A neuroscientist and some grape skins vs. the pharmaceutical industry.
The most riveting article on pain cream you’ll read today.
In late 2017, NPR aired a two-minute segment on the science behind our new pain cream. It became such a popular segment that it left our customers hungry for more detail. So by popular demand and for the first time ever, here’s the whole story, from the beginning.
This is the entirely true, behind-the-scenes story of the first breakthrough in over-the-counter pain relief in a generation. It has everything: science, jealousy, luck, surprise, betrayal, pathos, and of course, more science. All it’s missing is a love story. Unless you count the love of a scientist for a good confocal microscope, which is between you and your own conscience.
The heroes to date: Dr. Ted Price. A neuroscientist with some international recognition in the study of pain, and his fellow neuroscientist cohort, Dr. Greg Dussor, a noted expert on migraine.
How it all began
The time: the not-too-distant past. The setting: Ted’s university neuroscience lab.
Ted, having abandoned his initial research focus on cannabinoids as potential pain relievers (long story short, although some specific conditions have recently been shown to respond well, at that time the clinical evidence for general efficacy was pretty thin), was in some pain himself. An old high school football injury left him dealing with constant, lingering effects, effects which prevented him from enjoying his favorite pastime, basketball. On this particular day, the pain was enough that it was also preventing him from doing any decent lab work.
“I remember thinking to myself how pathetic it was that I’m supposed to be some kind of expert in pain, I’m sitting in a pain lab with my name on the door plate, and I’m completely unable to do anything to help my own pain,” recalls Dr. Price.
That’s when it finally hit him. For some time, he’d been investigating an interesting therapy involving a promising new compound. Well, technically, it was an old compound. But it was new in the pain world. He’d even published a few peer-reviewed articles on its success in treating specific pain conditions. A natural compound found in particularly strong concentrations in grape skins, it was called resveratrol. And it just so happened that Ted had some lying around his lab.
A brief primer on a tarnished miracle cure
Now before we get too far ahead, we’re going to need to go on a brief resveratrol aside. If you’ve heard of resveratrol before, you likely know it for its alleged heart-health or anti-aging properties. Resveratrol is a powerful antioxidant, and became big years ago in the health food supplement scene as a miracle age-defying treatment. Sadly, the claims of its purveyors didn’t hold up, and resveratrol’s reputation had been on a steady decline – at least in the evidence-based world of the scientific community.
But that was before Ted and Greg came along. Their peer-reviewed research suggested that resveratrol, when used to fight pain instead of aging, and when applied topically instead of taken orally, might be truly special. Once-in-a-generation special.
To understand why, we need to go on one last aside (or you can skip to the punchline and just read this overview). This time into the high-energy, glamor-oozing world of topical pain treatments..
The most stagnant aisle at the pharmacy
All things being equal, a topical pain treatment should really be everyone’s first choice for dealing with serious pain. No need to take a pill, no need to send a drug where it’s not needed, no risk of addiction or overdose. You apply where it hurts, and that’s it. It just makes sense. The problem is that all things are not actually equal. Why not?
If you’ve used a topical before, you already know the answer. Sadly, topicals just don’t work that well.
And the reason they don’t work that well? On that question, science has something to say. For as long as there have been drug stores, there have been only two ways of treating pain topically: either numb it, or distract from it. That’s it. In the “numb it” camp we have the lidocaines and benzocaines. In the “distract from it” camp we have, surprisingly, most of the big enduring brands, most of which use various mixtures of menthol or capsaicin.
Numbing is a less than ideal strategy for obvious reasons: one, it only works as long as you happen to have fresh medicine on your skin; and two, you numb the whole region of all sensation, whether it’s pain or heat or cold or pressure – valuable information without which you risk greater injury. This strategy is especially dangerous for athletes, who need to know when to listen to important pain and protect injuries while they heal.
Distraction is the other strategy. It may be less dangerous as a strategy for dealing with pain, but it’s also less effective. “Cool” and “heat” treatments (menthol and capsaicin) fall into this camp, and they’re essentially counterirritants. They trigger a low-level irritation which fills the nerve pathways, so you are a little less aware of the pain for a while. Not exactly state-of-the-art thinking. People in real chronic pain don’t need to be told that if either of those strategies were good long-term solutions, then the Chronic Pain Crisis may have been averted. To say nothing of the Opioid Crisis.
The true enemy: “False Pain”
Which brings us back to resveratrol. As Ted likes to explain, pain often outlives the injury that triggers it (in some cases for years). The reason for this is that after you heal, your nerves don’t always reset their pain threshold, so the mechanism designed to help you protect a wound while it recovers gets stuck in permanent “on” mode. Meaning you feel minor sensations like heat or pressure as pain. This is what Ted and Greg call “false pain,” (and in their words, the longer you ignore it, the more stubborn it becomes). What they showed in their published research was that resveratrol seems to do something entirely new. Something no other topical did. Instead of numbing all sensation, or adding a new sensation, it may actually turn the volume back down on over-sensitive nerves, and eliminate the false pain.
Here’s a video that explains it in more detail.
Making a test subject of himself
Back to Ted in his lab. He’s in pain. He appears to be sitting on the first topical pain breakthrough in a generation. Why hasn’t he tried it himself?
“That’s a great question.” Ted muses. “I guess, as a scientist, you are rightfully pretty cautious about testing things on yourself.” Explains Ted. “Often the compounds you’re playing with are entirely untested and could even be toxic.”
It finally took an especially frustrating day of pain to get Ted to realize that resveratrol was neither untested nor toxic. Found in many fruits like blueberries and grape skin, resveratrol has been consumed by humans for ages. We’ve eaten it, stomped on it, drunk it for thousands of years. So Ted figured, “what the hell?” He grabbed the cream he had in the lab, rubbed it on his ankle, reapplied every few hours, and waited.
Three days later, he was back on the basketball court. “In all honesty, I was shocked. I was hoping for some pain cessation, but I wasn’t expecting this,” recalls Price. “For the first time in months, I had some real relief of my tendonitis in my achilles. And I also realized I might have something that could make a real difference in people’s lives.”
A medicine that made itself unnecessary?
Just to be sure it wasn’t a fluke, he made more cream and started passing it out to friends, family and colleagues as an experiment, asking them for honest feedback so he could adapt the cream and understand how it could be used. As the reviews poured in, he began to notice a pattern. While nearly everyone reported some relief, the users who raved the most were the ones who applied the cream a few times a day for several days. Many even reported that the effect lasted long after discontinuing use.
This was significant for a couple of reasons. One, it was a helpful confirmation of Ted’s own experience with the cream – after that initial week of use, he only needed to apply the cream to his ankle now and then. But more importantly, the user reports seemed to validate Ted and Greg’s hunch about resveratrol’s mechanism of action. If indeed resveratrol was doing what they suspected, then it made sense that it would take time to reset a hypersensitive nerve to its optimal pain threshold. But once reset, in theory, the nerve should stay there on its own without needing any further help.
This was exciting for both of the neuroscientists, who had long believed that the origin of the Opioid Crisis was due in part to the prevailing cultural idea that more medicine is better. Ted and Greg wanted to help create a world where less and less medicine was necessary. The fact that they may have a product that could upend the entire pharma business strategy, well, that appealed to their subversive sides.
To prescribe or not to prescribe
Now our subversive professor heroes had a tough decision to make: how to take it to market. They could pursue clinical trials and hope to get their cream approved for use as a prescription drug, which as data-driven scientists was their preference. That’s how you prove efficacy to the skeptics. But after trying to find financial backing, they realized there was an unfortunate business flaw in that approach. Investor types were quick to point out that even though resveratrol has never been used to treat pain, it’s already on the market as a supplement, which means it would not have the same kind of legal protection that a truly new drug would. Even if it ended up being the most effective prescription pain treatment of all time, it would be tough for any single company to own it for long. Making it far, far less attractive for investors.
So Ted and Greg had to consider other options. Interestingly, the same attribute that made resveratrol less investor-friendly for clinical trials also opened another door entirely. Since resveratrol is already on the natural market, it can be used in any herbal product. If they listed resveratrol as an herbal “other ingredient” and not as an active ingredient, they could put it in any product they wanted. The question was, “Should they?”
Opening that door had some obvious downsides. Some advisors cautioned them against it altogether. Without clinical trials, they said, you put your product on the same shelves as snake oils, you risk losing credibility with the scientific establishment, and make yourselves, in the eyes of many, no different than the homeopathy peddlers of the world.
A crisis in need of more solutions
So they deliberated. They put it out of their minds. They continued teaching their classes and running their pain lab. Then they deliberated some more. During those deliberations, it slowly dawned on them how much time they were spending in the lab making cream for the people who kept asking for more. “We very literally couldn’t keep up with demand,” laughs Greg. In the end, after much discussion, they decided they had to risk the backlash and go full steam into plan B.
If resveratrol is so great, why is it so far down the ingredient list?Find out why
It was also about that time they realized they may be able to carve out a middle road, one that could allow them to avoid the homeopathy aisle entirely, and sport an FDA approved label in the process. All they had to do was add another ingredient, one already approved by the FDA for pain relief. The question was, which one? They quickly stumbled on the answer: wintergreen oil. Also known as methyl salicylate. Why? Well, like resveratrol, it’s also natural and has also been in use by humans for thousands of years. But more importantly, its mechanism of action is well understood. And given their understanding of how resveratrol seems to work, Ted and Greg had sound neuroscience-backed reasons for believing that it would work very well in concert with resveratrol, helping to magnify its effects.
What’s in a name?
Some time passed, careers blossomed, and Ted and Greg had moved to another university where they continued their quest. Now that they had a product and a strategy, they needed a name. The scientists suggested calling it “Resveratech,” but their friends in marketing were lukewarm at best. The name the marketing people liked was something a lot simpler. “You should just call it ‘Ted’s,’” they said. Ironically, Greg was an immediate fan of the name, and it was Ted himself who was iffy. “It was my wife who actually talked me into it,” Ted laughs. “I blame the whole thing on her now. In hindsight, though, she was right, as she always is!”
Their next decision was, from their point of view, even more important than the name. Ted and Greg agreed that they wanted their discovery to help support a meaningful cause. But finding the cause that felt right took some time. Some obvious non-profits jumped out immediately. Both of them had experienced the tragedy of a friend’s overdose. And both shared a passion for helping disrupt the cycles of pain that can lead to addiction. So addiction and recovery causes were strong considerations.
But they also believed passionately in the value of education, with a particular awareness of the rising costs of higher education. After much discussion, it occurred to them that the right cause could scratch both of those itches.
“There’s a shortage of support for good neuroscience being done in the pain field,” explains Greg. “And there won’t be a single solution to the Opioid Crisis. It’s going to take lots of new thinking and lots of new treatment.”
Ted and Greg agreed that the best thing they could do was to make sure deserving students in the field were getting the right opportunities to advance their new ideas. “The best way to share new science is by attending science conferences. Unfortunately,” says Ted, “the travel is too expensive for all but the most privileged students.”
That’s how they decided that Ted’s would support the Larry Cauller Neuroscience Travel Fund. Which connects students doing important work with experts all around the world, helping advance both basic scientific understanding, and the careers of talented young people.
“People in pain need better basic science,” says Ted. “This is how that science begins.”
All the peer-review in the world couldn’t prepare them for this next part
With everything in place, all they needed was a team to handle the details. They found some talented folks who believed in the science and the mission, and who were willing to put in sweat equity. They designed a commercial form of the cream, built a website, set up a fulfilment center, got started on stability tests, designed packaging, ran costs analyses and pricing models, and placed an alarmingly large initial order for tubes and cream. They crossed their fingers that they could meet their projections for the first year of sales without losing their shirts. And then they turned it all on, prepared to get down to the slow, daily grind of spreading the word.
That’s when disaster struck. Well, a kind of disaster anyway.
NPR’s national science correspondent got wind of Ted’s research, through a chance meeting at a Rita Allen Foundation meeting in Silicon Valley, and decided to do a story on him. When the interview finally aired, coincidentally on Ted’s birthday, it was short and open-minded. But Ted worried that since they didn’t even mention the name of the product, and since it took a pretty skeptical angle (it even used the word “snake oil” in the story title, which you can listen to here, if you’re interested), it might not end up doing much good.
It only took a few minutes to realize he was wrong. Orders began to pour in by the hundreds. There were so many orders, they sold out of their entire first year’s supply of product in a single day.
“It took us almost three months to make more product,” laments Ted. “We were definitely not prepared for the level of demand. We were losing new customers every minute, and the ones we had before NPR were not happy with the new wait.” But eventually they restocked the warehouse shelves and began shipping it out in quantities well above their initial, naïve projections. The demand sparked by the radio interview held strong, now bolstered by the strong word of mouth from those NPR listeners leaving glowing reviews on the homepage and on Amazon.
People Pay for Five Star Reviews?
“We had a pharmaceutical marketing director call and ask us how much we paid for those reviews,” recalled Ted. “I was stunned. I didn’t even know you could buy reviews, and the fact that I was stunned, stunned him. He assumed that with feedback as positive as ours we must have paid for it.”
Ever the scientists, Ted and Greg realized that with as many users as they had, they could do some interesting segmenting research on the resveratrol and wintergreen combination. It wouldn’t be clinical-trial-level reliability, but it could still help improve their understanding of their product. They designed a questionnaire to pinpoint the conditions most (and least) responsive to the cream, and sent it to their entire customer base with a plea for input, good or bad.
What they learned surprised even them. (Ted gave a three-part Facebook live presentation on it, which you can watch starting here). Close to 90% of respondents experienced some relief from their pain. Even more impressive, over half of those reported that in fact, most of their pain was gone altogether. But the bigger surprises were deeper in the data. Several conditions responded particularly well to Ted’s Pain Cream. Two in particular stood out. The first was carpal tunnel. No surprise there, since the hand and wrist are fairly thin, making it easier to get medication through the skin and muscle. The real surprise was the magnitude of success. Almost every single user with carpal tunnel reported that the majority of their pain was gone after a week of use.
People are putting this WHERE?
Even more surprising was the second stand-out condition: migraine. Migraine sufferers reported relief in overwhelming numbers and magnitude. While exciting, this finding presented a real puzzle to the whole team. Especially to Greg.
“I have studied migraine most of my career, and I feel a little foolish that it never once occurred to me to try our cream for headache,” recounts an embarrassed Greg. “My first question was ‘how is this even possible?’ My second question was, ‘where are they putting it?’”
So Greg contacted some customers to find out. The answer helped shed some light on a potential mechanism of action. “Turns out,” he says, “They were applying to the back of the neck and the temples.” That helped answer some questions for Greg, and softened his initial skepticism. The skull is surrounded by a network of nerves that convene at the spot where the neck meets the skull. Getting some medicine into that area could in fact, according to Greg, disrupt the electrical storms that lead to migraine. “I’m still tickled by this,” he says.
Room for Improvement
The other important finding from the surveys: not everyone was a fan of the smell of wintergreen (that’s even more true for migraine sufferers, who often have scent triggers). So they began to work on a new gel formulation, with a different active ingredient (but still, of course, containing resveratrol). It would be many months before it was ready to launch, so in the meantime, they continued to push their research, while having some fun finding new ways to reach more customers.
They debuted an Internet ad featuring Greg, in which he pretended he was harboring secret resentment over his name being left off the product. The ad was a hit, and went on to win some advertising awards (it was even written up in Adweek).
Eventually, the gel was ready. Ted and Greg settled on an active ingredient called Trolamine Salicylate, which is a similar compound to wintergreen oil, with the important distinction that it has no odor at all. When it finally debuted, the gel was met with strong sales and glowing reviews (even more glowing than the cream, it turned out.)
So what’s next?
Ted and Greg continue to study pain in the lab. After their initial work on resveratrol, they also discovered that males and females actually experience pain differently at the cellular level, a surprising but compelling finding that they continue to publish work on. And they’ve published peer-reviewed work showing certain immune cells play a really important role in promoting chronic pain in male mice and humans but that these chronic pain mechanisms appear to be completely different in females. A big area of current focus is figuring out how pain becomes chronic in females with a special attention to migraine and neuropathic pain.
They continue to take pride in their students, using revenue from Ted’s Brain Science Products to support stand-out neuroscience students. Students who wouldn’t otherwise be able to present their work at important international science conferences.
As for the company they built, the team at Ted’s Brain Science Products are hard at work trying to spread the word of this deceptively simple new solution to chronic pain. They hope to continue growing until they have enough income set aside to fund a slow, expensive clinical trial on their own. A possibility that would open the door to even more novel ways to treat previously untreatable pain.
And that’s where the story ends for now. Looking back, Ted wonders if starting this company may end up touching more lives than he ever guessed. “We get letters every day. We just got one from a cancer patient with severe neuropathy, expressing that Ted’s Pain Gel was finally the one treatment that actually gave her relief,” recounts Dr. Price. “It’s such a gratifying feeling to see your work make a real difference in people’s lives. It definitely keeps us pushing forward.”