Why Does Sumatriptan Only Work for Headache Disorders?

A new study further advances the case that the drug suppresses central sensitization, acting only in the trigeminal nociceptive system.

Triptans have served as first-line therapy to treat migraine attacks ever since these drugs became commercially available in Europe in 1991. But precisely how they help, and where they act, has remained a source of debate in the field.

A new study in healthy participants now further builds the case that sumatriptan, a member of the triptan family of drugs, specifically suppresses central sensitization, without an effect on sensitization of peripheral nerve fibers that innervate the skin. Further, the research, from co-first authors Kuan-Po Peng and Tim Jürgens, from University Medical Center Hamburg-Eppendorf in Germany, shows that the drug acts only in the trigeminal nociceptive system. Together, the findings help explain why triptans are effective for certain headache disorders such as migraine but not for somatic pain.

“This study has, for the most part, validated what we and other people who did similar studies, primarily in animals, had previously published: Sumatriptan does not inhibit peripheral pain fibers,” said Rami Burstein, a migraine researcher at Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, US.

“Instead, it binds to primary afferents in the dorsal horn of the spinal cord and prevents the release of neurotransmitters involved in central sensitization. This paper adds one more set of data to the huge puzzle of why migraine drugs are not anesthetics or analgesics – they are migraine drugs,” according to Burstein, who was not involved in the current study.

The paper appeared in the November 2022 issue of the European Journal of Pain.

How do they work? Where do they work?
Researchers have proposed a number of sites in the nervous system where triptans might act. One possibility is that the drugs work only at peripheral nerve terminals in the trigeminal ganglion, which relays sensory information to the brain.

Another idea is that sumatriptan acts in the central nervous system. And a third possibility is that it functions somewhere in between, in particular, at the synaptic gap between the ends of peripheral sensory neurons and the cell bodies of secondary sensory neurons in the central nervous system that receive input from the peripheral neurons.

The lack of clarity around the mechanism of action of triptans piqued the interest of Peng, Jürgens, and collaborators.

“We know lots of migraine preventative medications work; we have lots of randomized controlled trial data showing they are better than placebo. But the interesting part is that we don’t know exactly how they work,” he said.

The researchers hypothesized that triptans help people with migraine by preventing central sensitization. This phenomenon, as defined by the International Association for the Study of Pain, is “[i]ncreased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input.”

With central sensitization, painful stimuli can become even more painful than usual (hyperalgesia), and innocuous stimuli may also now cause pain (allodynia).

Setting up an experiment
To test their hypothesis, the researchers undertook a double-blind, randomized, placebo-controlled study involving 40 pain-free participants (21 men and 19 women, with an average age of 24 years) from a cohort of medical students at Hamburg University. Participants attended one session for the study, with half of them receiving sumatriptan, and the other half saline, as a placebo, via subcutaneous injection.

After the injection, the researchers applied capsaicin – the active component of chili peppers that gives them their burning sensation and that is commonly used in experimental pain studies – to one side of the forehead and into one ventral forearm (the area of the forearm on the same side as the palm of the hand).

Importantly, the forehead represents a site innervated by the trigeminal nerve, while the forearm represents an extra-trigeminal region. This would enable the researchers to learn if sumatriptan acted in one or both sites.

The investigators would perform quantitative sensory testing (QST), which measures somatosensory nerve function, at both sites in the test group and in the placebo group, at baseline and after capsaicin injection. They were interested in the effects of sumatriptan on the warm detection threshold (the point at which a thermal stimulus is first perceived as warm), and on pain hypersensitivity in response to a brief heat stimulus (primary heat hyperalgesia), within the zone of capsaicin application.

A third outcome was secondary mechanical hyperalgesia. Here this refers to hypersensitivity around the site adjacent to capsaicin application, which is a proxy for central sensitization, in response to a mechanical stimulus, in this case, a pinprick. To assess potential effects of sumatriptan on allodynia, the researchers also examined responses to light stroking of the forehead or forearm with a cotton wisp or a soft brush, which normally do not cause hypersensitivity.

Finally, the fourth outcome of interest was the extent of secondary hyperalgesia in response to a punctate stimulus, in this instance, to being poked with a thin fiber called a von Frey filament. Specifically, the investigators mapped the area of secondary hyperalgesia around the capsaicin application. They also mapped the extent of capsaicin flare, which refers to the area of skin that becomes red in response to capsaicin.

Specific to the trigeminal system
Compared to baseline QST measurements, participants in both the sumatriptan and placebo group reported a decrease in warm detection thresholds (meaning they first detected warmth at lower temperatures), at both the forehead and forearm, after receiving capsaicin at those sites. This decrease was apparent on the side of the forehead and on the forearm where subjects had received capsaicin, while a trend toward a decreased warm detection threshold was also observed contralaterally.

Similarly, after capsaicin administration, both the drug and the placebo group showed an increase in thermal pain sensitivity (primary heat hyperalgesia), in response to brief heat stimuli, on the side ipsilateral to capsaicin application. This finding suggested that sumatriptan was not acting peripherally, since those who received the drug showed primary heat hyperalgesia just as placebo subjects did.

But the results would now begin to diverge between groups when the investigators turned their attention to secondary hyperalgesia. Here, hypersensitivity in response to being poked with the von Frey filament increased at both the forehead and the forearm in the placebo group.

However, the sumatriptan group displayed an increase in mechanical hypersensitivity only at the forearm, and not at the forehead. This suggested that sumatriptan eases secondary hyperalgesia by acting solely in the trigeminal system. (There were no differences between groups in dynamic mechanical allodynia.)

Finally, sumatriptan decreased the area of capsaicin flare, but only at the forehead, again suggesting solely a trigeminal action of the drug.

“The primary hyperalgesia is not surprising, because capsaicin is a strong activator of the sensory system,” Peng said. “What’s surprising is that we found sumatriptan specifically inhibits secondary hyperalgesia in the trigeminal dermatome, but not in the peripheral dermatome. That suggests that even though we gave sumatriptan systemically, the effect is trigeminal-specific.” (A dermatome is an area of skin supplied by a single spinal nerve root.)

“One important step closer”
Burstein said the findings have clinical significance.

“By understanding the mechanism of action of drugs like sumatriptan, we learn how to treat patients better,” said Burstein. “It’s these kinds of studies that were at the origin of the revolution of instructing patients to treat their migraine with sumatriptan no later than 20 to 30 minutes after the migraine starts.

“The only thing that’s missing here is a mechanism to test why sumatriptan only works for migraine and potentially a few other headache types, and does not work for any other trigeminal pain. But that’s how science is built – you get from the entire body to the trigeminal system, and then from the trigeminal system to migraine, a pain attributed to activation of the trigeminovascular pathway. They’ve brought us one important step closer,” he added.

Peng hopes future studies will again use QST to figure out how other migraine medications work.

“Because quantitative sensory testing is a well-established method to assess primary and secondary hyperalgesia, this method can be applied to other acute medications used in migraine.”

Lincoln Tracy is a researcher and freelance writer from Melbourne, Australia. You can follow him on Twitter @lincolntracy.

Reference
Sumatriptan prevents central sensitization specifically in the trigeminal dermatome in humans.
Peng et al.
Eur J Pain. 2022 Nov;26(10):2152-61.