A newly studied opioid compound is reshaping assumptions about pain treatment and addiction risk.
Researchers at the National Institutes of Health (NIH) have identified a powerful new opioid that could be used to treat both pain and opioid use disorder. In a study published in Nature, the scientists tested the drug in laboratory animals and found that it delivers strong pain relief without causing respiratory depression, tolerance, or other warning signs linked to addiction risk in humans.
“Opioid pain medications are essential for medical purposes, but can lead to addiction and overdose,” said Nora D. Volkow, M.D., director of NIH’s National Institute on Drug Abuse (NIDA). “Developing a highly effective pain medication without these drawbacks would have enormous public health benefits.”
Revisiting a Forgotten Class of Opioids
The researchers turned their attention to nitazenes, a little-studied group of synthetic opioids. These compounds target mu opioid receptors, which play a central role in how opioids affect the brain and nervous system. Nitazenes were largely abandoned in the 1950s because of their extreme potency.
In this study, scientists revisited these compounds with a new goal: retain their receptor selectivity while redesigning them to improve safety.
“Our goal was to study the profile, or pharmacology, of these drugs,” said Michael Michaelides, Ph.D., senior author and NIDA investigator. “We wanted to decrease the potency and create a potential therapeutic. What we discovered exceeded our expectations.”
The team began by studying a compound called FNZ, which can be labeled with a radioactive tracer for positron emission tomography (PET). This imaging method allowed researchers to follow the drug’s movement through the brain in real time.
They found that FNZ remained in the brain for only about five to 10 minutes. Despite this short presence, its pain-relieving effects, known as analgesia, lasted for at least two hours.
Because nitazenes can produce active metabolites, the researchers explored whether a breakdown product might explain the longer-lasting effect. This led to the discovery of DFNZ, another opioid described as a “superagonist” due to its very high activity at the mu opioid receptor.
A Safer Pharmacological Profile
FNZ itself carries serious risks, including suppressed breathing and a high potential for addiction. DFNZ, however, appears to avoid many of these problems.
At preclinical therapeutic doses, DFNZ increased brain oxygen levels in a steady and moderate way instead of slowing respiration. Repeated dosing did not lead to tolerance, dependence, or significant withdrawal symptoms. Of 14 standard opioid withdrawal signs, only irritability, measured through vocal responses during handling, was observed in rats given DFNZ.
To better understand its addictive potential, the researchers studied rats trained to press a lever to receive the drug. The animals did self-administer DFNZ, showing that it has some rewarding effects.
However, when DFNZ was replaced with saline, the animals quickly stopped seeking it. This rapid change differs from what is seen with drugs such as heroin, morphine, and fentanyl, where animals often continue drug seeking even after the drug is no longer available.
Further analysis pointed to a possible explanation. DFNZ increases slow and sustained dopamine release in the brain’s reward system, but does not produce the sharp dopamine spikes that help form strong drug-related cues. These cues are known to drive cravings and relapse.
“DFNZ has an unprecedented pharmacology for an opioid,” Michaelides said. “It is a potent and high-efficacy analgesic, but in certain contexts it resembles partial agonists, drugs that activate the receptor with low efficacy, which is what scientists think is needed for safety. Its capacity to be administered at therapeutic doses without producing respiratory depression is very important.”
Implications for Treatment and Future Research
These findings challenge the long-held belief that highly active mu opioid receptor drugs cannot be developed into safe pain treatments. The researchers suggest that DFNZ could be explored not only as a pain reliever but also as a treatment for opioid use disorder. It may offer advantages over existing opioid based therapies, which still carry a risk of respiratory depression.
The team plans to continue preclinical work to support regulatory approval for human studies. They believe DFNZ could benefit patients in surgical settings as well as those with cancer-related or chronic pain who require effective and reliable pain relief.
Reference: “A µ-opioid receptor superagonist analgesic with minimal adverse effects” by Juan L. Gomez, Emilya N. Ventriglia, Zachary J. Frangos, Agnieszka Sulima, Michael J. Robertson, Michael D. Sacco, Reece C. Budinich, Ilinca M. Giosan, Tongzhen Xie, Oscar Solis, Anna E. Tischer, Jennifer M. Bossert, Kiera E. Caldwell, Hannah Bonbrest, Amelie Essmann, Zelai M. Garçon-Poca, Shinbe Choi, Michael R. Noya, Feonil Limiac, Ali Arce, Grant C. Glatfelter, Margaret Robinson, Li Chen, Angelina A. Mullarkey, Dain R. Brademan, Garrett Enten, William Dunne, César Quiroz, Ingrid Schoenborn, Chae Bin Lee, Rana Rais, Daniel P. Holt, Robert F. Dannals, Lei Shi, Ruth Hüttenhain, Sergi Ferré, Eugene Kiyatkin, Jordi Bonaventura, Yavin Shaham, Venetia Zachariou, Michael H. Baumann, Georgios Skiniotis, Kenner C. Rice and Michael Michaelides, 1 April 2026, Nature.
DOI: 10.1038/s41586-026-10299-9
This research was supported in part by the NIH Intramural Research Program and by NIH/NIDA grant DA056354.
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14 Comments
Just a thought..replace the saline with sucrose H20.. there will be a different results . Today’s diet consist of many dopamine spiking ingredients that play a role on individuals ability to wean off of opioids. The condition/ health of ones G.I system greatly effects the Mu receptors duration of retiring to a pre-dependent stage.
Very interesting news,
One would have to be mentally challenged to believe that THIS time, they got it right. Opium was used to destroy empires, but then came HEROine, the work hero is in the name because it was supposed to be more manageable, which of course it wasn’t. Then morphine, then oxy, then hydro, and every single time the exact same claim on the front end “no addiction! And the manufacturers kept up the lie until the courts eventually called them out.
Insanity has a definition, and anyone who believes that this time is different fits this definition to a “T”.
lots of grey areas. I can
elaborate but why try. boomers look at millenials as pieces of s**** that dont do s*** and we look at boomers like why didnt u get a lock box u moron. For your teenagers friends not to tell them what GOLD they just found ( if not educated since elementary school- engrained ( still not a talk till highschool).
Not talking about personal experience, grew up in affluent community. my Mom needed pain pills. she had the size of a grapefruit tumor by time they found it when i was 14. I took care of her and dispensed it but knew better. never would steal her pain meds. I had no interest bc she treated me like A human. alot of parents dont. they whip/ belittle/ trash their kids bc their pissed about something. liwhy did u belt ur kids and treat them like they were not little humans. Why did you work so much as a father that you didnt notice your son was struggling right away. why dont you believe in therapy- family therapy. Why didnt you hug your kids and make them feel valuable no matter what test grade they got. Why didn’t you listen to your daughter if her tennis coaches were abusing her.
spouting off about Pharma helping manage pain is a grey area. no one wants to be in excruciating pain that is debilitating all day, theres ways to get off that werent explained earlier on. without resorting to heroin.
when its a parents job to prevent all this- get a lock box for christ sake. Speaking from millennials who would of done great things. There all dead now, most left are snobs who think saying Hi is foreign. Just like they were taught. No manners.
.BC of boomers. struggling w s***. I grew up very affluent and even my best friends Ortho surgeons father who sent his patients to pain management that was his best friend was giving patients pressed fent bc it was cheaper then real. From
Mexico. If the Saxxons or whatever the hell there name is were still around all those people wouldnt be dead.
I agree that opiods destroy lives. but no ones been more destroyed then the kids of the parents who didnt use a lock box or choose love before work/ patience before scolding, and Moms who let it happen or turned blind eyes. Reckless and of course there the ones that blame pharmacies and the friends. not themselves.
There are SOOOOO many solutions in this silent disease- still. It is shocking how many ppl on west coast were on streets when i visited Seattle. I live in Florida, maybe ppl arent dying as much- but there still overdosing just as much.
Why tf cant Older people stop belittling addicts and look inside themselves. Taking opiates is a symptom of trauma if recreationally.
Second, You want pressed pills from ur pain mgmt dr one day bc u never know. So be careful what you say and are judging about. Third. D you want China and Mexico to continue destroying the working class/ bc if you are older good for you for your social security, but my husbands paying so much and we will never see it bc our country has been destroyed by Fentanyl/ not saxxons. bc that was their intention; pharma didnt do it- Suing and making a stink about pharma did.
No one wants to
open rehabs anymore bc insurance doesn’t pay for it unless you have an amazing job.
My friend was saving lives multiple lives and closed down bc of policies made a long time ago about nonsense.
if anyone needs a formula to actually help, as in, someone has to be intelligent enough to build a career with a disease, grind, have good health care, have willpower. I know the answer. I know the answers for those who dont- but truly u have to go around the system and doctors to rly do it. aka sublocade. which they dont give u unless ur 2 weeks clean. one problem- u have to be 3 days clean on subuxone strips to even take it or feel like hell- or u microdose it. So until Drs take the risk- okay this man will die without the sublocade shot, it will not make the user sick. bc it doesnt have nalaxone. Keeping an 11 year clean user ( not dealer ) from getting a job is criminal. How can one get out. Whats the point if opiates are here or not, NEWSFLASH there here, and enoigh to kill every american twice. Opiode meds that are real. ehhh ill take it over more Drs burnt out thinking there getting something else and now are in wheelchairs.
When you live in constant pain, you will try almost anything. Yes, I’m desperate; desperate to live as pain-free as I can get.
Pain is alike to DM; it effects every part of your body. You don’t move, sleep, breathe, or function properly. You become beaten down mentally. I haven’t been on pain meds since 2018. The degrading, child-like way in which I was treated, was beyond the pale. I weaned myself off of everything, and quit “their” clinic. Only, since I was on a fentanyl patch with breakthrough pain pills, I weaned myself off in a month, not the three days they give you. The pain clinic doesn’t understand the first rule about pain: it’s never static! After eight years, I have about 20 pills remaining, for the absolutely brutal days. When those are gone, I will be also. I’m 68, educated in the medical field, and was T-boned and pushed into a tree head-on.
I refuse to let politicians decide what amount of pain meds I need, and I will NOT buy off the street. I want to know exactly what I’m taking, from a pharmacist. But since I’ve moved to either FL or TN (Both major pill-mills that gave out thousands of meds at a time, and helped create this nightmare). I refuse to be treated as an unruly child who takes too many cookies.
I’m so sorry. And I agree with what you said. Why is the government and even CDC involved in our pain control? Drs are scared to death to treat pain. So pain medication is not coming from our Drs. The problem is these meds coming through the borders and people buying them off the streets not knowing what they’re getting. Just try mentioning you’re dealing with chronic pain 24/7 to your Dr. They’ll tell you take Tylenol. I hate to see people that are in chronic pain just being blown off. It’s a proven fact that if you’re a chronic pain patient working with a DR and getting the correct medication, you don’t overdose. It’s what comes from the borders and off the streets that’s killing people. Do something about that!
I agree, but no alternative to when it does the job except be extremely mindful and careful. Use at lowest doses possible and taper off as soon as possible. I wish I had the answers for my chronic back pain but unable to have surgery. I take as much pain as I can endure and if I need one at the end of the day. I hold off until I absolutely cannot take it anymore. Crying and rocking
Doctor, I would do anything to be able to relieve the chronic pain I am forced to live with everyday. In 2015 I was hit by a vehicle doing 60 mph outside my own vehicle refilling my tank with a gas can. I broke every major bone, including my neck. My family was told to make arrangements as I was not expected to survive the night. After 3 months in ICU and 6 more in a nursing home my life has been forever changed. Medically I am considered a success, but that’s where anything resembling success for me ends. I can no longer be the successful electrician I was, Gone are the very large paychecks, the far more than I ever could need 6,000ft2 home I built largely myself, the love of my life wife, the dream car, my plan on full multi million dollar retirement by age 45. I am disgusted in myself, and how my life has become. No one seems to care that you are in incredible pain constantly, but they do seem to care a hell of a lot about how you treat it. I’m actually sorry I survived.
This is very interesting, can you expand on your thoughts on this a bit more please? I am a bit confused because I would have guessed that mixing sucralose with H20 would lead to a small brief spike in dopamine in the brain which would seem to run counter to what you are hypothesizing, but maybe I am misunderstanding you. In either case I would love to hear more on your thoughts about this topic, thanks
I really hope this is for real, it’s relieving knowing that this is actually being looked into still, kind of felt like after creating the hell that is suboxone they stopped caring. Crossing my fingers this is for real because it would be so so life changing
Even if it does work much better than anything we have now….us “little people” ..the average person won’t be able to afford it… even with so called “insurance.”
What could possibly go wrong?
In the drug and alcohol world it is being added to other drugs as a filler in illegal manufacturing.Overdose and respiratory arrest is the concern.
I had a terrible spine injury on 1/1/2003.
After medication for years I finally found a surgeon. 2 of my 4 herniated discs were “fixed”. I did however still require low-end pain relief like Tylenol 4 & Robaxin for YEARS. Finally, after years of taking them I just could not live with the side affects. CONSTANT constipation & still pain. PHYSICAL THERAPY is essential and MUST also continue at home ON YOUR OWN. You learn while going to PT & you continue to do what you can at home. Getting in & out of the car wrong can RUIN an entire day. Solution? Don’t get out of the car wrong!!
I forced myself to start walking with a cane at first 2022. That was almost 5 years ago. I still walk – started goal of 5,000 steps/day. Then 10,000, I have lost 100 pounds and it took me four solid years. My weight loss was only .3 pounds a week but I kept at it.
I have kept the weight off and the back pain at bay by WALKING. It is 2026. I still walk. I still move in the ways I learned during years of PHYSICAL THERAPY.
And it’s YOUR LIFE so do what you need to do.