s vision is for patients one day to be able to attend a headache disorders clinic where, like in the provocation experiments, they can be tested for the types of substances they react to, and then be treated with an ‘antidote’ in the form of monoclonal antibodies. 

“It would be amazing if we one day have three or four approved drugs that block the specific substances that cause headache,” says Al-Khazali.

“Then the patients would only need to attend the clinic three or four times before we can identify the treatment that is a perfect match for their particular need. At present, the process of trying one medication after another takes months.”

Headache has major personal and socioeconomic consequences. According to the Danish Headache Society, around 200,000 people in Denmark daily are affected by headache, which is estimated to result in 3 million sick-days annually.