When a Headache Treatment Actually Makes the Headache Worse

medication overuse headache

A new study in mice provides an explanation for the phenomenon of medication-overuse headache. Image credit: Alexander Raths/123RF Stock Photo.

Migraine is a type of chronic headache that affects millions of people across the globe. While there are several types of drugs available to treat migraine, these medications can cause a range of side effects. Paradoxically, one of those side effects is headache itself, a phenomenon called medication-overuse headache (MOH).

A recent study in animals now provides a new explanation for why MOH occurs, by focusing on a protein called Nav1.9. This protein plays an important role in the electrical activity of pain-sensing neurons.

Using a mouse model of MOH, researchers led by Patrick Delmas at the French National Center for Scientific Research (CNRS) in Marseille, France, show that nitric oxide, a well-known migraine trigger in people, abnormally activates the Nav1.9 protein on pain-sensing neurons in the dura mater, a membrane that surrounds the brain and spinal cord.

In addition to causing headache features, activation of Nav1.9 led to a host of other changes that further increased the activity of this protein, creating something of a vicious cycle.

The findings could one day speed the path towards new treatments for migraine.

“Adding information to the big puzzle of MOH, and migraine more broadly, is essential for scientists to find novel targets for the development of new therapeutics,” said Milena De Felice, University of Sheffield, UK, referring to the search for molecules that new drugs could affect to ease headache. De Felice studies migraine in animals but was not involved with the new work.

The research appeared September 18, 2019, in the journal Nature Communications.

All eyes on a well-known suspect in pain
Past research in animals and in people has shown that mutations in the gene that provides the instructions to make the Nav1.9 protein can cause pain, as well as insensitivity to pain, depending on the type of mutation. So, it made sense to focus on a possible role for Nav1.9 in MOH too.

To begin, Delmas and colleagues looked at the trigeminal nerve and its associated blood vessels. The trigeminal nerve is responsible for sensation in the face, and problems with this nerve are present in most people who suffer from migraine.

After showing that Nav1.9 was present on trigeminal nerve cells, the researchers tested whether Nav1.9 was involved in MOH. To do so, they created genetically engineered mice lacking Nav1.9. They then gave these so-called “knockout” animals sumatriptan, a common migraine medication, for six days to produce MOH. Then they compared the behavior of the knockouts to normal “control” mice receiving a harmless saline solution.

Mice that received sumatriptan were more sensitive to a poke to the paw with a thin filament—a common experimental technique to study pain in animals—compared to the mice that received saline. The increased sensitivity lasted for about three weeks, after which pain sensitivity returned to normal levels.

Next, the researchers gave the animals sodium nitroprusside (SNP). This is a medication that is broken down by the body into nitric oxide, a well-known trigger for migraine in people.

“Mice behave similarly to people and become extra-sensitive to migraine triggers when treated chronically with triptans,” Delmas said. Triptans, the class of drugs to which sumatriptan belongs, are commonly used in the treatment of migraine.

As expected, SNP caused normal mice that had received sumatriptan to become more sensitive to the paw poke. However, this sensitivity was not seen in the knockout mice missing Nav1.9. This was evidence that Nav1.9 played a key role in MOH, since sumatriptan did not cause problems in animals lacking it.

The disabling symptoms of MOH commonly include increased sensitivity to light (photophobia) and sound (phonophobia). So, the scientists next looked at how the knockout mice behaved in response to light and sound.

Normal mice that received sumatriptan showed increased sensitivity to light. But knockout animals missing the Nav1.9 protein did not show this sensitivity after receiving the migraine trigger SNP. Nor did they show signs of phonophobia. This showed, once again, that Nav1.9 was a significant player in MOH.

A vicious cycle
Other experiments would reveal that nitric oxide increased the activity of Nav1.9 in neurons from normal animals exposed to sumatriptan. And so, the investigators wanted to understand the consequences of that.

Increasing the activity of Nav1.9 with SNP resulted in the production of calcitonin gene-related peptide (CGRP), a molecule known to cause inflammation and headache pain. Once again, this happened only in normal mice that were treated with sumatriptan, and not in the knockout mice.

Elevated activity of Nav1.9 also increased the amount of blood flow in the membranes covering the brain, which can contribute to headache. Furthermore, there were increased levels of substances, made by certain immune cells, that cause inflammation. These substances also activated Nav1.9 in the pain-sensing neurons of the dura mater.

In short, the increased activity of Nav1.9 ultimately leads to even more activity of this culprit in MOH.

“It really is a vicious cycle fueled by Nav1.9,” Delmas said.

However, there is a silver lining. Now that the researchers have shown that Nav1.9 contributes to MOH, it’s possible that medications that quiet the activity of this protein could be effective at treating migraine.

This news article is a plain language summary of a story that first appeared on the IASP Pain Research Forum.

Lincoln Tracy, PhD, is a researcher and freelance writer based in Melbourne, Australia. Follow him on Twitter @lincolntracy.