Reprinted with the kind permission of Cort Johnson and Health Rising.
Twenty billion dollars a year… That’s how much Americans in chronic pain spend on prescription pain-killers every year. Most of these are opioid drugs, but the increasing regulatory burden foisted on them and the growing realization of how ineffective and even harmful they can be means their days are numbered.
Three non-opioid drugs have been approved for fibromyalgia, but studies suggest that they’ve been of limited effectiveness in reducing pain in the overall fibromyalgia population. Surveys suggest that about thirty percent of FM patients take opioids and many consider them more effective than the FDA-approved FM drugs.
Solutions to the chronic pain problem will probably come in many forms, but one of the more intriguing is more effective and safer next-generation opioids. Recently, a Smithsonian article, “America’s Long-Overdue Opioid Revolution Is Finally Here,” suggested that if the opioid revolution is not quite here yet, it’s coming fast.
In the early 2000s, researchers realized that opioid receptors were more complex than they had thought. Depending on how they were activated, these receptors could turn on two pathways: the “good” pathway, which turned down nerve pain activity, and the “bad” pathway, which turned down pain nerve activity but also caused things like respiratory depression, addiction and constipation.
You can guess which pathway virtually all the current crop of opioid pain-killers is using. The finding sparked efforts to create forms of opioid drugs. Currently three drugs are leading the pack, but better ones may be coming as researchers better understand how the opioid receptors work.
Opioid drugs have been the mainstay of pain relief for decades but are ineffective for chronic pain and come with many potential side effects.
At least three next generation opioid drugs – each using a different approach – are under development.
Oligocerine, which may be helpful in tamping down fibro-flares, could be approved next year.
Another drug built off an unusual opioid drug called buprenorphine, which has been tested and found effective and side-effect free in primates, could enter human trials in two years.
A third drug (PMZ21) built entirely from scratch using computer modeling could enter human trials in perhaps three to five years.
Oliceridine by Trevena has gotten all the way to Phase III clinical trials in humans. The Phase II clinical trial results indicated Oliceridine produced similar amounts of pain relief as morphine but with less nausea, hypoventilation (respiratory depression) and vomiting in the short term. With 90 deaths a day from opioid painkiller overdoses in the U.S., reducing respiratory depression would be a major step forward.
If the trials are successful – the results should be announced any day now – the company plans to proceed with FDA approval at the end of the year. If the drug is approved, it will be the first novel pain drug approved by the FDA in ten years.
The catch is that Trevena hopes to market Oliceridine for acute, not chronic, pain and a recent mouse study may suggest why. It found that side effects do emerge in Oliceridine over time. Oliceridine may be a step up for acute pain management, but it may take a different drug to do anything for people with chronic pain.
A key for fibromyalgia and other chronic pain patients will be the ability of the next generation opioid drugs to avoid the tolerance problems that crop up when the drugs are used over time. Tolerance occurs when more of a drug is needed over time to reduce pain. A paradoxical reaction can also occur in which the drug actually increases pain sensitivity. (The first thing some FM doctors do is try to get their patients off the drugs to see if they improve.) Plus, there’s the potential problem with addiction.
Researchers at the Wake Forest Baptist Medical Center are tackling opioids in a different way. Based on a rarely used opioid drug – buprenorphine – which has less addictive properties, BU08028 latches onto the opioid receptor in the same way that current opioid drugs do but it comes with a twist: it also targets opioid receptors which may block addiction. When given to primates – which share many features of the human brain – the drug proved to be highly effective at relieving pain, was long-lasting and was non-addictive. It also did not cause respiratory depression, constipation or other side effects.
Trials for this drug could start in two years.
There’s the ‘tweak an existing drug’ and there’s the ‘build a new drug up from scratch’ approach. Designing a pain drug, a molecule which not only turns on the right kind of opioid receptor but only activates the right pathways, however, is no easy feat. In fact, it couldn’t have even been contemplated until the last few years.
As reported in the Stanford Medical News, Nobel Laureate and Stanford researcher Brian Kobilka laid the foundation for a new drug in 2012 by producing the first atomic level structure of the mu-opioid receptor. Stanford, UCSF and other researchers took that model and used a computer to throw over 3 million molecular compounds at it. First they winnowed the potential candidates down to 2,500 molecules and then to 23 molecules. In the end one stood out. After researchers at Friedrich Alexander University in Erlangen, Germany, tweaked it so that it would bind tightly to the receptor, they had PZM21 – perhaps the first effective and safe opioid pain-killer ever developed.
In 2016, the researchers reported in Nature that PZM21 appeared to be more effective at pain relief than morphine and caused fewer side-effects – including no signs of tolerance and addiction. Further testing is needed, but as of now the drug’s future is bright.
The opium poppy and the drugs obtained from it have been used for thousands of years. They’ve proven a great boon to mankind but contain a dark side marred by addiction, tolerance and other problems. About 30,000 people a year die from painkiller overdoses in the U.S. Many others can’t get relief from pain or do so at the cost of debilitating side effects.
PZM21 isn’t ready for show time yet. It will take more investigation and mouse trials for human trials to begin, but the stage may have been set.
Pain is one of the more complex sensations produced by our bodies, and it’s likely there will never be a drug that works for everyone or that is completely effective. One next-generation opioid that may be more effective at tamping down fibro flares could, however, be FDA approved for acute pain relief next year. Two more that may be effective against chronic pain could enter human trials in the next two to five years. The race for a safe and effective opioid is on, and the monetary stakes – hundreds of millions, even billions of dollars in sales – couldn’t be higher.
About the Author: ProHealth is pleased to share information from Cort Johnson. Cort has had myalgic encephalomyelitis /chronic fatigue syndrome for over 30 years. The founder of Phoenix Rising and Health Rising, he has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort's and other bloggers' work at Health Rising.