Could an Addiction-Proof Painkiller Finally Be on the Horizon?

New research on a drug that boosts the pain-relieving effect of opioids, while cutting their addictiveness, hints tantalizingly at non-addictive treatment options for pain patients

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A drug that enhances the effectiveness of prescription painkillers, while reducing their addictiveness and cutting chronic pain may be on the horizon, if a new line of animal research pans out.

A recent study, published in the Journal of Neuroscience, found that when rodents were given a drug called (+)-naloxone — which is a mirror-image molecule of the drug naloxone, an overdose antidote — along with opioid drugs like morphine they did not display the typical signs of addiction, such as self-administering the drug or developing a preference for the place that they received it. Such behaviors typically occur when rats and mice are exposed to the same kinds of drugs that people tend to enjoy that have a potential for addiction. When these behaviors don’t manifest, it suggests that the animals aren’t feeling pleasure from the drugs.

Most surprisingly, while (+)-naloxone blocked the high from opioids, it enhanced the drugs’ pain-relieving effect. Many previous attempts to dissociate these characteristics of opioids in the brain have failed, leading researchers to believe it wasn’t possible. But the new research suggests it is — it’s just that until now, scientists may have been looking at the wrong pathways in the brain. The new study indicates that the high and most of the negative effects of opioids, such as tolerance and withdrawal, are actually caused by immune cells in the brain — not the neurons involved in pleasure and pain.

“This is a paradigm shift in how one views drug reward,” says lead author Linda Watkins of the University of Colorado, Boulder. “All prior concepts of why drugs like opioids are rewarding, why drugs become abused, have focused exclusively on neurons.”

While cautioning that the overall significance of the findings cannot yet be assessed, pioneering opioid researcher Dr. Gavril Pasternak of New York’s Memorial Sloan-Kettering Cancer Center said that the new work “opens a new area of study and potential insights that are important.” He was not associated with the research.

(MORE: The Prescription Painkiller Experience: Less than a Third Say They Like It)

Neuroscientists tend to focus on the function of neurons, the nerve cells that are responsible for transmitting information throughout the brain. But about 90% of brain tissue is actually made of immune cells called glia, whose actions are less clearly understood and have often been considered mere “support” cells that lack important roles in emotion, perception or thought. Increasingly, however, studies like this suggest otherwise.

The study drug, (+)-naloxone, acts on glia, blocking a type of receptor called toll-like receptor 4 (TLR4), which is found on glial cells. Activation of this receptor appears to be important for both the pleasure and dependence-producing effects of opioids: when the receptor was blocked by (+)-naloxone, rodents didn’t seek opioids or become tolerant to them. Blocking this receptor also enhanced opioids’ pain-relieving power.

But while giving (+)-naloxone to block TLR4 seemed to mitigate the development of opioid tolerance and withdrawal, mice that were bred to lack the TLR4 receptor altogether still experienced some withdrawal symptoms when opioids were stopped, suggesting that the function of the receptor doesn’t fully account for opioid dependence.

Here’s how the system may work: when exposed to opioid drugs like morphine, glial cells become active; in turn, they ramp up the activity of the neurons that respond to opioids, which are critical to pathways involved in pleasure and pain, explains Watkins. When this activity occurs in a pain pathway, glial activation amplifies pain. This counteracts what the opioid is “trying” to do for pain control, she says; morphine suppresses pain by acting on neurons, but it simultaneously enhances pain by activating glia. But since the morphine suppression is typically greater than the glial activation, the drug cuts pain overall.

Over time, with continue use of painkillers, however, glia become increasingly activated — that’s what reduces the drugs’ pain-relieving effect, producing tolerance and the need for larger and larger doses.

The same holds true for the neurons involved in opioid-related pleasure, according to Watkins; glial activation revs up the neurons, “but now the neurons are in the reward pathway so you get amplification of reward,” she says. “You can think of glia as volume controls. They can dial up pain. They can dial up drug reward.”

And (+)-naloxone seems to turn glia down. Some types of chronic pain may in fact be caused by inflammation related to glia turning up pain circuits; earlier research by Watkins and colleagues has shown that (+)-naloxone can also counteract this type of pain, at least in rodents.

(MORE: Could Medical Marijuana Reduce Patients’ Need for Opioid Painkillers?)

So far, (+)-naloxone has not been tested on humans. However, another drug that blocks TLR4 has undergone early stage clinical testing for use in addiction treatment to reduce withdrawal symptoms and block the opioid high. That drug, ibudilast, is already approved for other uses in Japan.

Potentially, ibudilast or a drug like (+)-naloxone could be added to prescription painkillers like OxyContin to increase pain relief, prevent the high and mitigate the development of tolerance and withdrawal upon cessation of use. “Combinations are an interesting possibility,” says Pasternak, adding that there’s not enough data yet to know whether they would work.

Also, it is not clear whether preventing the high would hinder certain aspects of pain relief in humans. Subjective experiences of opioid use suggest that the “high” — the relief of anxiety and sense of distance from the pain — is not totally separate from the actual physical pain relief, and multiple previous efforts to dissociate the two have failed.

By itself, however, (+)-naloxone or a similar drug could be developed to treat chronic pain. “We are trying to [raise the funds to] start a company to take this to clinical trials,” says Watkins. “There is a huge unmet need for effective therapies for chronic pain.”

Of course, the long history of the quest for non-addictive opioids is one of repeated failure. Heroin was supposed to be a less addictive form of morphine, and OxyContin was supposed to be a less addictive pain reliever, too. But these new immune system connections are only just beginning to be explored — and they may open up many new possibilities for relief.

MORE: Fueled by Growing Painkiller Use, Overdose Deaths and Child Poisonings Are on the Rise

Maia Szalavitz is a health writer at Find her on Twitter at @maiasz. You can also continue the discussion on TIME Healthland’s Facebook page and on Twitter at @TIMEHealthland.


in my experience, alternative treatments for pain do genuinely work. meds are over-prescribed and the "go to" for many docs. i prefer to use alternatives for pain relief that did NOT include prescription medication. i use something topical and natural like Imbue patch, it has no interactions or complications. it works great in conjunction with massage, acupuncture, and chiropractic.


if glia are deactivated by +-naloxone, couldnt that drug also find use in treatment of spinal cord trauma? since glias are one of the reasons that prevent the nerves from reconnecting

Lyla Burns
Lyla Burns

I have known many people that have suffered from painkiller addiction. Typically it starts out with a surgery of some sort. It would be nice if there was an addiction proof painkiller out there, and many people could benefit from it. 

Curtis Mayberry
Curtis Mayberry

Wow, this is great if it truly works, helps the pain meds work better is my focus, but I do question one part of it. Why is it so important to take the high out of these drugs, I see why addiction is bad and we would all benefit from something that stops the addictive properties. What I dont get is how someone in pain cant benefit from the High part too, if your in pain your depressed and if anything the high helps reduce the pain more by making you feel good too, its more than just taking the pain away. Dont get me wrong Im all for keeping addiction rates down but I also suffer from pain and though I have moved past the whole pill popping sage of my life to stop pain, I cant say that the high part of it didnt help me get though having the pain! IDK, I just dont get that part of it, its like "we sure dont want anyone to feel good do we" seems we would want that. On the flip side Im not sure Big Pharma will like this, they would be losing huge profits if this ever came about, Big Pharma normally gets what they want so if there is less profits involved we may never see it happen, just a thought!

Marcin Cieslik
Marcin Cieslik

Glia are  not immune cells, microglia are. Stop calling yourself a "neuroscience journalist"  it is pathetic if you do not realize the difference.


All card-carrying members of the DEA need to read: Shoulda

Robbed a Bank Here is one of its reviews: 5.0 out of 5 stars... If

David Sedaris had written 'Catcher in the Rye'..this would be it, June 30,


Amazon Verified Purchase

This review is from:

Shoulda Robbed a Bank (Kindle Edition)


I have never smoked pot in my life...nor do I ever care to.

I read about this book in numerous Huffington Post comments. Thought I would

read it because I know nothing about marijuana or the people involved with it. I

am ecstatic that I did. Funny, Funny, Funny!!! The chapters are like short

stories. Stories about unloading boats with helicopters, close encounters with

law enforcement, traveling through the jungles of South America. The chapter

about the author's first time smoking marijuana made me feel like I was with

him...coughing. All of the characters were just a group of loveable, nice

guys and girls. Not what I had been raised to believe...hysterical maniacs high

on pot bent on death and mayhem. They were nothing like that. If you have

ever read any of David Sedaris' books, and like will love Shoulda

Robbed a Bank. And the crazy things happening reminded me of Holden Caufield

in 'Catcher in the Rye' and the way he staggered through life. The way the

words are put together are like nothing I have ever heard. I am sure I will use

many of the sayings found in this book just to dazzle my friends. A terrific

read. I love this book.


Roy said I am shocked that some one able to earn $8793 in 1 month on the network. have you look this(Click on menu Home)


Several years ago, I had surgery on my right shoulder. Pain medication was

prescribed..."take one capsule every 4 hours."

I took one capsule.  

I was down for over 20 hours. When I came to, I felt like I had been hit by a

truck. The next time I felt discomfort, I smoked a small amount of marijuana

...pain gone, no after effects.

I threw the pills out.

Then I wrote:

Shoulda Robbed a Bank

My contribution to helping point out just how ludicrous our pot laws truly


I hope you check it out.

D.j. Euphoria
D.j. Euphoria

It's really time to start putting these "pain management" clinics, doctors, and community licensing boards under the microscope.