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


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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.

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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.

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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.

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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.

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If tolerance develops, would drug holidays work?

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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.

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

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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.

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Ketamine infusions centers springing up.

Is that all they do?

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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.

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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.

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

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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.

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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.

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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.

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

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  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.

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    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]

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

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    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.

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    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.

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    “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.

     

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    The material on this site is for informational purposes only.

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

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

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Gliopathic Pain — when Neuropathic Pain Treatment Fails


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Coming soon, though these stand on their own:

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Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness.

Abstract

Microglia play a crucial role in the maintenance of neuronal homeostasis in the central nervous system, and microglia production of immune factors is believed to play an important role in nociceptive transmission. There is increasing evidence that uncontrolled activation of microglial cells under neuropathic pain conditions induces the release of proinflammatory cytokines (interleukin – IL-1beta, IL-6, tumor necrosis factor – TNF-alpha), complement components (C1q, C3, C4, C5, C5a) and other substances that facilitate pain transmission. Additionally, microglia activation can lead to altered activity of opioid systems and neuropathic pain is characterized by resistance to morphine. Pharmacological attenuation of glial activation represents a novel approach for controlling neuropathic pain. It has been found that propentofylline, pentoxifylline, fluorocitrate and minocycline decrease microglial activation and inhibit proinflammatory cytokines, thereby suppressing the development of neuropathic pain. The results of many studies support the idea that modulation of glial and neuroimmune activation may be a potential therapeutic mechanism for enhancement of morphine analgesia. Researchers and pharmacological companies have embarked on a new approach to the control of microglial activity, which is to search for substances that activate anti-inflammatory cytokines like IL-10. IL-10 is very interesting since it reduces allodynia and hyperalgesia by suppressing the production and activity of TNF-alpha, IL-1beta and IL-6. Some glial inhibitors, which are safe and clinically well tolerated, are potential useful agents for treatment of neuropathic pain and for the prevention of tolerance to morphine analgesia. Targeting glial activation is a clinically promising method for treatment of neuropathic pain.

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Microglia: a promising target for treating neuropathic and postoperative pain, and morphine tolerance.

Source

Department of Anesthesiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA.

Abstract

Management of chronic pain, such as nerve-injury-induced neuropathic pain associated with diabetic neuropathy, viral infection, and cancer, is a real clinical challenge. Major surgeries, such as breast and thoracic surgery, leg amputation, and coronary artery bypass surgery, also lead to chronic pain in 10-50% of individuals after acute postoperative pain, partly due to surgery-induced nerve injury. Current treatments mainly focus on blocking neurotransmission in the pain pathway and have only resulted in limited success. Ironically, chronic opioid exposure might lead to paradoxical pain. Development of effective therapeutic strategies requires a better understanding of cellular mechanisms underlying the pathogenesis of neuropathic pain. Progress in pain research points to an important role of microglial cells in the development of chronic pain. Spinal cord microglia are strongly activated after nerve injury, surgical incision, and chronic opioid exposure. Increasing evidence suggests that, under all these conditions, the activated microglia not only exhibit increased expression of microglial markers CD 11 b and Iba 1, but also display elevated phosphorylation of p38 mitogen-activated protein kinase. Inhibition of spinal cord p38 has been shown to attenuate neuropathic and postoperative pain, as well as morphine-induced antinociceptive tolerance. Activation of p38 in spinal microglia results in increased synthesis and release of the neurotrophin brain-derived neurotrophic factor and the proinflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor-α. These microglia-released mediators can powerfully modulate spinal cord synaptic transmission, leading to increased excitability of dorsal horn neurons, that is, central sensitization, partly via suppressing inhibitory synaptic transmission. Here, we review studies that support the pronociceptive role of microglia in conditions of neuropathic and postoperative pain and opioid tolerance. We conclude that targeting microglial signaling might lead to more effective treatments for devastating chronic pain after diabetic neuropathy, viral infection, cancer, and major surgeries, partly via improving the analgesic efficacy of opioids.

 

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The material on this site is for informational purposes only, and is not a substitute for medical advice,
diagnosis or treatment provided by a qualified health care provider.
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