It wasn't until her young niece started exhibiting similar symptoms that Reid did some detective work. She was just starting a master's degree program that gave her access to scientific research journals, and she started hunting for anything that could explain her symptoms.
"That's when I discovered the Man on Fire Syndrome," Millius said. "I was like, 'Oh my God, this is the first thing I've ever read that actually sounds like what we have!'"
Genetic testing confirmed Millius was right. Both she and her niece, as well as three of her siblings, and now her two daughters, have all tested positive for inherited erythromelalgia, also known as Man on Fire Syndrome.
It too is caused by mutations in the SCN9A gene that affect the sodium channel NaV1.7. Where Steve Pete has a loss-of-function mutation, Millius and her family have gain-of-function mutations. And that means they endure excruciating pain.
"These are patients who experience searing, scalding, burning pain in response to mild warmth," Waxman said from his labs in West Haven. "Wearing shoes, putting on a sweater or a sport jacket, entering a room at 69, 70 degrees Fahrenheit — they describe it as feeling as if hot lava had been poured into their bodies."
What Millius and Pete didn't know, as they separately endured their medical mysteries, was that Waxman and other scientists had been looking for them for years.
"Neurologists see neuropathic pain all the time; we see it every day, but we never see families," Waxman said. "We launched a search for families with inherited neuropathic pain."
Why families? Because "rare genetic diseases can teach us important lessons about more common diseases," Waxman explained. "We were searching for rare experiments of nature."
Those experiments have now entered the labs of half a dozen biopharmaceutical companies. The hope: development of a new class of medicines that can mimic Pete's genes, to treat families like Millius', and the millions of people living with other forms of chronic pain.
The need is urgent. About 100 people in the U.S. die each day from an opioid overdose, according to the Centers for Disease Control and Prevention. By far the most-prescribed pain drugs now are opioids, which generate $6 billion in annual revenue, Cowen Research said in a recent report. The market for non-opioid pain medicines could reach $10 billion, Cowen projects, with good alternatives.
Medicines focused on NaV1.7 hold the potential to avoid the side effects of opioids, including addiction, because they aim for a target that's important for pain signaling in peripheral nerve cells, rather than working in the brain, Waxman said.
"The big need in this country, and internationally, is improved treatment — more effective treatment — for chronic pain: medications that will more effectively alleviate pain and that will not have unacceptable side effects, particularly side effects on the brain, [such as] sleepiness, confusion, loss of balance [and] double vision," he said.
Scientists within the drug industry say they feel the urgency too.
"The opioid crisis — we're living it right now," said John Dunlop, vice president of neuroscience discovery research at biotech giant Amgen. "There are many, many individuals in our country who are dying from this opioid crisis, and so we are very committed to this approach to try to develop non-opioid medications for pain."
Amgen's researchers are testing molecules of every shape and size to find the best approach to targeting NaV1.7. One potential medicine is based on the venom from Grammostola porteri, more commonly known as the Chilean tarantula.
"Venoms have been a very rich source of compounds against a number of different ion channels," Dunlop explained. "Spiders and other species use these toxins to incapacitate prey and to protect themselves."
Seeing the promise of targeting NaV1.7 to treat pain, Amgen screened its library of about 300 toxin venoms. The Chilean tarantula was the best fit. The company then worked to modify the peptide to make it more selective for NaV1.7, Dunlop said. Amgen is also working on other approaches.
Specificity is crucial. NaV1.7 is one of nine sodium channels in the body, and others are implicated in important other functions.
"A classic one is NaV1.5, in the heart," said Dan Sutherlin, director of discovery chemistry at Genentech, which has NaV1.7-targeted pain medicines in human clinical trials. "Others are in other peripheral organs and the central nervous system that are important for many different physiological functions."
Genentech, a unit of Swiss drugmaker Roche, has finished phase 1 clinical trials of two molecules targeting NaV1.7. The goal is to find a therapy that's selective, convenient and optimally potent.
"We really believe in this target and are convinced that if you inhibit it in the proper way — that if you can affect the channel in the right way, you will have a profound effect on pain," Sutherlin said.
Pain-sensing neurons aren't the only cells that express NaV1.7, though — it's also found in cells essential to giving us our sense of smell. Thus, Steve Pete can't smell anything at all.
Researchers say effect on smell could be a side effect to potential medicines targeting NaV1.7.
Work is also underway at Biogen, which acquired its NaV1.7 program from Convergence Pharmaceuticals. Its experimental drug, dubbed BIIB074, is in phase 2 studies for trigeminal neuralgia, stabbing pain that attacks patients' faces.
Regeneron also has work underway, in preclinical development (it hasn't yet started human trials). And Vertex has a program targeting another sodium channel, NaV1.8.
Despite the support of elegant genetics work, targeting NaV1.7 to develop successful medicines has not been easy. Already the field has seen some setbacks.
In late June, Israeli drugmaker Teva and Canadian biotech Xenon said a midstage clinical trial in post-herpetic neuralgia, a complication of shingles, failed to meet its goals. The companies didn't make clear why. Denise Bradley, a spokeswoman for Teva, said the companies are discussing next steps for the compound, called TV-45070.
Xenon was a major contributor to research on genetic drivers of CIP, leading a search for people like Steve Pete. The company has also partnered with Genentech on its NaV1.7-targeted programs.
Drug giants Pfizer and Johnson & Johnson also at one point were in the hunt for NaV1.7 medicines, but both have left the space.
One reason for setbacks is simply that developing medicines, even with clearly defined genetics work supporting the research, is very hard. And developing pain medicines has its own particular set of challenges.
There's no biomarker for pain, Yale's Waxman points out, such as measuring blood pressure or tumor size. And the gauges of pain are subjective. Patients are often asked to grade the intensity on a scale of 0 to 10; what may be a 7 to one person could be a 9 to another.
"Despite that," Waxman said, "I was pleased to see that the biopharma community has been attracted to this target."
Steve Pete and Reid Millius, with their mirror-image mutations, both say they're hopeful and excited their rare genes may contribute to medicines that could help with the opioid epidemic.
"To think that, hey, within the next 5-10 years that could potentially end people's pain without negatively impacting their life?" Pete said. "It's pretty exciting."
—CNBC's Jodi Gralnick contributed to this report.
More from Modern Medicine:
Two patients show the promise of a historic treatment, with an equally historic price tag
A bot designed for chatting about death
Bill Gates: For polio the endgame is near