Why Do Opioids Cause Itching?

Why Do Opioids Cause Itching?

By Staff

Opioids are an important part of pain management for both acute and chronic pain.  Opioids can cause side effects, and one such side effect is itching.

Scientists have been trying to find out why certain side effects occur with the hopes that they can create modified opioid painkillers.

Scientists believe they have found a receptor protein on the surface of mast cells that can trigger the immune system and lead to itching.  The protein is MRGRPX2, and it was identified by researchers at the UNC School of Medicine, who published their findings in the journal Nature Chemical Biology. 

“Receptors in mast cells - part of the immune system - respond to an activation signal and release inflammatory factors like histamine, in a process called degranulation,” said Kate Lansu, the paper’s first co-author and a graduate student in the lab of Bryan Roth, MD, PhD. “When that happens, other cells are recruited to the site of inflammation to clear the infection. This response is also important for things like allergies. And this is what presents itself as itching.”

“Opioid drugs have been linked to degranulation also, but it was through an unknown mechanism. We think that our data could potentially explain why degranulation occurs as a side effect of opioid ligands (morphine and other drugs), something that is well-known but not well-understood.”

The findings are significant not only because they offer a potential explanation for opioid-induced itching, but also because the data suggest a way to characterize the function of the orphan receptor MRGRPX2.
A media release from the University of North Carolina School of Medicine continues with the following information on the study:

Currently there are about 120 orphan receptors in humans. They are “orphan” because, though we know they exist, we don’t yet know what they do. The Roth lab screens these receptors against thousands of small molecules to find out what might activate them. This process involves a combination of physical screening and computational modeling.

“We start with the physical screening data to give us a sense of what types of molecules interact with the receptor,” Lansu said. “Working on MRGRPX2, I screened around 7,000 molecules, and that data gave us a sense of what the binding site might look like. Once that tentative picture was in place, we were able to use computational tools to create a more precise model of the site.”

The computer modeling, performed by co-first author Joel Karpiak, a graduate student at the University California at San Francisco, tested 3.7 million models for potential interaction with the receptor.

“And that’s so many more different types of chemicals than I could do by hand in an assay,” said Lansu.

The physical data combined with the computational models allowed the researchers to create a chemical probe designed to interact specifically with MRGRPX2. This new tool made it possible to gain a more precise understanding of this receptor’s effects without the noise of other receptors. An opioid might activate the orphan receptor, but it might also activate other receptors that it interacts with.

Imagine trying to recreate a musical score by listening to an orchestra perform a piece of music. “You hear the whole ensemble play and you might think ‘this is very moving’ but it may not explain much about how that effect is achieved,” Lansu said. “But if you had a tool that allowed you to isolate just the trumpets, for example, it could teach you something about how that part contributes to the whole - something you may not be able to hear otherwise.”

Understanding what triggers the itching response could help pharmacologists develop an antagonist for this receptor to reduce the itching side effect. In other cases, clinicians may want to induce histamine release, thereby boosting the immune response, as in the case of vaccine adjuvants, where an increased immune response may improve immunity. These findings suggest there may be a way to do that selectively.

The researchers will now move onto other orphans. There are four receptors in the same family as MRGRPX2, and Lansu hopes to find chemical probes that can interact with each one.

She also emphasized that work like this would not be possible without the cooperation of a wide variety specialists.

“This kind of work speaks to the importance of collaborative sciences because you have modeling, you have pharmacologists doing in vitro experiments and you have chemists making stepwise changes on the molecule. And all of these specialists working together makes findings like these possible.”

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Candice Hawkins

My son had bilateral foot surgery at 2 yrs if age for Rocker Bottom feet. It was to facilitate his ability to walk. We as his parents were ectactic that he could finally walk, not normal, but walk. As a nurse I should have known what the outcome would be when he grew up. At 28 he developed osteoarthritis due to the manipulation and pinning of the talus and navicular bones during that surgery. He was put on Darvocet due to such horrific itching from opioids. As we all know Darvocet was taken off the market after 50 years due to the cardiac problems that affected 1000 people in 70 years. We were at a loss. My son became couch ridden. It was devastating. We finally found a pain doctor who felt my son might be able to take Oxycodone with less itching. My son is allowed 2 tabs a day and along with that he is given Vistaril or Dihydramine. At 30 years of age he can no longer go for medium length walks, work in our family garden, play with his dog or work. He gets less than $400 from the govt since he hadn’t worked long enough to build up Social Security. He is learning disabled which went hand in hand with his foot deformity. Due to that he doesn’t have a concept of pain control or pain tolerance.
I’m still baffled with the lack of the use of Marijuana (he did try it once and it helped the itching and pain but due to urine tests I forbade it) for medical use here in Texas and if we didn’t need my husbands job that pays well in this area I’m sure we would move. Even though I am a 20 yr survivor of chronic pain I too am only allowed 2 Oxycodone tabs a day and would gladly take my sons pain from him and bear it myself. As I too am affected by opioid itching I seriously believe that more agressive itching problems can be a genetic predisposition.
Of course this is just my theory but it does seem to follow through with reasonability.

Jean Price

Tim…Yes, so many medical…and non medical…people have bought into ALL the scare tactics and the deceitful statistics and the unscientific and ridiculous rhetoric about opioids! For the life of me, I STILL just don’t understand why!! But then, I also don’t understand why addiction centers have such a poor rate of really HELPING people recover…those who are addicted to street drugs who routinely go back to drugs! Nor do I understand why our doctors haven’t stood beside us in this craziness!!

I do hope people will read this book…I’ve read excerpts and heard many good things about it! Yet more than this…I hope they will have their eyes opened to the TRUTH…and WILL realize that banning and reducing ALL OPIOIDS ACROSS THE BOARD IS JUST PLAIN IDIOTIC! And THIS will accomplish ABSOLUTELY nothing for those addicted, nor decrease overdoses, since they are USING largely ONLY illegal street drugs!! And THEY ARE NOT those in physical pain!

The only possible outcome of all this is the horrible and inneccessry devastation caused to the lives and wellbeing of those with persistent daily pain! ITS ALREADY IN FULL SWING! And affecting their families, too! As this all begins to impact more people with acute pain or post surgical pain…those who don’t routinely take opioids…perhaps there WILL BE AN OUTCRY THEN! Yet it is already too late for so many, those who are no longer with us because they could endure NO MORE OF their tortuous, UNTREATED pain!! God help us all! This is like a never ending nightmare! And until many more speak up, with s united and powerful voice….we are left to take to our beds IN PAIN…and lose the little functioning we may still have left!

It will very likely take some time to regain what we’ve lost in the way of treating ALL pain! Coming back from this road that led us to the Dark Ages in pain care will not happen overnight. How many more will we lose? How many more will not be able to climb up out of the dark place they are living in now? And all this for WHAT, exactly? For the sake of money and power and greed and control…and WITH TOTAL lack of compassion and common sense!

This isn’t me being negative…it’s me being realistic, and continuing to see this darkness spread! Every day! This book may well be a light in the tunnel…yet it must be read and understood…and change must happen before anything positive will start trickling through! A tough place to be in for so many who are hanging by their fingernails NOW, isn’t it!?! So tremendously sad!

Ben Aiken Longfellow

Medication side effects with MANY medications do and will occurr. Does the benefit of the med outweigh the side effect? Can the side effect be more efficiently dealt with than the underlying cause for the medication? Pain causes a world of problems and hardships but, the chronic pain community deals with them because PAIN is hard to overcome and have any kind of a “normal” existence. I witnessed the ongoing CDC war on the “opioid epidemic” on CBS morning news Friday March 1st. The statistic presented on CBS was the “overdose” rate with opioids ( did not distinguish between heroin, illicit opioids and prescribed opioids) and the suicide rate. I did not see the beginning date to present the statistic represented. A line graft picturing the overdose rate had in fact fell below the suicide rate with sharply,still falling overdose rate. The suicide rate at about the same point in time had SHARPLY rose and was still SHARPLY rising. Now, does the CDC see the overdose rate falling as a victory on the “opioid epidemic”? What about the suicide rate sharp increase? I, as a long time prescribed opioid medication patient see what is happening. It has been thought and wrote that good people in chronic pain would in fact seek to end their continuous severe pain if sufficient opioid medication was dammed up to all Americans. Is suicide an acceptable option to chronic pain due to the rise in overdose? Is this how government sees the situation. WE ( the gov) will not enable you to kill yourself with medication but, if you do it own your own (do to insufficient prescribing of opioid medication for pain) we(the gov) have no control over that? I maintain neither is acceptable but again the misguided effort from the CDC sees suicide over sufficient medication as a better end! WHY does the DEA or branches thereof not attempt to govern the illicit opioid intake and distribution OVER prescribed opioid medication that ACTUALLY helps people? I, along with MILLIONS of other non cancer chronic pain patients have NEVER re-distributed my personal medication that has enabled me to earn my living for 23 years? I, with millions of other patients have broken no law. I with others have acted in a responsible, manner with opioid medication. I have ALWAYS known that opioid medication was NOT a right to receive but, it was there, prescribed by educated physicians, following a previous protocol of prescribing and has helped with……life. Illicit opioids on the other hand only seem to be addressed after the fact of being imported into our country. Arrests. Overdose. Jail. Bad records for people in regards to law. Chronic pain patients can do without illicit opioid medication. A funny thing. Methadone “clinics” in my part of the country are STILL very much active and should be. They are NOT being tempered as much in “prescribing” methadone as our trained, educated, physicians prescribing opioid medication for chronic pain..A human life span without disease causing pain,… Read more »

Tim Mason

Hi Jean,
I am reading a new book by Lynn R. Webster M.D, “The Painful Truth”
Its a good one. Let me quote from her introduction for all the millennials and the anti-opioid group:
“”Even if you don’t currently have pain or know anyone close to you that does….this book is still for you. It will open you mind and heart to the number-1 health problem in America [pain].
It will make you better able to respond to others’ pain or your own when that time comes—and it will” end quote.
I can just see the mid 30 group of non-pain professionals now focused on “itching” and never seeing far enough around the curve in their own lives or momma or daddy’s life to understand.
One day they will realize how naïve they were….

Sandy M.

I’ve never had any itching with an opioid medication. However, I’ve only taken one kind and never had any itching, nor any other problems. I’m not saying there are some people who may have itching or other side effects. There are many side effects with many different medications, even Ibuprofen. I can’t take Codeine, so it’s indicated on all my records and I don’t take it.

Judy J

Pain relief VS itching/constipation……..seems like a no brainer to me.

Tim Mason

Although not an opioid, this medication produces a serious itching, rash side effect not see with opioids.
I think opioids were singles out because they are considered “News Worthy”

What are the possible side effects of diclofenac transdermal (Flector Patch)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Although the risk of serious side effects is low when diclofenac is applied to the skin, you should be aware of side effects that can occur if the medication is absorbed into your bloodstream.

Stop using this medicine and call your doctor at once if you have a serious side effect such as:
•chest pain, slurred speech, problems with vision or balance, and feeling weak or short of breath;
•bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;
•fever, chills, body aches, flu symptoms;
•pale or yellowed skin, dark colored urine, confusion;
•swelling or rapid weight gain;
•urinating less than usual or not at all;
•nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
•skin rash, bruising, severe tingling, numbness, pain, muscle weakness;
•fever, sore throat, and headache with a severe blistering, peeling, and red skin rash; or
•the first sign of any skin rash, no matter how mild.

Tim Mason

Opioids are chemical molecules. Almost all SDS (safety data sheets) for chemicals list “irritation” as an effect if one come in contact with said chemical. Some are acute and some are chronic.
Aspirin,( acetylsalicylic acid ) is an irritant and effects the stomach when swallowed, You just can feel it in your gut, However, once hydrolyzed and entered the blood stream it too can cause itching.
Nothing to worry about here.
Even water has a lethal dose.


Excellent article and one that I needed to see! When I first started using opioids years ago…my nose and neck itched all the time! Eventually it went away.
But, I think there are more companies are making them now and the itching is back! Recently it was out of control on my arms only. I know for sure it is my med. I’ve often wondered if others itched also. Thank you for posting this info.

Gary A Stoklosa

I was prescribed Hydroxyzine and experienced sleepiness too. But after taking it for a few days the drowsiness diminished and finally stopped.

Jean Price

Hmm, I haven’t heard of this supposedly common effect from opioids ever before! Maybe I just haven’t been listening closely! I’m wondering if anyone else here reading this has heard of this!? It seems to me many people who have pain also have autoimmune diseases, and I wonder if this would cloud the issue somewhat…and if there actually isn’t as significant an issue with itching from the medication, but rather just itching from the underlying medical conditions!

All in all, I think research about itching and our complex body responses in itself is great…I just have to wonder why this is “useful” in relation to opioids!! Or is this type of research possibly the beginning of saying opioids cause many immune reactions…and therefore shouldn’t be used!!? I really hope not…I’m guessing most of us would much rather itch than hurt…IF we itch at all!! I suppose I could be just overreacting…yet it’s hard not to, in this current climate of negative press about opioids!!


People do have allergies to all types of meds not just opiods, this can include meds for blood pressure, antidepressants, antiseizure meds, and the list goes on. Kind of a trial and error with any meds. Just like when people find out they are allergic to a medication. Wish everyone would redirect off of opiods and deal with your real drug addicts and that are those on the street. Your herion and cocaine users along with illegal recreational users. Everyone is always trying to find some way to make it all about opiods these days. Pain patients are real not addicts…. All pain meds do not cause itching. The only one I can’t take is codeine. So guess what don’t take it.

Carla Cheshire

I live in Florida and have been having a great deal of problems with insect bites. Fleas, no see um’s, and mosquitos. I get bit and it becomes like a welt, super-itchy and then of course I scratch it and have a wound. It seems to take weeks for these bites to heal. Doctor prescribed Hydroxyzine 10mg but it made me so sleepy I almost fell asleep standing up! I thought it was because I had cancer years ago and my white blood cell count is lower. This article has me wondering if this is not somehow related to use of opioids for chronic pain.