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Inside the Ongoing Search for the the ‘Perfect’ Painkiller

Even as the country reels from the opioid epidemic, doctors believe the safer, non-addictive future of pain medicine may still lie with opioids themselves

What if the most effective way to mitigate the current opioid crisis — which claims the lives of 130 people in the U.S. every day — isn’t by scrapping opioids altogether, but rather, developing an entirely new type of opioid? A perfect painkiller that isn’t addictive, and is 10 times more effective at treating chronic pain than morphine?

I know what you’re thinking: It sounds like the Orwellian overture for Big Pharma’s next wave of too-good-to-be-true-because-they’re-actually-life-decimating painkillers (in 2017 alone, more than 47,000 people died from an opioid overdose). But for lab-locked pharmacologists seeking ways to remedy the opioid crisis — conveniently carried out at the behest of pharmaceutical corporations — the best solution isn’t necessarily reducing opioid prescriptions. Instead, their solution is to fight fire with a variation of the same flame. 

It’s not a novel theory — in fact, one search for non-addictive opioids was dispatched nearly 13 years ago. Around 2006, Professor Mei-Chuan Ko and his team at Wake Forest School of Medicine found that, unlike morphine, analgesics [painkillers] that activated two different opioid receptors didn’t induce dependency in non-human primates. “Fentanyl, morphine, oxycontin, this type of opioid analgesic, they mainly bond to the mu [opioid] receptor [considered a gateway to drug dependency],” says Ko. “But for our compound [AT-121], they bind to at least two different [opioid] receptors. One is mu and one is NOP. So some people could call them bifunctiona.” 

The result of this bifunctional opioid compound, according to Ko, is that the patient requires one-tenth the clinical dose of morphine. “That’s the first exciting finding,” he says. “The second finding is, we know from scientific study that all the abused drugs, to some degree, cause dopamine release. That specific dopamine release is one of the key mediators of euphoria — a mechanism underlying the abuse potential of any substance.” But in the case of this newly developed compound, Ko says the activation of the NOP receptor could inhibit dopamine release, potentially interfering with or blocking the reinforcing or rewarding effects of any abuse substances. “So when you need a tenth or less of a dose, and at the same time, you know that the activation of the NOP center could also interfere with dopamine release or dopamine neuron function, this type of drug may be able to make it less addictive, compared to clinically used opioid analgesics,” explains Ko.

To put this in context, Ko’s newly developed drug, if approved, would be nothing short of a medical miracle for the estimated 50 million U.S. adults suffering from chronic pain. Caught in the middle of the fight against opioid abuse, those who suffer from chronic pain (often characterized as the “invisible disability” and defined as any pain lasting longer than six months) aren’t just looking to painkillers to take the edge off — they’re desperate for anything that enables them to have some semblance of a normal life. 

For those who’ve never experienced chronic pain, the enormity of its impact can be hard to grasp. “I have a feeling like metal filings under my skin,” Mary, a 70-year-old woman suffering from breast cancer, told “It is pulsating like waves that come and go. Sometimes the pain is so bad that it brings tears to my eyes.” Unfortunately, the current crackdown on opioids has left many legitimate patients like Mary stranded. “I made it this far,” Rita Kimbrel, a 57-year-old neurogenic pain sufferer, told the National Pain Report in 2017. “I’m not ready to die yet, and someday I will get oxycontin back so I can function. Not even my best friend knew I was taking it.”

This desperate yearning to kill pain — whether it’s via cutting holes in the head to alleviate pressure, sacrificing animals or the ancient Egyptian practice of laying electric eels on the wounds of patients — is, of course, as old a human struggle as pain itself. Opiates, specifically, trace their origins to the earliest years of human civilization with the cultivation of the opium poppy, first discovered in Mesopotamia around 3,400 B.C

It was the isolation of morphine — the precursor to all other opioids — by German scientist Friedrich Sertürner in 1803, however, that would ultimately lead to the first modern iteration of an opioid epidemic. “By the second half of the 19th century, scientists had begun to look for a less addictive form of morphine, and in 1874, an English chemist named Alder Wright first refined heroin from a morphine base,” reports “The drug was intended to be a safer replacement for morphine.” In fact, 16 years later, German pharmaceutical company Bayer would market heroin as a less addictive morphine substitute for use in treating children suffering from coughs and colds. As a result, heroin addiction in the U.S. and Western Europe skyrocketed.

“After that [epidemic], many physicians had what they would call opiophobia,” says Andrew Coop, an associate dean of academic affairs at the University of Maryland School of Pharmacy. That is, until, according to Coop, three pivotal things occurred that would forever change the scope of opioid addiction. “In 1980, there was a letter to the editor published in The New England Journal of Medicine and what they effectively said — and I know that the authors at this point wished they’d never published this letter to the editor — was that they’ve looked at their files for the number of patients who become addicted after taking medications in hospital, and they found that it’s extremely rare in medical patients with no history of addiction,” says Coop. “People cited this without reading it — they called it a seminal study and all this other stuff. And it really changed the thought process for many of us in terms of prescribing [opioids].” 

At the same time, Coop tells me that the pharmaceutical industry had made large doses of Oxycontin available. “It was a formulation, a tablet that released the Oxycodone, the active ingredient in Oxycontin, slowly over time,” he says. “So you could give less doses that last longer. Of course, while releasing the dose slowly, that means there’s actually more drug in the tablets.”

The final part of the “triple threat” that unleashed the perfect storm for the opioid epidemic came with a decision by The Joint Commission, a body that sets standards for medical care in the U.S. “They established standards for pain assessment and treatment in 2001,” says Coop. “And although they claim that they didn’t say that pain should be treated as ‘a fifth vital sign,’ the document they put out was interpreted that way. So that when patients were now leaving hospitals, they were assessed on pain. That’s how I think we got to where we are.” 

“Where we are” is a place where, by 2017, the number of overdose deaths involving opioids (including prescription opioids and illegal opioids like heroin and illicitly manufactured fentanyl) was six times higher than in 1999, according to the CDC. “We have this Jekyll and Hyde character to opioids in that they’re medications that treat patients that really need the pain-killing effects of opioids,” says Coop. “However, they’ve also got this other effect [dependency] that leads to what’s currently the opioid crisis. It’s a matter of balancing the two to maximize their use and minimize their misuse.”

According to Amy Feehan, a neuroscience grad student at Tulane who’s part of a group of researchers studying a different non-addictive opioid compound, the complicated part in developing a non-addictive opioid is that, “addiction is way more complex than one gene, protein, receptor or neurotransmitter,” she says. “The process seems to have more to do with how any drug [including opioids] affects the increase in dopamine [a neurotransmitter] in reward centers of the brain. Drugs like heroin make dopamine surge and cause euphoria. Since this effect is in the central nervous system (brain and spinal cord), you can avoid it by making drugs that only work in the periphery.” Unfortunately though, the best pain killing occurs in the brain, “which is why most peripherally restricted opioids haven’t gotten very far,” she says.

However, one such peripheral approach undertaken by Christoph Stein, professor of anesthesiology and critical care medicine at Freie Universität Berlin, has shown a great deal of potential. “All currently available opioids activate opioid receptors all over the body, i.e., both within and outside the brain,” says Stein. “Adverse side effects [e.g., addiction, respiratory arrest and sedation] are mediated by activation of opioid receptors within the brain. Therefore, our concept [selective activation of opioid receptors outside the brain] can produce pain relief without eliciting addiction, respiratory depression or sedation.” 

To that end, Stein and his team have designed a new compound (NFEPP) that can be administered “systemically” (read: intravenously), activating opioid receptors exclusively in peripheral injured tissue without eliciting side effects in the brain the way current opioids do. The drug, in essence, targets only the pain-afflicted area, and nothing else. “NFEPP is targeted for any type of inflammatory pain associated with tissue injury, e.g. pain during and after surgery, musculoskeletal pain (e.g. arthritis), nerve injury (neuropathic pain), inflammatory bowel disease, cancer, trauma, etc.,” says Stein.

Feehan’s team, meanwhile, is developing an engineered variant of the neurochemical endomorphin, which is found naturally within the body. “With morphine, you get a pretty quick onset, then you get analgesia [pain relief] for an hour or two, then the effect is gone, so you have to re-dose,” Feehan explains. “With our lead compound [ZH853] that we’re taking into clinical trials, in some cases, it lasted six-plus hours, which means that you don’t have those highs and lows, which is where a lot of people get in trouble when they’re having to dose multiple times a day or they’re withdrawing overnight.” 

The other unique facet of these new painkilling compounds discovered by Feehan and her team is that, while morphine, heroin and the other plant-based opioids activate the immune system, causing an inflammatory response, their compound, being found naturally in the body, doesn’t cause any interaction with the immune system. “That’s turning out to be an area where a lot of side effects come into play, like addiction or constipation,” she says.

While these new approaches sound promising — potentially even miraculous — it should be noted that they’re still a long way from hitting the market. “It heavily depends on so many different factors,” says Feehan. “Funding is a big one, and for a phase one clinical trial, a Big Pharma company [won’t lift a finger], so we have to do a lot of fundraising.” Not to mention, she adds, “A million things can go wrong in phase one. Then you have to get through phase two and three, which are even bigger and more expensive. So it’s a long time.” 

Ko says that his compound (AT-121) — still in clinical trials in non-human primate models — is, conservatively speaking, six to eight years away from getting FDA approval. “They have to go through a lot of FDA requirements, and then after the FDA, after they file the IND [Investigational New Drug], they have to have another four or five years of clinical trials to demonstrate that, over a specific dose range, that particular drug is safe and doesn’t cause any toxicity issues or safety issues,” he says. “So it takes years and years to reach that stage.” 

“Even the closest-to-market non-addictive opioid (NFEPP) is still seeking collaborations with pharmaceutical companies and/or investors,” says Stein. “If we find such, NFEPP may be on the market within three to five years.”

Not surprisingly, Stein says that at the moment, Big Pharma is shying away from any opioid compounds due to the opioid crisis and its associated (enormously expensive) litigation issues. “This may hamper the future development of non-addictive opioids,” he says. To his point, in 2018, the FDA narrowly voted against recommending approval of Trevena’s intravenous opioid oliceridine, which was shown to induce less respiratory issues than morphine, according to a Reuters report. “In its efforts to curb opioid abuse, the FDA has been encouraging drugmakers to develop alternatives to addictive painkillers, while declining to approve new opioid therapies,” per the news agency.

Coop tells me that one positive outcome stemming from the general mistrust of opioids is that it’s led scientists to research alternative (non-opioid) pain-killing medications. In fact, in his testimony earlier this year, Coop says that he told U.S. senators at a hearing on Managing Pain During The Opioid Crisis that the most promising new drug is actually cannabis. “I don’t think any of the senators wanted to bring medical marijuana up, but once I brought it up, they were all — including Mitt Romney, by the way — excited to talk about it,” he says. “Medical cannabis has its potential. There are many different mechanisms we can study for treating pain. [Cannabis] isn’t evil, it’s not snake oil, it’s somewhere in the middle.”

Still, Coop says the reason his focus remains on developing less addictive opioid compounds, rather than pivoting his research to other medications, isn’t only because his expertise lies in opioids, but because opioids work far better than anything else in terms of duration of action and ability to kill pain. “Opioids treat so many levels and such severe levels of pain,” he says. “Cannabinoids treat certain types of pain, not all kinds of pain.” Yet despite this — and despite his optimism with regard to the development of his less addictive opioid compound — Coop is unwilling to risk bringing another analgesic opioid to the market that has any potential for abuse. “I prefer to make sure that it may take a little longer and do it correctly,” he says. 

Even if pharmacologists are able to synthesize a new brand of opioid-based compounds that don’t have the same abuse potential, however, Ko warns that there’s no silver bullet for solving the opioid crisis. “The opioid epidemic has several factors that contributed to the current situation,” he says. “If, in a clinical setting, a physician prescribes an opioid with abuse potential, that could cause one problem. But at the same time, a lot of individuals on the street like to use opiates in a recreational sense to experience the euphoria.” It’s a facet of the opioid crisis that Ko says won’t be fixed by a less addictive form of pain killer. “That has nothing to do with the opioid analgesic,” he says. “It’s so easy to synthesize fentanyl, or it’s so easy to have someone buy fentanyl and ship it by international mail. That’s causing most of the overdoses.” Essentially, the population of people who Ko says is the “main driving force for the opioid epidemic” — those doing it for kicks — won’t be saved by these new drugs.

Plus, with so much carnage left in the wake of the opioid epidemic, it’s hard to see how even those suffering from chronic pain might be willing to trust in these new, non-addictive painkillers once they become available. After all, it will likely be the same pharmaceutical companies responsible for the current crisis pushing the new drugs. “There’s going to be a credibility issue,” Coop admits. He then pauses for a moment, before continuing, “But have you ever suffered from chronic pain? Go speak to a chronic pain patient and that will answer your question. They are desperate for medication.”

So desperate, in fact, that when he published news of his compound to small websites, Coop tells me that he already got phone calls from people asking for the drug. “First we swung too far in that we gave them out too quickly,” he says. “Now we’ve swung too far the other way. Trust will need to be built again, but people are suffering.” 

And when people are suffering, the solution is very often whatever it takes to make that suffering end, the baggage attached to it be damned.