Ketamine & Opioids Stop Working – TOLERANCE – the body no longer responds no matter how high the dose




The comments below on ketamine tolerance apply to its use either for intractable pain or major depressive disorder. I have written about ketamine several times since April 2009. Tolerance means the medication no longer has an effect. If ketamine is to be needed for decades to come, we don’t have more than 10 years experience with repeated use to understand if and when it will stop working for our patients.


Tolerance to ketamine is a growing potential as more infusion centers open each year.

Infusions are being used at fixed dosages

that are often too high or toxic

and predispose to tolerance and loss of efficacy.


I’ve seen two cases of ketamine tolerance since about 2009 among persons with Complex Regional Pain Syndrome (CRPS). And the neuropathic pain of CRPS responds differently than other pain syndromes. We are all snowflakes, not one of us is alike another. But CRPS is unpredictable in many ways, and very predictable in others. It is also more dynamic and capable of being reversed in many who have it.


Ketamine is given usually IV in a few centers in the country for CRPS and for Major Depressive Disorder. I prescribe it either via nasal spray or under tongue. I may, later this year, offer IV infusions to a small number of my patients who need both.


If tolerance develops, would drug holidays work?


Some people develop tolerance to their medication. In the old days, when I was training in the 1970’s, Parkinsons medication over time would stop working. Our only recourse was to do an inpatient drug holiday for weeks. We had to stop the drug. The resting tremor, the constant flailing, was exhausting and life threatening, especially if you had a heart condition. Newer Parkinson’s drugs completely circumvent this.


Would drug holidays work if tolerance develops for ketamine or is it a goner forever?


Opioids can cause tolerance through a known mechanism. They produce inflammation that causes more pain. Higher and higher doses fail to help pain. Addicts seek the high they once felt but cannot capture. This is why addicts die, chasing the impossible. Detox. Drug holiday. In the case of addiction, many are placed on Subutex, an opioid that acts on two opioid receptors and seems to prevent craving, in part at least because it has such a long half life that the blood level never dips.


Ketamine infusions centers springing up.

Is that all they do?


NIH and Yale began to test IV ketamine infusions in the 1990’s for major depressive disorder, and Robert Schwartzman, MD, at Hahneman in Philadelphia was one of the early ones to infuse ketamine for CRPS and contribute a large body of research on this pain.


But in the last 2 or 3 years I receive a growing number of mailings advertising ketamine infusion centers. Just that, nothing more. Ketamine infusion centers, not pain specialists. All these young anesthesiologists popping out of training every year have a cash pay business; insurance doesn’t cover.


Will ketamine stop working for patients who need to use it regularly for decades and decades? We don’t know. It should be studied.


The first patient I saw with ketamine tolerance, I referred from San Diego to Professor Schwartzman in Philadelphia. She received inpatient IV around the clock for one week, then outpatient IV boosters every month. After eight months, she stopped responding. That’s when I called him to ask what to do? He did not know. So I used glial modulators. I posted her case years ago. She is in her 70’s, pain free since 2010, and two weeks ago, as a volunteer for the Red Cross, she supervised RN’s and evacuees from the flooding at Oroville dam. Tens of thousands of people, emergency care for families and homeless.


A recent patient has had more than 20 surgeries in her hand that has CRPS. She has failed  IV ketamine, opioids, propofol given together in ICU for weeks and weeks. Surgery triggers the glia to produce neuro-inflammation.


Another case though unusual, also posted years ago, a young male athlete, bedridden with CRPS affecting almost entire body. Flew to Professor Schwartzman 9 times and each time, the relief was gone by the time they reached the airport. He was taking opioid medication that may have been impossible to offset.


This is what I advise when I prescribe ketamine for my patients to use at home as a nasal spray or sublingual:


  1. Do not use it with opioids.Opioids cause inflammation, ketamine does the opposite. It modulates (reduces) inflammation.

  2. Never use it alone. It is a glial modulator, it is not only an NMDA receptor inhibitor.

  3. For intractable, treatment resistant cases, use as many glial modulators as you can.

  4. Ultra low dose naltrexone (20 micrograms TID) can profoundly reduce tolerance in patients on opioids: they may now need 1/2 to 1/8th the dose of opioid that simply had never quite done enough. Naltrexone not only relieves pain, it may profoundly improve function.

  5. Opioids stimulate glia to produce pro-inflammatory cytokines -> pain. Stop opioids if you can. You are likely to get far better results with glial modulators, especially if you have CRPS.

  6. Pain specialists should be offering a trial of glial modulators before they choose opioids for life.

  7. Use glial modulators as needed: ketamine, oxytocin (a hormone), tricyclic antidepressants (weaker than the others but can be profound for some), metformin.

  8. Metformin, a glial modulator!  for pain! in people who do not have diabetes. I will be posting on it this coming week — inshallah

  9.  Use it sparingly. Whether ketamine or opioids, use sparingly because of tolerance.

  10. If it is a good day, use less and use sparingly. If pain spikes, use higher dose, use sparingly.

  11.  When tolerance develops to ketamine, what then?

  12. Is it possible that a drug holiday would work? Should that be in months or years? we may never find out.

  13. Use ketamine and/or opioids sparingly. Prevent tolerance. You may not always need the same dose on a good day or when pain spikes.

  14. Make sure you are doing other things to relieve pain, not just ketamine or opioids.

  15.  Dextromethorphan helps, a sigma I receptor antagonist that reduces the excitotoxic glutamate

  16. Try as much as you can to exercise.

  17. Lift the mind to positive things. Learn to block thoughts of pain, dissociate from that. Choose life and doing and being.

  18. Develop momentum. Try never to judge; that includes being hard on yourself and others.

  19. Expand your spiritual life. Find your path if you don’t already have one. It may begin for all sorts of reasons, but figure it out. It’s real. Spiritual giants from all paths have had direct perception of the infinite in many ways and forms. Direct perception.

  20. S-ketamine clinical trials are now ongoing in the US. I was very disturbed to hear the side effects of S-ketamine infusion related last week. S-ketamine deeply disturbing. It is wrong to give everyone the same dose of ketamine. Not once have I ever heard anyone recount similar side effects from ketamine infusions. I got the impression from her they were not inclined to attribute it to S-ketamine, but it would be disturbing if they did not. Ketamine’s dose no matter how you give it is idiosyncratic, meaning some respond to 2 mg, some to 400 mg. It is wrong and should be unethical to subject someone to doses 200 times the dose they may need. It is dangerous and promotes tolerance.

  21.  If you’ve been stuck in bed, branch out and vary the things you do. Find music and poetry and literature. Maya Angelou suffered yet her words make you soar. Check out James Baldwin in the Oscar-nominated documentary “I Am Not Your Negro.” Baldwin’s immensely powerful analysis deconstructs movies, not as a mirror, but as a window into the imaginary; and how movies shape our thinking. As a movie critic, his writing is about poverty, class and “not everything that is faced can be changed, but nothing can be changed if it is not faced.” …  “There are days — this is one of them — when I wonder, how precisely are you going to reconcile yourself to your situation here…” So many writers fail to teach us how to analyze and think with such clarity. Something we don’t always do. We need to train ourselves to become critical thinkers. Baldwin brilliant mind demonstrates critical thinking at its best.

    Critical thinking is not a partisan issue. Tens of millions will lose jobs as robots rapidly take over in the next 3 years. Industry will reap more than ever in history. We all need to rethink our lives at some point.


    Dylan’s song is about “the possibility that the most important (and least articulated) political issue of our times is that we are all being fed a false picture of reality, and it’s coming at us from every direction.”[10]

    “Propaganda, all is phoney,” Dylan says in “It’s Alright, Ma (I’m Only Bleeding).”


    Advertising signs that con you
    Into thinking you’re the one
    That can do what’s never been done
    That can win what’s never been won
    Meantime life outside goes on
    All around you.








    Public Warning:

    Ketamine is a controlled substance.

    Administered improperly, or without the guidance of a qualified doctor,

    Ketamine may cause injury or death.

    No attempt should be made to use Ketamine

    in the absence of counsel from a qualified doctor.




    “Off label” means ketamine is FDA approved for another purpose, decades ago it was approved for anesthesia. In qualified hands, ketamine is one of the safest medications we have in our formulary.



    The material on this site is for informational purposes only.


    It is not legal for me to provide medical advice without an examination.


    It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.


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    If you wish an appointment, please telephone the office to schedule.


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4 Responses to “Ketamine & Opioids Stop Working – TOLERANCE – the body no longer responds no matter how high the dose”

  1. Alex Says:

    Two cases of tolerance in 8 years prescribing ketamine is a small number. In most cases are you able to keep patients at the same dose?

    • Nancy Sajben MD Says:

      Research is needed for long term followup.

      Ketamine was only available in a handful of places when I began to prescribe 16 years ago and many follow with their local MD’s in other countries or states. Now thousands are being treated regularly.

  2. Sara Says:

    I am a veteran with Systemic CRPS for 29-yrs. I have had to fight to get the VA to pay for and provide ketamine-infusions for me. I found in 2009 a Dr who took insurance and also had been using ketamine since late 1990s for pain. I was able to use TriCare then. Over time many places are refusing to take insurance or TriCare sadly, hence my fight to get the VA to pay for it. Currently 7 VAs are providing ketamine infusions, for CRPS, pain and a few for mental health reason as well, but only for their veterans within their “40-mile treatment radius” as those VAs put it, sadly. Three VA s have done the RSDSA’s Surgical protocols for major joint replacements but have told my VA they will not do it as I do not belong to their VA.

    The new VA Sec Dr D Shulkin basically took up my case, and when the VHA Under Secretary for Health and forced my VA to get my last ketamine infusion with a well renown Dr who has had great success and speaks for RSDSA as well. After treatment earlier last month my pain went from 9 to off the charts at times to 0-1 the CRPS pain that is. That Dr and his other Drs and PA, NP, and RN all agree to utilize the RSDSA Surgical procedure of ketamine before, during, and afterwards especially for major joint surgery as I do required a total knee replacement and now hip replacement.

    Now I am told by my local VA I cannot get anymore ketamine infusions as someone in WashDC VA Executives thinks ketamine will kill grey matter and is unproven. Untreated pain kills the body and kills grey matter! Now being forced to go to another location 1600 miles for 75-miuntes, was told would see 5 people over 2-days, not true when called for appointment. To see if I have CRPS AGAIN, my 7th time in the last 8 years, let alone since 1991; let alone if ketamine is safe for me AND for all veterans in the VA System and active-duty they way the conversation was related to me.

    I am afraid for others too not just me. I appreciate all that you have researched let alone put on your website for all to learn and read!
    IF you can help on any cognitive research you may have on ketamine especially, that would be great you can send it to Jim Broatch Dir RSDSA , so he can forward it on to the VA Sec Dr Shulkin (who I honestly do not think knows this is going on! and to others there.)

    Thank you,

    • Nancy Sajben MD Says:

      I have likely tagged the word “neuroprotective” to more than one post on ketamine. Hopefully among those you can find a good link to publication.

      I run into ignorance constantly, all glial modulators not just ketamine. I don’t like the odds when a patient such as one of mine last week, pain free the first time in 40 years since encephalitis coma, CRPS RUE, RLE, with fibromyalgia, and anaphylaxis to every known medicine for epileptic seizures including phenobarbital, as well as benadryl and prednisone.

      Try to explain to university docs that ketamine is the only drug in the world that can stop seizures when all others failed, including the otherwise lethal seizures from organ-phosphate pesticides. Anti-inflammatory.

      Ketamine is neuroprotective. Look at its ability to block the glu-NMDA receptor. Without that, the hyper excitable glutamate floods the receptor channel with calcium. That kills cells, causing brain atrophy and memory loss demonstrated in those with major depression and others with chronic lumbar pain.

      Opioids cause inflammation. We ought to be treating many conditions with glial modulators that reduce inflammation. Conditions such as intractable epilepsy in Italy shown to respond to glial modulators that reduce inflammation. Yale with NIMH showed that inflammation in depressed rats. I’ve posted on that within 2 days of publication in the fall 2 or 3 or 5 years ago.

      Opioids are the only drug offered. It’s up to doctors to care to figure things out. But so far the tools used are 50 years old.

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