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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Avoid opioid use in surgery to reduce postop pain


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Science for years has confirmed that opioids trigger inflammation and that creates pain. Trauma and surgery also create inflammation that leads to pain. How logical is it then to continue use of sufentanil for anesthesia when it is the most highly potent opioid 500 to 1,000 times stronger than morphine. Where is the logic in creating pain by using sufentanil as the anesthetic? A new one on the market will be 10,000 times stronger than morphine. Inflammation is not always easy to reset after you strafe the innate immune system with an opioid.

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Why is ketamine not used more often for surgical anesthesia when we know ketamine profoundly lowers the inflammatory response thus reducing pain more than ever. Studies for years have shown that even a small dose of ketamine reduces postop pain. This is not new.

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A study needs to be done comparing patients who receive no opioids. At least this study showed that when fewer opioids are used, pain scores are 37% lower than if more had been given. Patients given higher doses of opioid, had higher analgesic requirements postop. That increases the risk of persistent chronic pain and the tragic risk of addiction.

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Opioids inflict known lasting harm, pain and suffering, perhaps disability and addiction.

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Reduced opioid use in surgery linked to improved pain scores
Written by Brian Zimmerman

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After anesthesiologists at the University of Virginia Health System in Charlottesville began administering fewer opioids to patients during surgeries, patients’ self-reported pain levels dropped, according to a study led by three UVA anesthesiologists.
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For the study, the team examined 101,484 surgeries that took place in the UVA Health System from March 2011 to November 2015. During this time period, the amount of opioids administered via general anesthesia at the system was reduced by 37 percent.
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For the same time period, self-assessed patient pain scores recorded in post-op recovery units dropped from an average of 5.5 on a 10-point scale to an average of 3.8, marking a 31 percent improvement.

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One of the study’s leaders, UVA anesthesiologist Marcel Durieux, MD, PhD, said the impetus behind the pain score improvements is likely attributable to several factors. One, previous research has indicated opioids can ultimately make people more sensitive to pain. And two, the increased use of non-opioid painkillers like lidocaine and acetaminophen during surgeries at UVA was likely effective.

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….”There is very clear evidence that people can become opioid-dependent because of the drugs they get during and after surgery,” said Dr. Durieux. “I think that by substantially limiting opioids during surgery, we’ve made an important step in addressing that problem.”

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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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Ketamine Consensus Statement for Mood Disorders Needed


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I just had a call from a student writing a paper on ketamine. Question #1: What % respond to ketamine.

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Why are we still asking this rather than treating with ketamine?

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3.7% of Americans are disabled with Major Depression, many for decades, or entire lives. Antidepressants may work on only 30%. It’s time we had a consensus statement on use and training of ketamine.

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Read Cornel West: Pity the sad legacy of Obama, before you read on.

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Pity the sad legacy of psychiatry. Even neoliberals fail to speak up, stuck in the dictates of the few. We’ve known for decades that ketamine is effective treatment. It can work in hours. IV ketamine clinics are popping up like Jack in the Boxes and will continue to increase in number.

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It is time to ask: Is IV the only way to administer? Is it cost effective? Do these doctors have the right training?

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We need a consensus statement from psychiatrists and from the American Academy of Psychiatry and Neurology on training in inflammation, the innate immune system and treatment with ketamine.

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Every psychiatrist and mental health specialist should be instructed in rationale, the innate immune system, glia, inflammation, addiction medicine, glial modulators (ketamine is only one), and how to look at the whole system, holistically, not just one more drug. Inflammation, diet, exercise, among these.

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A focus on Ketamine alone in treating a complex organ like the brain is incomplete. Think inflammation, brain, spinal cord, glial modulators, not just drugs, not just ketamine. Ketamine is potentially addicting, a schedule III drug. Evaluate a patient just as you do when prescribing opioids.

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Then we need consensus on its use for intractable chronic pain including RSD/CRPS.

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Why don’t schools teach anything on the human body and the immune systems rather than biology and cutting up frogs?

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 Data below is from National Institute of Mental Health:

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Major Depression Among Adults.

  • Major depression is one of the most common mental disorders in the United States.

  • The 12-month prevalence data for major depressive episode presented here are from the National Survey on Drug Use and Health  (NSDUH). Based mainly on the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), in the NSDUH study a major depressive episode is defined as:

    • A period of two weeks or longer during which there is either depressed mood or loss of interest or pleasure, and at least four other symptoms that reflect a change in functioning, such as problems with sleep, eating, energy, concentration, and self-image.

    • Unlike the definition in the DSM-IV, no exclusions were made for a major depressive episode caused by medical illness, bereavement, or substance use disorders.

  • In 2015, an estimated 16.1 million adults aged 18 or older in the United States had at least one major depressive episode in the past year. This number represented 6.7% of all U.S. adults.

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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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Abuse & Misuse Risk Assessment Tools from FDA – for Opioids, Ketamine, Adderall, Xanax, Ativan, Valium, Any Drugs of Abuse


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Risk Assessment Tools Examples from FDA.gov

page 11  (pdf)

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We must always remember, all of us, families, friends and physicians alike, the possibility of opioid use disorder (OUD) in anyone on chronic opioid therapy (COT) and those who are prescribed any drugs of abuse such as Ketamine, Adderall and benzodiazepines such as Valium, Ativan, Xanax. None of us should be taking medications that interfere with our ability to think and function. None of us should be taking more than we need. Many of us do not realize that less is more.

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Details of many tools for risk assessment are reviewed previously here.

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Keep this in mind:

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  • “Assessing risk of abuse and OUD in patients receiving COT is a dynamic, ongoing process.

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  •  Diagnosing misuse, abuse and OUD in patients with pain is complex

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  • Current screening tools do not diagnose abuse or OUD but only misuse and not intent”

     

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Tools

# of Items

 Administered

Patients considered for long-term opioid therapy:

ORT Opioid Risk Tool

5

By patient

SOAPP® Screener & Opioid Assessment for Patients w/ Pain

24, 14, & 5

By patient

DIRE Diagnosis, Intractability, Risk, & Efficacy Score

7

By clinician

Characterize misuse once opioid treatments begins:

PMQ Pain Medication Questionnaire

26

By patient

COMM Current Opioid Misuse Measure

17

By patient

PDUQ Prescription Drug Use Questionnaire

40

By clinician

Not specific to pain populations:

CAGE-AID Cut Down, Annoyed, Guilty, Eye-Opener Tool, Adjusted to Include Drugs

4

By clinician

RAFFT Relax, Alone, Friends, Family, Trouble

5

By patient

DAST Drug Abuse Screening Test

28

By patient

SBIRT Screening, Brief Intervention, & Referral to Treatment

Varies

By clinician

 

Ketamine in Bipolar Depression – A Review


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An excellent review of Ketamine, a rapid-acting antidepressant and anti-suicidal agent, in Bipolar Depression

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Efficacy of Ketamine in Bipolar Depression: Systematic Review and Meta-analysis. 

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Parsaik AK1, Singh B, Khosh-Chashm D, Mascarenhas SS.

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OBJECTIVE: To consolidate the evidence from the literature to evaluate the role of ketamine in the treatment of bipolar depression.

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METHODS: Major databases, including MEDLINE, EMBASE, Cochrane, and Scopus, were searched through October 2014, for studies reporting the role of ketamine in the treatment of bipolar depression. Only randomized controlled trials were included in the meta-analysis. We calculated standardized mean differences (SMDs) with SE for each study included in the meta-analysis. A random effect model was used to calculate the pooled SMDs. Heterogeneity was assessed using the Cochran Q test and I statistic.

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RESULTS: Of the 721 articles that were screened, 5 studies that enrolled a total of 125 subjects with bipolar depression (mean age, 44.6+/-4.3y and 65.6% females) were included in the systematic review; 3 randomized controlled trials (69 subjects) were included in the meta-analysis. The meta-analysis showed significant improvement in depression among patients receiving a single dose of intravenous ketamine compared with those who received placebo (SMD=-1.01; 95% confidence interval, -1.37, -0.66; P<0.0001). The maximum improvement was observed 40 minutes after the ketamine infusion. No heterogeneity was observed between the studies (Cochran Q test P=0.38, I=0%). The 2 studies that were excluded from the meta-analysis also showed significant improvement in depression after ketamine therapy. Individual studies also reported improvement in anhedonia and suicidal ideation after ketamine therapy. None of the subjects had serious side effects, and the side effects were similar between the ketamine and placebo groups.

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CONCLUSIONS: This study suggests that ketamine is effective in treatment-resistant bipolar depression and may reduce suicidal ideation and anhedonia.

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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.

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

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The advertising below is not recommended by me.

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Veterans Suicides 20 per day – MD not paid in 12 months for 5 approved visits


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VA Conducts Nation’s Largest Analysis of Veteran Suicide

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Read the report all you want, but for 12 months I’m not reimbursed. And no explanation why. No wonder they can’t get doctors.

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Yet another call just now from TriWest asking me to treat a veteran. VA crisis lines leave vets in limbo. Calls go to voice mail. Veterans have killed themselves just after calls to crisis lines. A lot of these suicides are due to PTSD. Veterans cannot get the help they need.

 

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I believe it is TriWest who won the contract to schedule suicidal veterans who have Treatment Resistant Depression or PTSD or Bipolar Depression. I treat that. It works except in the most extreme cases, in minutes to just a couple days. It’s simple and safe for outpatient use. It has been tested at NIMH and Yale since 1991. The VA-UCSD psychiatrist referred him and then continued care.

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I will not see one more veteran until I am reimbursed for the 5 pre-approved visits for a veteran I treated 12 months ago. He was better in a few days, the first time in decades he had relief of depression. If you cannot pay me who can relieve treatment resistant Major Depression in 2 days, then honey, no wonder you can’t find docs to help. They limited me to their chosen codes for billing. I spoke to psychiatrists who work with veterans and they have never heard of those codes. I guess they just mean loud and clear: NO PAY. Fine. It was a pay cut to offer and took weeks of paper forms, months of approval – you have to really want to do it. With frequent help from a very experienced clerk and a doggedly informed veteran who knew all the ropes, it took months for paperwork to get rushed through. Plenty of doctors just graduating this month don’t know how many months paperwork takes and they won’t get paid.

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San Diego VA has the worst reputation in the nation. I understand it is the San Diego VA that has the worst lag time delays of several months before veterans can even be seen. Worst in the country. Correct me if I’m wrong. And we have a lot more veterans because warm sunny weather is easier on their bones. Is that any excuse to dis-incentivise any doctor by not paying for services?

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The new veterans suicide hotline does not even return all calls. Public Radio just had an expose’ on this one or two weeks ago.

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Twenty veterans take their life daily.

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Only 30% of people with depression respond to antidepressants.

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Based on publications from major academic centers, treatment resistant depression, it seems, is diagnosed after failing as few as 3 or 4 antidepressants.

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Compare any antidepressant to ketamine with potential relief in hours to a couple days.

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It’s not like this is new. In 1991 ketamine was first studied at NIH for depression. Yale has carried the work forward with them. But people live at home and it has to be cost effective. It is unnecessary and/or unaffordable for most people including taxparers to be paying for IV infusions when many or most patients do well on sublingual or nasal use. It is the #1 drug of abuse in China, so don’t just offer it to any person who needs it. Make sure you understand how important glial modulators are in depression. See Yale with NIMH publication on inflammation in depression, I posted on these pages about 3 or 4 years ago when it came out.

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Yale with NIMH had published that ketamine rapidly creates synapses.

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And Yale has published:


Activation of a ventral hippocampus–medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine

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In January 2012, I posted detailed information:

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Depression PTSD – Ketamine Rapid Relief

 

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  • PTSD has a more direct link to suicide than previously thought, a current Texas A&M University study concludes – references below.

  • A high lifetime risk of suicide occurs in women who have been sexually and physically abused as young girls.

  • More than 300,000 veterans have been diagnosed with PTSD or major depression – many not yet diagnosed.

  • Risk of suicide is the highest during the first month of standard antidepressant therapy, and a significant number of patients do not have adequate improvement even after months, resulting in harm to personal and professional lives.

  • Patients are at suicide risk upon discharge from psychiatric hospitals.

  • Significant predictors of both suicide attempts and preoccupation with suicide are guilt and anger and impulsive behaviors.

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  • Ketamine is the most important breakthrough in treatment of major depression with rapid and lasting effects.

  • Ketmine can help immediately, unlike all other antidepressants that may require weeks or months to work, if they help at all. See NPR report here – that appeared soon after I posted this (skip to their last section). It is FDA approved and legal. NPR again reports ketamine’s rapid relief of depression.

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    • The medical literature on ketamine use is profoundly important. There are over 6,800 medical publications. Ketamine has potent healing powers. Karl Jansen, psychiatrist in London, believes that “ketamine has potent healing powers when used as an adjunct to psychotherapy.” There is nothing like it; however, treatment for serious depression still requires team support, not medication only.

    •  The World Health Organization reports that disability to due depression is second only to heart disease.

    • Suicide is a catastrophic medical emergency. I cannot stress this enough. Depression is treatable.

    • Your death is unnecessary. It would be a terrible loss to all who love you.

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Please read that entire post January 2012 before you call to ask questions. The calls are very time consuming.

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There is no reason to restrict life and death matters to one drug, and then make it dependent upon only IV infusions. What kind of life is vegetating in depression for decades? It is a short acting drug. I have posted on why ketamine should never be used alone, but must be used with other glial modulators.

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Most troubling:

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Compounded Medications are Not Covered by Any Insurance

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Most people cannot afford compounded medications, especially if disabled due to Major Depression or PTSD or pain – same medications work on mood and pain.

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TAKE ACTION

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Healthy people can get back their lives. These simple steps can be taught across the nation. Millions are needlessly disabled, especially our young adults who are most vulnerable to these disorders, and several hundred thousand of our young veterans.

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An entire nation can get and breathe relief.

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DO THIS:

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Call your favorite politician and relevant organizations who care about healthcare and veterans to STOP the collusion and restraint of trade since all insurers began refusing to cover compounded medications. All these new $100,000 per year medications are paid for by the taxpayers and your insurance deductible that goes up every year. How long will you be able to afford medical care? How long can this restraint of trade be practiced under our noses unless we take action?

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Get this on the Democratic platform this presidential year. It’s a scam perpetuated by multibillion dollar pharma and their mighty rich contributions to congress who are killing affordable medical care.

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Affordable medical care

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These medications must be compounded. How many can afford $200 to $300 or more cash out of pocket just for medications? Or will this become another safe old drug that is bought by a financier, patented, and now they charge $100,000 a year? You know who pays for everything and it ain’t the 1%.

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Ketamine Survey for MD’s from RSDSA – Please Help


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Jim Broatch, Executive Director of RSDSA requests help from doctors giving IV Ketamine to treat CRPS. Please ask your doctor to do the survey. 

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 https://www.surveymonkey.com/r/ZPP9BXY

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And remember, if you shop Amazon, you can direct Amazon to contribute a portion to RSDS.org —- many thanks! 

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