Novel Research into Opioid Tolerance May Provide Future Pain Relief with Lower Levels of Pain Medicine

Novel Research into Opioid Tolerance May Provide Future Pain Relief with Lower Levels of Pain Medicine

bigstock-Painkillers-97670Many readers of our readers remember a time early in their chronic pain history when a low-dose opiate, like codeine, relieved a majority of their pain. When I was first diagnosed with degenerative spine disease, I was treated with a low-power opioid medication that is no longer in use – Darvocet-N with 30mg of codeine as needed for breakthrough pain. The Darvocet (containing the opioid medication propoxyphene) was highly effective in reducing my neck and shoulder pain by 75% on average, and one or two Tylenol #3 tablets easily handled any breakthrough pain. That efficacy against pain lasted for years.

Medicine has a term for people who obtain a great deal of pain relief from an opioid analgesic. These people are said to be opiate naïve, and in those days, I was opiate naïve.

Being opiate naïve is a good thing. It means that mild, moderate, and even severe pain can be controlled with low and safe levels of opioid analgesics. One reasons physicians are reluctant to start a patient on a long-term course of opiates is to maintain this state of naiveté, as opioids are the tried and true tool for controlling the pain of trauma and serious disease in medical practice.

As my disease progressed, my pain increased. My medication was adjusted, and when Darvocet no longer worked, my medication was rotated to 60mg of codeine four times a day.

Here’s where the story becomes both complicated and a mystery. To this day my doctors cannot say whether my pain increased due to the degenerative course of my cervical disc disease, or whether the Darvocet stopped being effective against pain because of changes in my nervous system through a process known as opiate tolerance.

With years, my spine continued to deteriorate at multiple levels and as MRI technology because available the degree of cervical and lumbar spine degeneration were revealed as severe. My pain increased and I was prescribed larger doses and rotated to stronger narcotics to control that pain. This process of climbing the opiate ladder of tolerance to the strongest pain medications available in our pharmacopeia occurred over many years, and today my doctors and I struggle with many treatment modalities to manage my pain while keeping my opioid medications as low as possible. I receive, at best, a 25% reducing in pain from my opioid analgesics now, and am disabled with pain.

Long term or chronic opioid therapy (COT) usually follows a course parallel to my journey, and long-time chronic-painers know that eventually their narcotic s will become less effective at managing pain, and they will require larger doses, opioid rotations, or more invasive treatments like nerve ablation or even surgery to achieve analgesia.

Opioid tolerance is hell on earth for chronic-painers and the practitioners who treat them.

Scientifically, opioid tolerance not well understood, but is known to be a property of our complex nervous system. There are many theories regarding how opioid tolerance suddenly “switches on” with COT and why it lowers the efficacy of opioid analgesics used against chronic pain. There is a long history of research on tolerance filled with the mind-boggling esoterics of neurophysiology discussing various molecules, proteins specific to the nervous system, the role of astrocytes and glial cells, neuroplasticity intrinsic to neural tissue, and the myriad other actors relative to research in this field.

Until recently, all research in this area has been performed upon rat subjects, as the methods of research involve inducing pain, treating with large dose opioids, and examining neural tissue through dissection and other means. Certainly no human being would be willing to submit to such a process.

But in a recent study published in Anesthesiology, researchers at the National Taiwan University College of Medicine have identified a specific neural protein directly related to human opioid tolerance.

According to the Department of Anesthesia’s Dr. Chih-Peng Lin, “We found that CXCL1, a protein produced by spinal cord tissue, contributes to opioid tolerance. By neutralizing CXCL1 in patients, we might help solve the problem of opioid tolerance.”

The landmark Taiwanese study was the first to examine tolerance in both humans and rats. Dr. Lin and his colleagues found elevated levels of the protein CXCL1 in both human cancer patients receiving COT and rat subjects deemed opioid tolerant. As part of this study, rats injected with CXCL1 in the epidural space exhibited an acceleration of the onset of opioid tolerance.

Dr. Lin said, “By suppressing opioid tolerance, we can help patients achieve prolonged pain relief without the side effects of increased opioid dosages.”

While this finding is far from being a cure for opioid tolerance, it may be an important piece of the puzzle in solving the causal relationships between chronic pain, COT, opioid tolerance, and opioid induced hyperalgesia, a rare paradoxical finding where treatment with opioids increase pain in some subjects. Eliminating opioid tolerance is an essential achievement in our initiative against pain.

Imagine a world without opioid tolerance, where long-time chronic pain patients maintained on COT can achieve more effective pain control with lower and safer doses of opioids, while new chronic pain patients who respond well to opioid therapy can receive those same benefits for as long as needed.

EDITOR’S NOTE:  Kurt W.G, Matthies, is a columnist for the National Pain Report.  He lives (and writes) in Colorado. The kwgm at Lake 12National Pain Report is interested in hearing your experiences and thoughts.

The information in this column is not intended to be considered as professional medical advice, diagnosis or treatment. Only your doctor can do that!  It is for informational purposes only and represents the author’s personal experiences and opinions alone. It does not inherently or expressly reflect the views, opinions and/or positions of National Pain Report or Microcast Media.

Authored by: Kurt W.G. Matthies

newest oldest
Notify of
Kurt W.G. Matthies

I can dig it, LouisVA. I’ve been very fortunate — many people in pain are having a difficult time receiving even minimal pain support with opiates.

And if opioid tolerance can be treated, we’d be getting better pain relief — maybe 50% or more — on a lower dose.

BTW, I do know of Dr. Tennant. He is very well known in the pain community. I know of his work with central pain syndrome, and I’m familiar with his writing. He’s the Editor of Practical Pain Management —, a good source of information for all pain patients and practitioners.

Thanks for your contributions to the Report, and best wishes.


Kurt, I apologize re my comment to ‘Onlinegames.’ It never dawned on me that English may be a second language for this person.

You said “While COT is not the only treatment for chronic pain, for many of us, and that includes me, it is the most effective part of our treatment regimen. For many, COT opens the door for other treatments — I could not get out and walk without my COT, and walking daily helps reduce my pain levels by 10-20%, and is the only treatment that helps relieve the chronic muscle pain that is associated with my degenerative spine diseases.”

I am in agreement with you that opioid treatment has totally changed my life for the better. Like you, if I pace myself, I can do things that I haven’t been able to do for a long time and walking is one of those things. B4 treatment, I was housebound - now I feel like I can participate in life.

Kurt W.G. Matthies

Thank you for your comments. Please, let’s not pick on onlinegames. I suspect that he or she may not be a native speaker of English. If you read his post carefully, I believe you’ll find meaning in his post. I know that many of us have learned to deal with lower dosing (sometimes down to zero dosing), and have experienced the increased pain of withdrawal and under-medication. While COT is not the only treatment for chronic pain, for many of us, and that includes me, it is the most effective part of our treatment regimen. For many, COT opens the door for other treatments — I could not get out and walk without my COT, and walking daily helps reduce my pain levels by 10-20%, and is the only treatment that helps relieve the chronic muscle pain that is associated with my degenerative spine diseases. I’ve lived with pain and pain treatment for over 30 years, and so have experienced many of the changes in attitudes in the medical treatment of intractable non-cancer pain that have occurred during this dynamic period in pain medicine. I have witnessed and thought a great deal about the pushback against the use of opioids we’re experiencing today in treating chronic pain, and plan to write a future column to bring together the many factors that have led to this pushback, in the hope that we may all benefit from a better understanding of the current battleground that is pain medicine. It is one thing to vent our frustrations with what we feel as an apparent lack of compassion toward people in pain, however, emotional venting about what we perceive as unfair and sometimes just plain foolish rarely helps us identify the problems we face as pain patients, and contribute to the discovery of sensible solutions. The days of Howard Beale asking you to go to your windows, throw them open and yell, “I’m mad as hell and I’m not going to take it anymore,” are gone. Recently, I saw the great 1976 film, Network. While the film remains great in many ways, and is almost prophetic in it’s vision of the evolution of network news, it is dated — nailed to the mid-70s period of protest and revolution in which it was made. One reason that we’re not being invited to the negotiation table is perhaps due to our tendency to vent our frustrations instead of using our intelligence to study and analyze the barriers to achieving adequate and effective pain control. We too often come at this issue from the emotional side. I’m often guilty of this approach, myself. I imagine this is because we’re the one’s feeling the pain. However, it is far more effective to understand the factors that have created the current adversarial situation that now occurs daily between doctors and their pain patients. The government agencies that monitor disease now label the use of opioids for the treatment of chronic pain as “an epidemic,” because 40,000 Americans die each… Read more »


I must agree with rk’s assertion. ‘Onlinegames’ appears to be playing online games, lol!


This is to “online games”your message made no sense r u drunk lol

Unquestionably believe that which you stated. Your favorite justification seemed to
be at the net the easiest thing to have in mind of.
I say to you, I definitely get annoyed at the
same time as other folks think about concerns that they just do not recognize
about. You controlled to hit the nail upon the highest and defined out the whole thing with no need side effect , other folks can take a signal.
Will likely be again to get more. Thank you


it’s the same deal with us hyper people and narcoleptics who have been on higher doses of amphetamines and were fine but all of a sudden “Adult ADD” comes along and they cut doses down and everything and can be life threatening with a severely hyper or narcoleptic. A hyper person would jump off a bridge for the fun of it but die not knowing the outcome or a narcoleptic could have an attack behind the wheel.


I have been on opites for 15years and they work fine for me I started on 5mg hydocodone as I climbed the opites latter I waited until I couldn’t take it anymore more then at the end of the gambit of pain meds I was put on methadone which was intended for pain and it has been working well for the past 5yrs with great results and have only had to up my dose once during the trial at initial starting date I wish all the best for you out there that are having problems with cronic pain I know how it effects every aspect of your life good luck
Rev. Smith

I am 79, spinal cord injury in 1989, then Spinal Meningitis. Pain chronic and worse every day. Then 2201434 fell and severely tore both shoulder rotator cuffs and they are so bad they are inoperable. I haven been on almost every pain med they make and am allergic to most. I have a high tolerance to pain and my pain level is so bad I can hardly stand it
I heard of a device called “Neuralumin”, ap0robed by the FAD, Medicare and other insurances will pay. It is supposed to stop or at lease reduce chronic pain. I am in process of acquiring one. It would behoove the national pain report to check on this for all its readers

Brenda Alice

Great article. Unfortunately I am one that has been on narcotics for 15 years. My tolerance of course is high and my pain is poorly controlled. The newer long acting expensive narcotics have not worked well for me. Kadian is one unbelievably expensive medication but did nothing for the pain. I recently had one nurse comment about the 75mg of morphine being a huge amount and I could not believe it. Not to mention that I was almost crying from pain. I so wish that someone will realize that one dose does not fit all. Thank you for writing.

Karen Zaccagnini

This is a very interesting article and I really hope that something good comes out of that study. I suffer from chronic pain and have been on opiods for at least 8 years now. Last month, when I ran out early because instead of a dose of 1 pill, I went to 1 1/2 pills, then 2 when that didn’t work, I decided that it was time to quit. I stopped cold turkey and dealt with the week of Hell that comes along with it. The medicine was not working for me for pain relief and the only reason that I was taking it is because it made me sleep or because it made me not “care” about the pain so much.

I am in a LOT of pain right now, and nothing over the counter touches is, so I stopped trying. Now, I feel like I just have to either deal with it, or go back on the Opiods whenever I can’t stand it any longer. The one positive that I have had since I went off of my medication is that I don’t feel like “I’m in a fog” or “stupid”. I hope that they are able to come up with something that can be taken long-term that actually helps.

The first decade that I was sick, short-term opiates worked, but around the 10 year mark they didn’t. I then went to a pain clinic where they put me on the horrible ‘opiate of the 90’s(apparently no side effects, addiction etc. Oxycontin! They now know it kills people(on CNN). I definitely have a tolerance, in other words nothing works! I am currently weaning off of suboxone..personally I think my ‘opiate brain receptors are fried’, and somehow I am going to have to live on nothing. But who know’s what will happen in the future, perhaps a cure, some new break-through

d hancock

Hello Kurt, thank you for your informative article. I have severe pain from trauma for 24 years. I am in mid forties young. You have described my pain medication path. First was prescribed antiinflammatories and panadeine ( panadol and codeine) then became ineffective and then codeine with digesics. I had pethadeine for uncontrollable pain . for twelve years I have been on opiates with one adjustment about a year ago when manufacturer changed.

Every little bit of education and good news is important.
Some questions: Are other drugs and chemicals affected by this? Can it be reverse engineered to control pain signals?

The sensitivities (to all things) seems to be a huge factor with chronic pain. I, myself, was able to use mental exercises on myself, like self-hypnosis and placebo effect. I practiced meditation and active meditation, self-talk training, relaxation techniques, positive reinforcement training, etc, etc. (What else do I got to do!) and found them to be about 50% effective. I take 3 pain meds which I’ve been on for 4 years now.

The only time I had sensitivity problems was when some shi_head from the DEA decided to “help” me by cutting my morphine in half. Upset the whole apple cart. It took me 6 months to level things back out.

Anything that would be helpful to getting people off of their crazy notions about drugs, sensitivities, addiction, dosages, taking them properly, I guess - education… would be great! I am a member of the “under-treatment ” of pain group! Someone in charge doesn’t seem to get the word “epidemic!” Remember, we are adults, we can make our own decisions, it’s our life…help us to live well, don’t tell us HOW to! And above all, keep us informed! Thanks Kurt.


I am sorry your opioid is not very effective. I have had problems with spinal and now neck pain for 40 years ( yes, I am old.) I have lost more than 2 inches in height and it is said that my spine is crumbling. I have been on every opioid and my Dr and I settled on one. I have had epidurals that did not help very long. I wake up in the morning and have a dear husband that does everything. I am hanging on. I read a lot, am on my PC, and I watch a little TV. I am grateful for the life I have and my memories. I wish they would find a better opioid so I could have a better life with my family.

I have diggenerative disc disease and have had two neck surgeries , two back surgeries and as of now need two. Ore back surgeries. I suffer on a daily basis. I had my second back surgery 5 weeks ago and they have me on oxycodone 20 mg which does not touch the pain… I’m i. Agony 24/7 and they will. to give me anything stronger. I have three more herniated discs that need to be fixed and severe spinal stenosis. I am at the point I am going to go to emergency because I can no longer handle the pain and I don’t know what to do

Mary Ellen

As a chronic pain warrior myself, I know a lot about pain tolerance. My doctors and pharmacists and family all have developed tolerance for my pain! It’s the “so what? You’re always in pain.” Attitude that burns my toast.
After being on doctor ordered OxyContin for five years, I took myself off.
It was hell, but I couldn’t think on it and felt like I was walking in jello. And people stole my meds and broke into my house. When the detective told me to go live in a nursing home this ADAPTer had to act.
No health insurance meant I had to not go to the hospital. I doubled up on blood pressure med and muscle relaxers. I envisioned life better and the pain was amazing and auditory and visual holucinations (I can have it but not spell it) were entertaining. They actually made me know I was going to make it.
My doctor didn’t think I could do it because he had never heard of it or seen it. I got myself off and, of course, still had treatable pain. I have been on low dose Percocet for years.
And I have a huge blessing. A bone previously fractured and healed “backwards” only hurts when my brain wants more. So, I learned to take myself off just the Percocet for a few days to reset my pain. I’m 61 and this has worked for me for 8 years.


Hello Kurt,
I have read your article with great interest because I am on opioid therapy and am taking the same dose for 4.5 years and have never needed an increased dose. A little background – I had a lot of pain as a child then it let up during my mid-teens, presumably when the growth & sex hormones kicked in. The pain returned in my early 20s (early 1970s) and of course could find no real help. I was diagnosed with fibro in the 1990s and by 1997, the pain was suicidal. I found some local doctors that would treat with small opioid doses but was still in agony. Finally, I went to a nationally known pain specialist, Dr. Forest Tennant (see: He found by genetic testing that due to a genetic defect, I am a poor metabolizer. Not being afraid of opioids, the good doctor started slowly titrating me upward until I was comfortable. Now, I am on an ultra-high-dose therapy (2000 mg. morphine equiv. per day) and since age 60 to present (age 65 next month), I have enjoyed the highest quality of life since adulthood. The most remarkable thing is I have stayed comfortable for 4.5 years on the same dose that he initially titrated me to about 4 and a half years ago.


I already have this issue and im only 40 and been on opiods for about 7 years so im in for a life of hell as my dr wont up my dosage either he just did last month and already after a week of new stronger meds it stopped working,i believe these drug companies are maning the meds much weaker and wish someone woild come out w a test so we can know for sure as i tested some of my old drugs on friends who felt nothing from some of them too.