Michael Oshinsky, PhD, is the Program Director, Pain and Migraine at the National Institute of Neurological Disorders and Stroke (NINDS) within the National Institutes of Health (NIH). Prior to joining NIH, Oshinsky was an associate professor at Thomas Jefferson University in Philadelphia where he developed the first behavioral model of headache in rats. He also discovered and bred a unique colony of rats that have day-to-day fluctuating head pain, similar to that seen in human migraine patients. Nathan Fried, a postdoctoral fellow at the University of Pennsylvania, recently spoke with Oshinsky about migraine, pain, the “hangover headache”, and NIH’s efforts to help scientists find new treatments. Below is an edited transcript of their conversation.
What is your current role at NINDS?
As the Program Director for pain and migraine research at NINDS, I’m responsible for curating a research portfolio that will lead to alleviating pain and migraine in the population. The goal of my position is to support the research community by helping scientists process their grant applications, identify unmet research needs—the questions scientists aren’t asking yet—and design their grant applications so that they meet those needs.
Before coming to the NIH, you did migraine research with rats at Thomas Jefferson University in Philadelphia. What was the focus of your work there?
When I started studying migraine around the year 2000, I noted two things. Number one, there were very few labs in the world that focused primarily on studying migraine. Number two, there was a very narrow research focus in terms of the animal models they used to study migraine.
The unmet research need I identified was that, in order to get more people to study migraine and make scientific breakthroughs, there had to be an advance in the models used to study headache in animals. So we developed a rat model of headache where we repeatedly stimulated pain-sensing neurons on the dura—the membranous tissue that surrounds the brain and is thought to be the site where the pain from a headache occurs—with chemicals that cause inflammation and activate pain-sensing neurons.
So you were giving these rats headaches?
We can’t say for sure that the animals had headaches because a headache is a very personal experience and an animal can’t speak to us. Instead, we have to rely on non-verbal behaviors to assess whether the animal is in pain.
After stimulating the dura three times a week for a month, essentially giving them three headaches a week, these animals would develop chronic head pain. We found that drugs for acutely treating migraine and for preventing the recurrence of migraine worked in these rats. They also had associated symptoms of migraine seen in patients, such as phonophobia, which is an aversion to sound.
This was the first model of headache we developed. Once other groups saw our paper describing this model, there was a tremendous proliferation of behavioral models of headache in animals.
The second model we discovered and characterized came from a very perceptive graduate student. She said that without ever stimulating the dura, one of the rats we were using had very high baseline pain sensitivity on some days—which we were using as a surrogate marker, or indicator, for the animal having a headache—and then on other days this animal had normal pain sensitivity.
So I recommended she not use this unique animal for additional experiments and, instead, just track its pain sensitivity. And sure enough, this rat had spontaneous episodes of changing pain sensitivity in the head and facial region, which we interpreted as the animal having spontaneous headache.
This was a rat, then, that was just naturally born with headaches?
Again, we can’t say for sure if they had headaches, but they had head pain and similar characteristics that you would see in humans. But, we bred the animal to other animals, and sure enough, in the next few generations, we found that 50 to 75% of the offspring had the trait. Right now that colony of animals is in its 26th generation, and they are showing a very strong trait of having an inherited headache disorder, many of which even have chronic pain sensitivity.
In addition, some of the animals—just like people—have a variety of headache patterns. Sometimes the headaches are very frequent where the rats have more headache days than not, similar to chronic migraine in patients, and sometimes the headaches are more episodic, where the animals have a few headaches a month.
Tell me about your work on the so-called “hangover headache.”
When we were developing these models, we wanted to know whether chemical substances that trigger headache in migraine patients also cause increased head pain in these animals. For instance, there are certain chemical compounds that dilate blood vessels and cause headaches in migraine patients that are much more severe than headaches in people without migraine.
One common headache trigger in migraine patients is alcohol. Migraine patients are notoriously known to be teetotalers—one or two drinks and the next day they get a whopper of a migraine. So we set out to test whether a small amount of alcohol could trigger headache in our animals. Lo and behold, it did just that. The animals essentially developed a “hangover headache.”
With this animal model, we could then explore how alcohol can cause pain. This is counterintuitive because alcohol is often considered as something that relieves pain.
Once we had this animal, we did experiments to increase or decrease different metabolites of alcohol, the chemicals that alcohol is broken down into, to determine which one was responsible for the hangover headache. What we discovered was that a large amount of acetate builds up in the blood after drinking alcohol, in both humans and our animals. It’s this acetate that will lead to a headache. We believe this occurs because when acetate is used as an energy source by the brain, one of its byproducts, called adenosine, is made at a greater rate in migraine patients. This increase in adenosine causes the headache.
People often think that migraine and headache are the same thing, but migraine researchers say otherwise. Why?
Migraine is a neurological disorder characterized by episodes of head pain and other neurological symptoms. It’s common in some people with migraine to have neurological symptoms even 48 hours before the onset of headache pain.
There was a study done at the Jefferson Headache Center in conjunction with other headache centers in the late 90s. Patients were asked several times a day about their symptoms, not just related to the headache, but to other things that were happening. It turned out that patients increase their urination and yawning, and have a general feeling of not having woken up in the morning, up to 48 hours before the onset of their headache pain. So these neurological symptoms start days before.
Patients can also experience neurological auras. These can be either visual disturbances or other sensory manifestations such as feelings of pins and needles or ants marching up a person’s arm—all before the headache begins. And when the headache starts, patients can have confusion or difficulty speaking. So, migraine is much more than a pain disorder because of these other associated neurological symptoms that accompany it.
Are there any lessons that pain researchers could learn from migraine researchers, and vice-versa?
Any time there are research fields that don’t often interact, they can always learn something from each other. Specifically, migraine and pain are both associated with other neurological disorders. For instance, chronic pain patients and migraine patients both often have depression. Researchers focusing on pain and depression, and researchers focusing on migraine and depression, might find a common neurobiological mechanism that underlies both pain and migraine. Joining their efforts and being aware of each other’s research could really move both fields forward in a faster way.
I also want to mention the concept of chronic overlapping pain conditions. Epidemiologists have noted that once patients are diagnosed with one pain disorder, five to seven years later, the average number of chronic pain disorders that patients are diagnosed with is three-and-a-half. That means if a person is diagnosed with fibromyalgia, several years later it’s likely that individual will have other chronic pain diagnoses such as chronic migraine, chronic low pain, or other musculoskeletal pain disorders. What we’re seeing here is that in the brain there is a convergence of pain signals, and changes in brain circuits associated with one pain disorder makes a person more likely to be diagnosed with other pain disorders.
What can you predict about the future of both pain and migraine research?
There are several academic researchers as well as pharmaceutical companies that have significant research programs with very high potential for changing drug treatment of pain within five to seven years—I think that’s really possible. That’s based on the research I’m seeing in academia, grants being submitted by pain researchers, and companies that contact me for advice.
One example is a new class of drugs that target calcitonin gene-related peptide (CGRP), a protein known to be involved in migraine. There are four companies poised to come to market in the next 18 to 24 months with antibodies that inhibit the function of CGRP. These antibodies will significantly change the landscape for literally millions of patients who suffer from frequent or chronic migraine.
Let’s switch gears to discuss how the U.S. government is helping to advance pain and migraine research. NIH recently released the Federal Pain Research Strategy. What is this and how might it affect patients as well as researchers?
There is an Interagency Pain Research Coordinating Committee (IPRCC), which was created by the Affordable Care Act under President Barack Obama’s leadership. The Affordable Care Act charged federal agencies to coordinate their efforts to relieve pain in Americans.
It’s important to note that the IPRCC is interagency, meaning that it involves NIH, the U.S. Department of Defense, the U.S. Department of Veteran Affairs, the U.S. Centers for Disease Control and Prevention, the U.S. Food and Drug Administration, and other parts of the U.S Department of Health and Human Services. It also involves academic and industry partners, and, importantly, a significant number of clinicians who specialize in treating patients. This is a collaborative effort by all the key players, if not all the players, who have a stake in improving the treatment of patients who are in pain.
In 2011, the Institute of Medicine published a report that noted there are 100 million Americans in chronic pain, and 20 million Americans with daily or debilitating pain—pain that is significantly changing their lifestyle. These are staggering numbers.
The IPRCC developed the National Pain Strategy in response to this report. In it, there are core recommendations about how to coordinate efforts between all the agencies I mentioned, to help patients. This initial strategy did not include research, which is an important part of addressing chronic pain. Instead, the research portion was released in July 2017 as its own coordinating strategy. This is called the Federal Pain Research Strategy.
The strategy identifies priorities in different research areas in order to accelerate the development of treatments that will alleviate pain in Americans, and in order to understand what is really going on with patients—how they are being treated, where they are, what kind of access they have to treatments, and so forth. So there are lots of different goals from these priorities. One goal is to have safer drugs that are not addictive for the treatment of pain.
There is also a public-private collaborative initiative on pain and opioid abuse at NIH. How did this come about?
Francis Collins, the Director of NIH, recognized the need for acceleration in the federal response to the opioid crisis. So this past summer, he convened three working groups—within and outside of government—to identify key areas where government, specifically NIH, and industry can collaborate to accelerate the development of safe, effective, and non-addictive treatments for pain.
One of the working groups is specifically addressing the addiction issue, the second is looking at treatments for pain, and the third is identifying potential basic science partnerships. All three working groups are public-private partnerships.
Should researchers focus on making opioids safer, or instead on finding non-opioid drugs?
Let’s first talk about why opioids are special. Opioids work very well in treating acute pain because they have effects at multiple levels of the nervous system—in pain-sensing neurons in the body, in the spinal cord, the brainstem, the thalamus, which is a region within the interior of the brain, as well as the cortex at the surface of the brain.
With that said, there are also reinforcing aspects of opioids that make them addictive and produce tolerance. There are efforts by academic researchers as well as companies to develop opioids that can be directed to certain molecular pathways as opposed to others, as a way to separate the pain-relieving properties of these drugs from their reinforcing/tolerance-producing properties.
The problem is that it’s very difficult to do this. Researchers have made really good progress on separating out opioid tolerance and negative effects on breathing from the pain-relieving properties. But the reinforcing aspects of opioids, where animals will self-administer the drugs and become addicted—there hasn’t been any significant progress.
In the short term, designing a better opioid is not the only path we should pursue to find better treatments for chronic pain patients. We have to look at multiple drug targets throughout the nervous system. That might be a more fruitful way to get new treatments into the hands of patients.
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