Antipsychotic Drug Opens New Pathway To Beat Chronic Pain

Pain in Mouse Sensory Neurons

Mouse sensory neurons are shown in magenta. BH4, the molecule driving chronic pain, is shown in green. Hence, the neurons “in pain” are seen in green/white. Credit: ©Cronin/IMBA

Fresh hope for pain management from newly identified link between chronic pain and lung cancer in mice.

Although it is uncomfortable, pain is an important alarm system that alerts us to tissue damage and prompts us to withdraw from harmful situations. Although pain is expected to subside as injuries heal, many patients experience persistent pain long after recovery. Now, a new study points to possible new treatments for chronic pain with a surprising link to lung cancer. The work, which was published in Science Translational Medicine, was spearheaded by an international team of researchers at IMBA – Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Harvard Medical School, and Boston Children’s Hospital. Their findings of the research, conducted in laboratory mouse models, open up multiple therapeutic opportunities that could allow the world to improve chronic pain management and curtail the opioid epidemic.

Acute pain is an important danger signal. On the other hand, chronic pain is based on persistent injury and can even be experienced in the absence of a stimulus, injury, or disease. Despite the fact that hundreds of millions of people are affected, chronic pain is among the least well-managed areas of healthcare. To improve how persistent pain is managed, especially in light of the raging opioid crisis, it is paramount to develop novel drugs based on a fundamental understanding of the underlying mechanisms.

“We had previously shown that sensory neurons produce a specific metabolite, BH4, which then drives chronic pain, such as neuropathic pain or inflammatory pain,” says project lead and co-corresponding author Shane Cronin. He is a staff scientist in the Penninger lab at IMBA and a former postdoc in the Woolf lab at Harvard Medical School and F.M. Kirby Neurobiology Center, Boston Children’s Hospital. “The concentrations of BH4 correlated very well with the pain intensity. So, we naturally thought that this was a great pathway to target.”

Visualizing Pain in Mouse Sensory Neurons

Mouse sensory neurons are shown in green. BH4, the molecule driving chronic pain, is shown in magenta. Hence, the neurons “in pain” are seen in magenta/white. Credit: ©Cronin/IMBA

To identify drugs that reduce BH4 levels in pain neurons, the scientists performed a “phenotypic screen” of 1000 target-annotated, FDA-approved medications. This approach allowed the researchers to start their search using medications that are currently in use for various indications, and to identify undescribed, off-target analgesic properties. Among the initial findings of this hypothesis-driven search, the team was able to link the previously observed analgesic effects of several drugs, including clonidine and capsaicin, to the BH4 pathway. (Clonidine is a prescription medication typically used to lower blood pressure and capsaicin is the active component of chili peppers.)

“However, our phenotypic screen also allowed us to ‘repurpose’ a surprising drug,” says Cronin. The drug ‘fluphenazine’, which is an antipsychotic that has been used to treat schizophrenia. “We found that fluphenazine blocks the BH4 pathway in injured nerves. We also demonstrated its effects in chronic pain following nerve injury in vivo.” The scientists also found that the effective analgesic dose of fluphenazine in their experiments in the mouse model is comparable to the low end of the doses safely indicated for schizophrenia in humans.

Additionally, the screen uncovered a novel and unexpected molecular link between the BH4 pathway and EGFR/KRAS signaling, a pathway involved in multiple cancers. Blocking EGFR/KRAS signaling reduced pain sensitivity by decreasing the levels of BH4. The genes of EGFR and KRAS are the two most frequently mutated genes in lung cancer, which prompted the researchers to look at BH4 in lung cancer. Surprisingly, by deleting an important enzyme, GCH1, in the BH4 pathway, the mouse models of KRAS-driven lung cancer developed fewer tumors and survived much longer. Hence, the research team uncovered a common signaling pathway for chronic pain and lung cancer through EGFR/KRAS and BH4, thus opening up new avenues of treatment for both conditions.

“Chronic pain is currently subjected to often ineffective palliative treatments. Furthermore, effective painkillers such as opioids can lead, if used inappropriately, to severe addiction. It is therefore critical to find and develop new and repurposed drugs to treat chronic pain,” says co-corresponding author Clifford Woolf, professor of neurology and neurobiology at Harvard Medical School and director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital.

One intriguing aspect of the study is the mechanistic link between pain and lung cancer. “The same triggers that drive tumor growth appear to be also involved in setting the path to chronic pain, often experienced by cancer patients. We also know that sensory nerves can drive cancer, which could explain the vicious circuit of cancer and pain,” adds co-corresponding author Josef Penninger. He is an IMBA group leader and founding director, who is currently also the director of the Life Sciences Institute at the University of British Columbia (UBC), Vancouver, Canada. “Understanding these cross-talks is therefore not only critical for cancer treatments but might also help to improve the quality of life for cancer patients towards less pain.”

Reference: “Phenotypic drug screen uncovers the metabolic GCH1/BH4 pathway as key regulator of EGFR/KRAS-mediated neuropathic pain and lung cancer” by Shane J. F. Cronin, Shuan Rao, Miguel A. Tejada, Bruna Lenfers Turnes, Simon Licht-Mayer, Takao Omura, Christian Brenneis, Emily Jacobs, Lee Barrett, Alban Latremoliere, Nick Andrews, Keith M. Channon, Alexandra Latini, Anthony C. Arvanites, Lance S. Davidow, Michael Costigan, Lee L. Rubin, Josef M. Penninger and Clifford J. Woolf, 31 August 2022, Science Translational Medicine.
DOI: 10.1126/scitranslmed.abj1531

Funding: Harvard Medical School, Austrian Federal Ministry of Education, Science and Research, Austrian Academy of Sciences, City of Vienna, Austrian Science Fund, T. von Zastrow foundation, a Canada 150 Research Chairs Program, Canadian Institutes of Health Research, Harvard Stem Cell Institute, NIH/National Institutes of Health

23 Comments on "Antipsychotic Drug Opens New Pathway To Beat Chronic Pain"

  1. This is horrifying to me as a pharmacologist. I don’t care about the benefits — let’s look at the chemical in question.

    It’s a powerful antipsychotic — a D2 receptor antagonist. This would lead to chronic weight gain amongst patients and a general inability to feel pleasure (this IS the D2 subreceptor we’re talking about here — a key fundamental element of mammalian reward reenforcement!). You’re talking about using this on cancer patients! This also seems likely to encourage reward seeking behaviour in addicts. I just can’t see this making it through human trials in good conscience. I only speed read this, so I’ll reread when I have more time this afternoon. Perhaps there’s something I missed here.

  2. Caroline Shulver | September 2, 2022 at 10:12 am | Reply

    That is horrifying.Not only the weight gain but to shorter life expectancy. Sometimes just into 50s in previously healthy males
    So I fear this may be used on females as health problems are not so bad. But in article it states a different walking pattern. What they mean is movement similar to parkinsonism.Tardive dyskenesia if I have spelt that right. But just recommending trials for this drug as a whole.Surely there’s a slightly different better balanced drug. How they describe the b2 is affected.what they mean as poster above described. A pleasure centre not enacting .I believe it is to negatively
    affects of dopamine.So yes the reward system is affected. Correct me if I am wrong. But it would probably be used to shut patients up! Like it is used on the elderly in homes.Most times is appropriate But I wouldn’t take it.Maybe if they could turn into a local or regional injection.But I would rather stick to the morphine.

  3. This is typical in the war against doctors and effective pain management, the framing of 100,000 deaths from personal behavior as a crisis and the insinuation that it is due to prescription meds. 90 percent of opiate overdose deaths are due to clandestine labs manufacturing illegal fentanyl and carfentanyl. The other ten percent are mostly people taking prescription originated opiates prescribed to someone else and taking those opiates in a manner against medical recommendations. So if we ended all effective opiate pain treatment and recommended people see quacks for non FDA approved pain treatment, quacks who will stick needles all over their body or suggest meditation or counseling, then we could stop ten thousand overdose deaths. Then deaths from suicide would rise, otherwise functional people are no longer able to go to work, and millions live in pain and have lower quality lives, for what? To save ten thousand lives of people who deliberately chose to take opiate prescriptions inappropriately? Is the cost to everyone else worth that?

    • It’s a shame that people that genuinely need pain pills like cancer patients have such a hard time getting them because they’re so tightly controlled. People should have to be informed by a doctor of the risk of addiction before they’re prescribed pills, though. Why penalize the many people that need to be prescribed strong pain medication because of the few that abuse them.

  4. Wow weight gain when this is world changing, how scary lmfao

  5. Joseph Rietdorf | September 2, 2022 at 7:22 pm | Reply

    We need to leave well enough alone
    I’m talking about opioid medications! Because these wonderful pain medications have been abused is no reason to try and get rid of them! They have worked for me for 6 years and I tried everything! Without Oxycodone, I’d be bound to my bed or couch! As it is now I can still stay somewhat active while remaining healthy from doing things that would be impossible for me to do without them. So please everyone, stop messing around with our wonderful pain killers!

    • Opiates are the most effective pain medication. Until something more effective is found, I don’t see any reason for the many people that need them to be punished because of it the few that don’t that abuse them. The crackdown on opiates has hurt more than helped by driving some that are addicted to pills to use heroin as a substitute.

  6. Julia, Caroline and Joseph all have good points.
    Using potent phenothiazines(Prolixin/fluphenazine)poses problems of their own. Another is akathisia, a drug-induced restlessness that is a hellish sensation. A danger here is that doctors might insist on using these drugs
    instead of REAL painkillers, with the intention of using non-addictive drugs.
    This fear of addiction is overemphasized because of all the fentanyl deaths. We can blame edicts from the federal government for planting the fear of prosecution into the minds of doctors and pharmacists when they are judged to be over-prescribers/fillers of opiates. This causes doctors to cut back on the needed opiate drug doses which results in inadequate pain relief. People in pain can be driven to buying opiates on the street and end up dead because there is no way to determine what actual drug they are buying or its potency. So, in a misguided attempt to stem opiate addiction(mainly among that percentage of opiate-prescribed patients that increase their doses on their own), the government has driven them into the arms of street dealers and often to their deaths.
    As is often the case, government
    interference made a problem worse by creating another problem.

    • You’re absolutely right, dead on. Why make people in pain suffer because somebody who didn’t need the pills chooses to get high on then. It went from doctors prescribing oxycontin like candy to being hard to get in a few years, after everybody had already got addicted to them. Cancer patients and seriously injured people shouldn’t have to suffer with no effective medicine because somebody else abused it.

  7. You said that “improper” use of opioids lead to severe addiction. As a person who is 7ft. Tall and 300 lbs heavy i was in a severe accident and tore my back severely. I have 8 discs impinging on my spine and have severe pain i would rather have not taken opioids but the pain is debilitating only by taking opioids “properly do i get a liveable existence
    Im on pain management but i know im addicted. I would still not want that drug but as the doctors said my pain is like suicide type pain. But i still wish there was a way. There is a drug called. Talwin XL with naloxone that isn’t addictable but insurances wont pay for. They would rather pay for opioids.

  8. I am a person with chronic pain and take oxycodone . First I’ll say I am addicted to it and that is a horrible lifestyle.
    So for the second statement I have on it is it has helped me physically function much better. I push through the pain with it . Another odd side effect is it makes me feel like I am super intelligent. So instead of suppressing and creating depression and thoughts it’s a increased my awareness. So maybe it could be used as an antidepressant drug . I have completely changed my whole outlook on life for the better since my doctor started me on oxycodone . I started a business from nothing after an injury on a job and two poorly executed shoulder surgeries. I’ve excelled in a field that’s hard to break into and be accepted also . The drug has opened up my mind and gave me confidence I’ve never had and I feel superior in intelligence to most everyone I’m working with. This is working with people that have trained in this field for decades.
    Without the drug my mind seems to work totally different in a cloud. But I also had so much pain I could barely step up onto a curb . I’ve lived a very very active lifestyle in extreme type sport’s injured often . As of 8 weeks ago I just broke my pelvis and sacrum . I crashed on a mtn bike on a technical downhill . I was alone and had left my cellphone at home , which I never do and will never again. I had to crawl out for help and luckily I was only a half mile into the course. It took me 6 hours to crawl a half mile an inch at a time . If I didn’t get out I’d have probably died of hypothermia , so it was a must to get out .
    The oxycodone has helped me through many mishaps and the chronic pain I live with. I am 59 years old and many years of very hard work and lifting. It’s a drug I hate because of its addiction and love because of how it lifts that cloud off my brain and also takes away the pain .
    It’s a catch 22 type drug . Taken properly it helps .
    I’ve found out the way it is given by most doctors does not work. It lasts approximately 3 hours. So I take a smaller dose every three hours. The 6-8 hour intervals leave a patient in pain for all the hours in between and then the bodies addicted Jones for the drug . I believe this starts peoples journey into the illegal world.

  9. Pain is a given as we age. When it gets to the level of 8-10 on a daily basis due to inflammation, arthritis, auto immune disorder, sports injuries, chronic back pain, any body pain . We are looking for QUALITY, NOT QUANTITY OF LIFE!! Stop denying anyone over 45 access to opiates. For God’s sake! Do we need to grow out own poppies? Do you need to control everything? Science changes daily. Doctors suck. I’ve never asked for pain meds but with psoriatic arthritis and trigeminal neuralgia and back pain, I better not be lumped in with drug addicts!

  10. When you’re in severe debilitating pain as I am in constantly, you will do just about anything to get some kind of relief. The pain mgmt offered is a joke. How is it the researcher’s have found so many cures for quite a lot of diseases but aren’t even close to finding anything for chronic debilitating pain or for the disease of addiction? I’ve come so close to committing suicide because my pain is so bad & nothing helps.

  11. Troy Phillips I was reading your comment about opiates & the effects. Your last paragraph about how doctors prescribe. It makes me wonder if you are taking oxycodone immediate release. I have taken oxycodone extended release every 8 hours for a long time & always did very good. Then, because of the opioid crisis & all of the lawsuits with the manufacturers, I could no longer afford the copays, which jumped up to $600 per month. I asked my doctor to switch me to the immediate release, which cost just penny’s & found that they do not come anywhere to working as well as the extended release. You are right, they only relieve my pain for 3 hours! I am now doing what you do taking much smaller doses every 3 hours & spreading them out for my daily dose. Basically trying to duplicate the extended release. The method is working better for my pain, but still not as well as the extended release. I am taking the same dose amount as the extended release. The reason I am bringing this up to you is if you are NOT taking the oxycodone extended relief, if you can afford to, you may want to try them. They work better & you are not having to spread your daily dose out! Just a suggestion because of my experience! I totally agree with you about the way oxycodone brings out our brain & intellect awareness! I noticed this right away. I am an older woman & the pain medications from 50 years ago I did not care for at all! I was thankful for them after a surgery but it felt like I was living with a “drug hangover”, foggy cloudy brain all of the time that I had to take them! The 1st time I took the oxycodones, what a huge difference, no more of the old pain medication symptoms! I could be “alive” & functioning just like I was before having to take any pain medications! Good Luck & I hope you are feeling better after your latest accident! Very scary to be in that situation with no help!

  12. Been in cronic pain for years no one cares you all are a joke

  13. Robin L Lindahl | September 4, 2022 at 12:58 pm | Reply

    I have been living with extreme pain for many ailments that only opiates relieve along extreme social anxiety all well documented and I have no alternative as I don’t do alcohol or weed can’t handle the effects but I due to people who od, ie can’t handle their meds or are forcd to use heroin laced w/fentynal, I am given option of anxiety medication or pain medication when for decades, received both and lived a normal existence. Now, I suffer as so many millions of barely holding on life to because of idiots who make ridiculous decisions/laws, when they themselves are addicted to some forms of relief including opiates because they have good insurance and money.. pot calling the kettle black syndrome.
    These citizens and lawmakers have no idea that we are all individuals and people with disabilities in need of opiates and nothing else WORKS. I CALL BULLS*** ON YOUR NEW WAYS OF HANDLING 100’s of different pains relieved easily by clean opiates.

  14. I do sympathize with all the pain patients. We should march(or however) on Washington and some testify before Congress.
    Hopefully there would be some physicians with chronic pain among the group.
    I did not realize the degree of pain that could be suffered until
    seventeen years ago when lumbar spinal degeneration caused neuropathic pain(sciatica). In the ER I was given large doses of morphine to no effect. I was horrified, fearing living(or not)with this pain. A neurologist prescribed Neurontin(gabapentin) and told me that it may or may not help. As the dose was increased gradually I began to sense a reduction of pain until I reached the maximum dose of 3600mg. per day. My pain is about 95% gone and although there are side-effect trade-offs I know I would have jumped off a bridge without it. There are instances where some people are using Neurontin to augment the effects of opiate use so it is now a quasi-regulated drug but fortunately not like Schedule I drugs are.

  15. I Had an accident at WORK. I Was a CARE-GIVER For the DEVELOPMENATALLY DISABLED. I DID ALL the Food Shopping WASED CLOTHES CLEANED the HOUSE & Took The 2 WOMEN I Cared for ON ALL THEIR APP. In MY Car. One day the 1 with DOWNS SYNDROME ASSUALTED ME. IT WAS HORRIBLE… My FOOT Was Where I Incurred the ORIGINAL INJURY Because it WAS-IT CAUSED My BODY TO TRY & COMPENSATE SO I HAD TO WALK DIFFERENTLY-WHICH THEN CAUSED “*MORE INJURIES*” My foot was Black(nothing broke)I HAVE HAD BACK SURGERY & HAVE A DIFFERENCE IN TEMPERATURES BETWEEN MY LEGS-INJURED FOOT & LEG IS 8 DEGREES COLDER. I ALSO HAVE HIP PROBLEMS. BECAUSE OUR BODIES ” CAN HEAL THEMSELVES ” My BODY SCREWED ME..I USED TO Jump in my car & go Anywhere& Everywhere I HAVE NOT BEEN ABLE to DO *ANY* of What I USED TO. I CAN ONLY DRIVE 15-20 MINUTES the PAIN I LIVE WITH IS EXCRUCIATING EVERY MINUTE OF EVERYDAY. EVERY1 HAS THEIR OWN OPINIONS ABOUT OPIATES/PAIN-KILLERS If I DIDNT GET THEM *I WOULD HAVE COMMITED SUICIDE A LOOONG TIME AGO.* Living (if that’s what you Call it)WITH CHRONIC DEBILATING PAIN I DONT WISH ON “ANY1″NOT ONLY ARE YOU Dealing with injury PAIN BUT YOU LIVE WITH WHAT YOU**CANT DO ANYMORE** ITS H O R R I B L E It’s Been 22 years living with THIS & it gets WORSE EVERY YEAR. I,ve BEEN ON Soo MANY DIFFERENT MEDICATIONS ITS RIDICULOUS 99% of the meds were OPIATES. I WILL LIVE LIKE THIS For Whatever TIME I HAVE LEFT ,I’m 68 NOW.. So in PLAIN ENGLISH THEY TAKE My OPIATES AWAY I PROBABLY Will lock Myself in my House & NOT DEAL WITH ANOTHER HUMAN. It REALLY ..IS THAT BAD. IN LONG RUN THEY N E E D to REMEMBER WE ARE HUMAN BEINGS WITH DREAMS-WISHES-HOPES & WE FEEL HAPPINESS & SORROW LIKE EVERY1 ELSE. GIVE US the PAIN RELIEF WE NEED OR FIND IT..PERIOD-STOP LOOKING DOWN ON US IF YOU Think WE LIKE THIS
    YOUR DUMBER THEN A BOX OF ROCKS….

  16. I have said for many years, if I could developed a pain medicine that did what morphine does without the addictive side effects, I could become a trillianaire.

  17. I am a retired Law Enforcement Officer and i suffer from radiculaphy in both legs after surgery in low back because a doctor hit a nerve. I am also a retired Correctional Officer and due to my job i had to do things that injured my back. I go to pain clinic and take hydrocodone APAP10-325 which barely helps and due to laws they say they cant give me more.I also suffer from Arachnoiditis which there is no cure. I had a previous doctor who gave me morphine and kadian which helped tremendous but they say they cant go up anymore.I wished they would change things and develope a pain medicene that would work without so called side effects. You would not believe all the people arrested because they started out with severe pain but it got bad and hooked them to find it on streets.I better shut up and get off. Good luck everyone.

  18. I was prescribed antipsychotics for insomnia as sleeping pills didn’t work. Big mistake taking them as the side effects ruined my life literally. Shame on these devils for using them on innocent people for pain. God does not forgot you!

  19. I was recently hounded by phone by pain management to try a new research drug. I follow my gut and never responded. Mostly because the way I am treated at the visits. I have no history of drug abuse (but my sister through no fault of her own did become an addict / hip dyplasia) I’m sick and tired of being put in the same catagory as someone drug seeking. This whole problem is so annoying.I almost DIED due to a drug interaction prescribed to me to avoid gibing me opiates. A pharmacist SAW me having a reaction and saved my life. IF YOU SUFFER FROM CHRONIC PAIN
    LIKE I DO..TRY “KRATOM” it is because of this leaf, that I have not needed any pain pills and it has given me my life back. Just dont mix it with tramadol I’ve heard. It stops opiate withdrawl dead in its tracks for heroin users etc. I have continued to see my Dr. and have not experienced ANY negative affects for 7 yrs so far. I am healthy. Its 2022 we need to stop using the frankenstein method of using chemicals and LISTEN TO THE PEOPLE WHO SAY THEY HAVE THE ANSWER TO ABUSE AND PAIN. God bless and I hope this helps someone.

  20. I did not read every comment because I just woke up. lol
    But I did want to thank Julia Voets and Kevin. My sister became an addict. She was born with hip dyplasia which went unchecked as a baby.When she hit her early 20’s her bones began to harden and it caused her an incredible amount of pain. She was too young to get hip surgery…so they kept her on pain pills for YEARS,with ever increasing doses. Finally when her time came for the surgery…she could not be weened off the opiates.I have read opiates cause a chemical change in the brain. After being THROWN OUT of pain management, my sister, who had always been terrified of needles, was now shooting heroin. Non of my siblings,now or ever would of ever become addicts if not for the medical profession themselves initially dropping the ball on checking my sister as a baby. CUTTING PEOPLE OFF of pain pills is only helping to create a lucritive black market and costing lives.I think they should LEGALIZE THE S*** so it can be given in controlled doses, so people can function enough to stop stealing from others, find gainful employment, etc. Otherwise..addicts live on our streets, spending their entire day looking for another “score”. Do I like that idea. NO. However it might be the only solution to saving addicted people who made a mistake and cannot find a way out…and several other lifee xperiences

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