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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    This site is not for email and not for appointments.

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

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    For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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    Please IGNORE THE ADS BELOW. They are not from me.

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Pain Much Better off Opioids


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Patient disabled with CRPS/RSD markedly better after off opioids. The intense nerve pain began in his left ring finger eight years ago, not the dominant hand. Now he has pain everywhere below the neck. He has been bed-ridden for years.  Now his “bones feel like ice, freezing from the inside out and shaking.”

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Had been on Fentanyl patch 100 mcg/hr for years. Dose was lowered to 75 mcg/hr, then his pain specialist did an involuntary taper off in two short weeks. Both of those doses are far higher than the new CDC guidelines from 2016. Fentanyl is 100 times stronger than morphine.
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He says his pain is feeling much better off the opiates. He is quite surprised. On Fentanyl 100 mcg/hr patch, he rates his pain then as 6 to 8 on scale of 10.
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Pain is now  2 to 4 off opioids the last 3 to 4 weeks. Even the hands are not hurting as much..

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Initially after the abrupt taper, he spent 7 days in bed, then says he “started getting out a little bit, now hands are not hurting as much. Neuropathy even isn’t hurting as much.”

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I have seen several patients who said opioids caused pain, all over the body in places they never had pain before or since.

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Yes, clearly many are helped by opioids. But many are simply afraid to taper off. I understand this. The question then is, what will we do to treat pain? Most doctors have nothing else. Patients rightfully fear stopping opioids.

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We need to understand there is outstanding science that demonstrated years ago that opioids cause inflammation in the CNS (brain and spinal cord). Inflammation causes pain.

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Treat pain with glial modulators that relieve inflammation in the brain, neuroinflammation. These are off label and most of them must be compounded. Compounded medications are not covered by your insurance — thanks to pharmaceutical donations to congress.

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Cannabis (medical marijuana) can help some with spasm, pain, insomnia. Also not covered by your insurance — thanks to pharmaceutical donations to congress. But patients in New Mexico were able to get insurers to reimburse them for the cost of their medical cannabis.  Congress should allow dispensaries free access to banking systems and allow insurers to directly pay the cost for medical use. We all know the emperor has no clothes. Lets be real. Pain leads to desperate measures.

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Let me say right now, to all those who will send in comments attacking science, attacking me, attacking my clinical experience (my patient reports) on opioids, I will not post your attacks on these pages. I do prescribe opioids to select patients. I strongly believe all pain should be treated initially by glial modulators that relieve neuroinflammation before we begin causing pain and inflammation by ultimately having nothing else to turn to and then prescribe opioids. There is no better solution because pharma wants you on a drug for life. That’s money in the bank, forever, every single month for decades. It’s awful.

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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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This site is not for email and not for appointments.

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

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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Please IGNORE THE ADS BELOW. They are not from me.

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PeaPure – Palmitoylethanolamide for Nerve Pain or Migraine


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PeaPure is a glial modulator. It is available in Italy and the Netherlands as a food supplement and has been studied in multicenter clinical trials in Europe for several years. It is well tolerated with no side effects and is very helpful for neuropathic pain, headache, and osteoarthritis. It is anti-inflammatory and neuroprotective.

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Because it inhibits astrocyte activation and the over-expression of pro-inflammatory molecules and signals, it is being investigated in Alzheimer’s Disease.

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The mechanism of action of PEA was discovered in 1993 by Nobel laureate Rita Levi-Montalcini in her work on nerve growth factors. She found it is involved in metabolism of mast cells and published a series of papers on its self-healing effect of the body in response to inflammation and pain. Two recent publications from Jan M Keppel Hesselink, MD, PhD, and his colleagues at the Institute for Neuropathic Pain, Amsterdam, The Netherlands, describe case reports, one of which is the case of a woman with CRPS.

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The purpose of this post is to clarify dosing of PeaPure and how to take it for a sudden flare of pain. My apologies for failing to recall the source of these instructions which I believe was from the manufacturer and from here and here. The latter includes an excellent review of its mechanism.

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Description of PeaPure® 400 mg capsules
PeaPure® is a food supplement based on a natural and fatty-acid like compound.
The substance palmitoylethanolamide (PEA) is a physiologically active molecule that the body produces naturally.
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What the user should know prior to ingestion:
•    There are no known significant side effects.
•    PeaPure® can be taken simultaneously with other medicine. In case of doubt, it is recommended to first consult your doctor or a pharmacist.
•    Use during pregnancy is NOT recommended.
•    PeaPure® does not contain sugar, yeast, allergens, sorbitol, magnesium stearate, povidone or other ingredients.

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Dosage and administration – please refer to the manufacturer.

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UPDATE SEPTEMBER 2014

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It is with a heavy heart that I report this news:

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Palmitoylethanolamide is

now available only from the Netherlands,

sold as PeaPure, a food supplement.

  It is no longer able to be imported by a pharmacy, but we are hoping

that may change if we can interest a supplement manufacturer to make it available for the US.

Patent rights, attorneys are far beyond the resources of my local pharmacy.

 

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I have published this year, 2014, on the treatment of

vulvodynia and proctodynia with PeaPure and a topical cream.

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There are no studies to show us how often it may relieve nerve pain, but it is astonishing when it works. No toxicity, no side effects. Your brain makes it, plants make it. There is a growing literature on it and I have posted on some of its mechanisms. And in particular, its Anti-inflammatory, Analgesic, Neuroprotective Mechanisms.

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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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Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, please telephone my office or contact your local psychiatrist.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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RSD, Complex Regional Pain Syndrome – a case report


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Severe Pain for Three Years,

 80% better in 10 days

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“This has been life altering.”

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This is a very bright young woman who was an all state volleyball player until onset of Complex Regional Pain Syndrome three years ago in the right hand and wrist. It began after blood was drawn from the hand for a chemistry study and, one week later, the fingers turned black, lost blood flow, followed by emergency surgery for removal of a blood clot from the back of her hand. She woke after surgery, tearing the sheet off due to intense pain on light touch — that is called allodynia — and then developed severe edema from the hand to the shoulder.

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It was four excruciating weeks before the diagnosis of complex regional pain syndrome was made.

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CRPS or RSD is a diagnosis that every MD,

every surgeon, every ER doctor,

every psychiatrist and psychologist, every nurse and therapist should know how to diagnose.

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Because she was a minor, they would not do nerve blocks.

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She developed contractures of the fingers and hand,

was unable to move the fingers.

  A major university hospital diagnosed Munchausen Syndrome;

mom was diagnosed with Munchausen’s by proxy.

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This happens so often. This is 2012.

If it’s not the doctors,

it’s the insurance companies

creating roadblocks to diagnosis or treatment or both.

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Why is pain management not taught at medical schools?

Only 3% of schools today give 30 hours instruction in four years, Yale most recently.

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At a major university hospital two hours away, she failed to respond to 14 stellate and brachial plexus blocks. But the wound reopened by itself, the stitch fell out. The psychiatry department evaluated her after she was so drugged with methadone, she does not even recall the interview. They diagnosed Munchausen Syndrome. That changed everything. Relationship went sour. Distrust of MD’s began and was confirmed many times in many places along the northeastern corridor and Texas.

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That fall, she became a student at the university of her dreams. The diagnosis of CRPS was confirmed at their university medical center hospital where they wanted to continue the same blocks that had failed. Elsewhere, the chief of a renowned ivy league university pain service wanted to talk to her only about spinal cord stimulators, declined by the family.

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In May 2010, she qualified for an NIH study of neurotropin double blind 6 weeks on, 6 weeks placebo. Failed.

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She was seen by Dr. Schwartzman in Philadelphia October 2011, and sent from there to NYC to rule out neuroma dorsum right hand, negative.

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On Lyrica, she gained 20 lbs, then back to 130 lbs baseline when off of Lyrica. Intolerance to Morphine – hives, Duragesic – total body itching. Ambien – hallucinations, Lunesta – hyper. Benadryl helped somewhat. Detoxing from Nucynta – lips were bright red.

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Her weight dropped from 130 to 115. Many medications were trialed and failed. Marinol helps pain slightly and gives the best sleep in years, better appetite. It does cause anxiety, but she had not slept in three years, and it gives 4 to 6 hours of good sleep. She developed sharp bitemporal headaches. I advised headache is a side effect of Pristiq —- now thankfully discontinued and better.

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Since August 2011, she has had CRPS pain in the right leg, worse walking, weight bearing.  There is discoloration of the dorsum hand usually, at times along proximal forearm, recently at right foot and leg. She had edema up to the shoulder measuring 30 cm. Nails growth faster at the right hand, possibly less hair growth right hand. Temperature usually cooler on the right hand, at times at night the hand and foot become hotter. No change in sweating noted.

The first year, she had almost total loss of function in the hand with pain and contractures —and forced herself to move the fingers with OT and PT, then home exercise. She still has days when the fingers remain flexed, but 98% of the time there is full movement as she continually tries to use the hand/fingers to write and type. Nose may become ice cold and tingly since CRPS spread to right side of face and right lower limb. At times tingling fingers. She struggles with memory when pain is severe and with lack of sleep.

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Pain ranges 7 to 10, average 8. Edema was significant for one year, now comes and goes. Allodynia is present hands and feet, now a different scale than before when she could not even be in the car.

However, with weight bearing and walking, pain of the right lower limb became most intense.  She will be 21 in July, but on a bad day was unable to leave her bedroom to walk downstairs as pain was too severe. She would communicate with family by loudly calling or texting. It was unthinkable to make plans for the next week due to severe pain. She has osteoporosis with atrophy of the right upper limb, and has had color changes and edema of the hand.

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She lives in an eastern state inland, two hours away from the mid Atlantic seaboard and major medical center. She failed ketamine infusion at a major university medical center on the east coast. The cost and inconvenience was significant and the family did not know that ketamine may fail to have any effect if taking opioid analgesics. Once mom discovered that, she was able to wean off the opioid medication. Ultimately, after many more interventions, much later, in crisis, she did benefit from IV ketamine infusion, and was able to regain some movement of her fingers on the right hand, but there was no lasting relief. It was a struggle to obtain approval through her insurance.

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She has been spending a great deal of time in bed for months. Morning stiffness is widespread for one to two hours. Bending is difficult, feels as if “hit by a bus,” but she does stretching, moving, distraction and Yoga when able.

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Much better in 10 days

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Day one: pain of the entire right side, face, trunk, limbs, rated 7 to 10 on a scale of 10, average 8. She guards the dominant right hand and the signature is difficult. Atrophy of the right upper limb is present, nails longer on the right hand, dusky dark erythema and long jagged scar over the dorsum right hand, mild erythema of the right upper and right lower limbs.

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On the first day, in the office, she tried the first dose of ketamine nasal spray and after a repeat dose, she was puzzled, thinking to herself, then let us know she realized she was able to concentrate. A small dose is not enough to relieve severe pain, but even major depression can vanish at that dose. Two sprays relieved the brain fog of depression; pain was still 8 on a scale of 10. Blood pressure and pulse did not change before and after doses. She felt hopeful.

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In the next few days she was able to do the unthinkable: make plans with friends, walk 45 minutes, become active, and remain active in a way that had not been possible. She was far more active with much less pain.  Over the weekend, six days after she arrived, after we had sequentially added several new medications, she found the dosage of nasal and sublingual ketamine that worked for her. She has actually had times when she was pain free. As noted during prior ketamine infusions, she requires a far higher dose than most patients to achieve effect. The plan now is to use higher doses at home when time permits for best effect, and booster sprays of nasal ketamine as needed when away from home. She can carry it in her pocket. There is no need for ICU infusions and the fight to get insurance coverage for those stays.

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Of great significance, she has even made plans for the entire summer.

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More details of her case will be added, as time permits. For now, this page is here to allow the patient and family and others to send comments. She will continue slow titration of other medications that will take three months before reaching the target dose, before we can assess efficacy. Based on my experience treating chronic intractable neuropathic pain including CRPS, it is possible these medications will be able to stabilize and relieve pain without ketamine.

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See other case reports of treatment of CRPS here, here, and here.

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You can read some of the science of pain, glia and inflammation. Ketamine is significantly anti-inflammatory. Three of her new medications are glial modulators. Treatment of severe chronic pain usually involves rational polypharmacy, not one medication and not medication alone. It requires a holistic approach to heal: P.T., O.T., massage, cognitive behavioral therapy, guided imagery, visualization, positive thinking, remaining active, and other modalities that depend upon the underlying cause: physical, emotional, spiritual, and financial. The treatment for CRPS is not specific for that condition alone, but the gains can be possible with tremendous discipline, effort, single minded determination and the loving support of friends and family.

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Be cautious of spinal cord stimulators. Try everything else first.

They can create pain and scarring or tether the spinal cord.

Be proactive.

Remember that guidelines and strategies for diagnosis and treatment are outdated.

Support RSDSA.org if you can.

They support high quality pain research.

You can go directly to their site or donate to them (not me)

using the link at the top of my site here.

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Patients and doctors do not understand that opioids create pain.

A 2006 publication from Vanderbilt shows how much better pain can be to taper off.

The abstract:

Significant pain reduction in chronic pain patients after detoxification from high-dose opioids.

The article:

Significant pain reduction in chronic pain patients after detoxification from high-dose opioids.

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More on this young woman’s journey coming.

It’s been busy!

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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.

~

Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, you will need to telephone my office.

~

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For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

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