Opioid Painkillers Under Attack

Opioid based pain drugs have dominated the pain relief marketplace for years but their dominance has more reflected a lack of other options than anything else. They’re quite effective at reducing acute pain but not so good at with chronic pain or with neuropathic pain.

Plus, their pain relieving capabilities can come at a high cost. The respiratory depression they can cause can result in death. They can produce a paradoxical hypersensitivity to pain and more mundane but still troublesome problems with constipation and itch. Plus there’s the euphoria that abuse causes which can lead to addiction and a host of other problems.

opioid pain relief

Opioid pain relievers dominate the pain relief marketplace but are under attack for the side effects they can cause

Plus, patients responses to the drugs vary so widely that pain medicine has been called more of an art than a science. Some people react well to one drug but poorly to a similar drug.  They may react well to one dose but poorly to another.

Citing some pretty alarming stats the CDC recently came down hard on opioid pain killer use; nearly two million Americans are either dependent on or are abusing prescription opioid pain relievers.  About forty people die every day from prescription drug “abuse” and over 400,000 people visit emergency rooms because of prescription opioid drug overdoses.

CDC director Thomas Frieden stated that “We know of no other medication routinely used for a nonfatal condition that kills patients so frequently. We hope to see fewer deaths from opiates. That’s the bottom line. These are really dangerous medications that carry the risk of addiction and death.”

With so much negative news one might wonder if opioid pain killers are on their way out?

They could be, but if Dr. Gavril Pasternak has his way they might actually be on their way in. In a recent Pain Research Forum webinarSafer Opioid Analgesics: It’s All in the Telling of the Tail” Dr. Pasternak talked about the new class of opioid drugs being developed that are able to effectively reduce pain without causing any side-effects.  At some point people in pain may be able to have their cake and eat it too.

New Pathways to Pain Relief

“The future for safer, potentially less abusable opioid analgesics looks bright” Dr. Pasternak

The breakthrough Dr. Pasternak believes is occurring began with the ability to “clone” and understand the genetic structure of the opioid receptors that dot our cells.  The receptors on our cells are the keys that unlock our cells potential.  Opioid drugs that lock onto opioid receptors in cells on our spinal cord and brain cause those cells to produce substances that reduce our pain.

Deep analyses of the genetic structure of the mu opioid receptor that traditional pain drugs interact with produced insights that may spark the production of a new kind of opioid pain reliever.

opiate receptors and drugs

Most opioid pain relievers activate pathways that reduce pain and cause side effects. Newer drugs will activate different pathways (From Dr. Pasternak’s PRF presentation)

It turns out that opioid receptor gene produces twenty different receptor types or “splice variants”. These splice variants allow a single gene to code for multiple proteins depending on which  portion of the gene is activated. Further research indicated that these 20 different receptor types fall into three classes of  opioid receptors.

These classes are based on the “signal transduction pathways” these receptors activate in a cell.  Once a molecule locks onto a receptor on a cell it activates a signal transduction  pathway which prompts the cell to act.

It turns out that most opioid drugs lock onto one type of receptor (7TM) which activates pathways which reduce pain but which also cause most of the side effects we associate with our current regimen of opiate pain killers.

The figure to the right indicates that most of the opioid drugs used activate the wrong pathways. The pathway with more side effects is in blue, the one with less side effects is in red. Notice that only two drug-receptor combinations are in red. The rest are in some version of blue.

The fact that the same drug can attach to different receptor types  helps to explain why such variable responses to pain drugs are present. If your cells happen to be littered with the MOR-1A receptor, for instance, you probably won’t have too many problems with methadone but if the MOR-1BA receptor dominates you can expect to experience lots of side effects.

A New Class of Opiate Pain Drugs

With its broad analgesic activity in thermal, inflammatory, and neuropathic pain models (5), as well as its lack of respiratory depression, physical dependence, and reward, IBNtxA may represent a new class of analgesic distinct from those associated with traditional opiates Pasternak et. Al.

new opioid pain killers

A new class of opioid pain relievers may at some point provide pain relief without dangerous side effects

The solution to the opiate drug problem that’s staring pain drug makers in the face right now is to produce a molecule or drug that targets the opioid receptors that activate the good opioid pathways. If they can manage to do that the news is very good indeed. Animal studies suggest that not only do these other pathways produce many fewer side effects but that they also appear to be better at reducing pain, particularly the hard to treat neuropathic pain.

At least three compounds have been produced, two of which are in clinical trials. The one Dr. Pasternak has developed called IBNtxA (3-iodobenzoyl-6β-naltrexamide) accomplishes a pain trifecta; it appears to be more effective against all three types of pain (inflammatory, neuropathic, thermal) than traditional opioid drugs….plus it’s side effects, with one possible important exception – are nil.

The one side effect that still appears to be present is tolerance. Tolerance occurs when more and more of a drug is needed to produce the same level of pain relief.  Dr. Pasternak said, however, that recent studies suggest that tolerance may have a ceiling; at some point if enough of the drug is provided no more will be needed to reduce pain.

Many groups, Dr. Pasternak said, are working hard to produce opioid drugs that activate these other pathways. IBNtxA – perhaps the most promising on the new slate of opioid drugs – is still being tested in laboratory animals. Two other drugs are in clinical trials.

In September 2016, PZM21 was shown in animal studies to deliver similar effects as opioids but without the side effects associated with them.  This molecule was  custom engineered to fit the opioid receptors in the brain, a feat made possible by the ability to image the atomic structure of those opioid receptors.

Opioid drugs are getting a lot of heat right now  but a different class of opiate drugs that are under development or in clinical trials now could end up spelling relief for many.


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