Opioids Kill White Americans – Is it opioids or suicide or addiction or untreated pain?

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Drug Overdoses Propel Rise in

Mortality Rates of Young Whites

New York Times

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Yes, white Americans, headlined yesterday by Gina Kolata and Sarah Cohen, New York Times science writers.  This article points to the highest mortality in young whites. See post early November on the Princeton researchers who reported deaths in white Americans. True, infants and children have severe pain, but this new article is on young white adults.


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Those who are anti-opioid and those who lost a loved one from opioids and heroin (an opioid that helps pain), will send in comments to the paper so that everyone can see how bad opioids are. Most patients who take opioids are too disabled from pain to write.

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Pain is stigmatized, opioids stigmatized, people in pain are stigmatized, doctors who treat pain are stigmatized. Any wonder 97% of medical schools do not teach pain management?

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Is it opioids or suicide or addiction or untreated pain that is killing our youth?

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How many suicides have opioids prevented? Americans make up less than 5% of the global population but consume 80% of the world’s supply of opioid prescription pills. What if your cancer pain now becomes severe intractable chronic pain? Cancer has been changing. The survival rate has increased, and many of these cancer patients treated with opioid therapy, survived the cancer but have residual chronic pain from cancer or its treatment. Surely they are among the 18,000 white people who died.

 

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Please read the earlier post this week on the ethics of opioid treatment, on

CDC’s imminent radical cut in opioid doses for 100 million patients nationwide.

Use search function above photo – type in CDC or DEA.

Your pain. Your lives. Their profit.

A thorny problem.

Tell us what happened to you. Doctors, tell us what you are seeing.

Have you been denied disability due to pain? Denied non-opioid treatment?

Chronic severe pain affects forty million Americans.

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KONICA MINOLTA DIGITAL CAMERA

Some insurers have denied or limited non-opioid treatments yet continued expensive opioids for decades. Has your insurance refused your treatment? Pain specialists have been barraged by denials for years.  Please comment below.

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As noted last week, I have spent 15 years developing alternatives to failed opioid treatment for chronic intractable pain and writing about that on these pages since April 2009. But opioids must be available as last resort.

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FACT:

  • Opioids killed almost 18,000 Americans in 2014 – prescription opioids, not street drugs.

  • 40 million American millions with severe pain, millions not thousands

  • 100 million with chronic pain.

  • CDC will imminently, radically cut everyone’s opioid dose

  • Health insurers will oblige, and incidentally show increased profit to shareholders

  • Suicide increases with untreated pain

  • Death rates for “whites ages 25 to 34 was five times its level in 1999”

  • This age group has more injuries from work and play that can lead to disability, job loss

  • Insurance is unaffordable or not purchased by many young adults

  • My own colleagues cannot afford high deductibles – prescriptions are now counted in deductibles, now unaffordable

  • Can you afford $20,000 per month for your opioid or is cheap heroin more affordable? Can you afford your usual drugs on Medicare once you are in the “donut hole.” Can you afford $28 per day, $840 per month for gout, when colchicine was 12 cents a day a couple years ago?

    • Do insurance denials increase liklihood of cheaper alternatives such as heroin or illegal marijuana resulting in death by drug dealer?

    • Do exhorbitant costs of opioids lead insurers to deny your medication?

  • Insurers have refused to pay for abuse-deterrent and tamper-resistant formulations of opioids

  •  Insurers have refused to pay for proven, widely accepted, nonopioid analgesics:

    • Lyrica

    • Horizant

    • Gralise

    • Cymbalta

    • Does it help the DEA and NIH and universities to teach those as nonopioid alternatives when they are not covered and not affordable the rest of your life?

    • Insurers deny every known compounded analgesic though low cost and effective, even for Tricare’s disabled veterans, even 5% lidocaine ointment for nerve pain, dextromethorphan, oxytocin, low dose naltrexone – Stanford published research on naltrexone years ago and now doing research on it again for CRPS, many many others

    • Insurers deny proven analgesics that are used by armed forces, university hospitals, select doctors, for life threatening pain: ketamine

    • Insurers deny off-label analgesics that may work better than opioids, e.g. memantine, an Alzheimers drug – can relieve intractable nerve pain (French publication on CRPS/RSD pain)

    • Insurers deny medications that reduce side effects of opioids, e.g. nonaddicting modafinil popular with students, to increase alertness when opioids cause drowsiness that may cause injury, death – gosh 10 years ago!

    • Is drowsiness the cause of some of those 18,000 opioid deaths?

  • Health insurers have refused coverage for treatments such as P.T., psychotherapy for coping skills, blocks.

  • Insurers deny medications that relieve the withering side effects of opioid withdrawal, making it impossible for many to taper off, e.g. Adderall, Wellbutrin (dopamine)

  • Cannabis, a nonopioid, classified by US Congress as Schedule I, illegal federally for human use, illegal to take on a plane or cross state/national borders, found on meteorites, made by sponges and some of the earliest living species on the planet, used for thousands of years for pain, while cocaine and methamphetamine are classified as Schedule II for prescription purposes.

  • Opioids, even vicodin, require monthly doctor visits, costs, monthly for sixty years

  • Why whites dying of opioids? People of color are denied prescription opioids. Stark data published for decades.

  • Heroin is an opioid, cheap and available; its “unAmerican” – used in England for pain, used thousands of years for pain

  • Untreated pain is one reason people turn to heroin, affordable is another

  • Violence and drinking and taking drugs can begin with chronic pain and job loss, not always the other way around, chicken egg

  • Opioids cost pennies to make, patient’s cost is $20,000 per month for Rx. Insurers paid what the market would bear… in the old days. Who is trapped in the middle of this fight for shareholder profit?

    • How many of us would take 2 or 4 extra pain pills when pain spikes to extreme for days?

    • If you are disabled, can you afford insurance or expensive prescription drugs?

  • “Poverty and stress, for example, are risk factors for misuse of prescription narcotics,” Dr. Hayward said.

  • When you are not getting enough sleep and rest, working too many hours overtime or 3 jobs, inflammation and pain spikes

  • Misuse of opioids in > 33% (perhaps 48%?) of cancer patients at Memorial Sloan Kettering Cancer Center in high resource settings when insurance was better, published 1990’s.

  • Cancer pain – usually time limited. Intractable chronic pain – forever.
    .How many jobs will be lost and how many suicides when CDC imminently imposes strict cuts in opioids?

  •  DEA recently requires every pain patient taking opioids, including those with cancer, to be diagnosed “Opioid Dependent” — not only addicts – the same diagnosis for pain patients includes addicts. The term “addiction” has been equated to dependence by most psychiatrist over the past 30 years. It may be interesting to see what criteria are used to define “addiction” if any, in DSM V. Some important members acknowledge that the addition of dependence into addiction in DSM-III was a mistake….the DSM-V criteria will get rid of “abuse”, and will include craving. it will also apparently eliminate the legal/criminal criteria. DSM comments are extracted from here, with many good arguments on this epidemic, such as: “The US is leading the way in eradicating pain, but in doing so has created an unwanted byproduct: painkiller addiction.”
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    What would you want if you had intense chronic pain?

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    “For too many, and especially for too many women,” she said, “they are not in stable relationships, they don’t have jobs, they have children they can’t feed and clothe, and they have no support network.”

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    “It’s not medical care, it’s life,” she said. “There are people whose lives are so hard they break.”

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Opioids kill – or is it untreated pain?

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Pain kills, a maleficent force.

No one can help you. Only you have the tools to do it

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Alarms went off for me on radical opioid cuts in October and I posted when

DEA suddenly held conferences across the nation on sharply cutting opioid doses.

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How many of us especially seniors and male persons refuse to learn or use coping skills that

reduce pain without medication?

How many of us refuse to diet and lose weight to reduce pain and/or disability?

Politicians are sued if they tax sales of sugar loaded soft drinks.

One single can of soda per day exceeds acceptable sugar limits for entire day.

Snacks need to say much much time it takes to burn off fat –

quarter of large pizza 449 calories, walk off 1 hr 23 min;

large coke 140 calories, walk off 30 minutes.

Foods can be anti-inflammatory or pro-inflammatory.

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Obesity is pro-inflammatory.

So is lack of sleep.

People who sleep with animals in their bed and their bedroom, I’m talking to you.

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Yes, pain is in your mind.

Chronic back pain is no longer in the back, it’s in the brain, the pain matrix.

It’s behavior, not just pills. Pain is an emotional and psychosocial  and spiritual experience.

Work on it! Constantly.

Lord forbid we should teach stress reduction and meditation in grade school

and improve school lunches before kids start looking for heroin for pain.

Yes, kids have chronic pain, are sleep deprived, often obese.

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Isn’t this all un-American?

Injuries, pain, habits, pace activities, learn to avoid and treat pain – start young.

Taxpayers end up paying for ignorance and disability.

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I will soon be posting published research that documents health insurers have refused to pay for nonopioid treatment and how health care policy aimed at all people with chronic pain leads to suicide when drastic cuts are made to opioid doses – Washington State we are looking at you. Florida you’ve made headlines and 60 Minutes TV specials years ago.

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Do please comment below if your health insurer has refused medication, physical therapy, psycho-therapy, cognitive behavioral therapy, stress reduction, for chronic pain.

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How many of you have been denied social security disability by doctors who don’t know how to diagnose RSD, Complex Regional Pain Syndrome? Let me know. I will pass on that data to researchers collecting information on untreated pain.

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I have written many times on these pages, and more often than ever these past years as insurers cut back more and more. This will rapidly get worse. We need your data.

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Please send in your stories. You are not alone.

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So many issues. Steven Passik, PhD, was interview by Lynn Webster, MD – emphasis in bold is mine. Dr. Passik pioneered in management of chronic pain and pain in addicts. He has read some of Dr. Webster’s book. “You’re calling, the need for love and connection and all those things in the book, I’ve been – what’s largely lacking is outright, at times animosity towards people with pain and I think there’s a lot of projections sometimes because the therapy – the stigmatized disease – treated in stigmatized people with stigmatized drugs and interventions and so, it’s like a hat trick of stigma.  I’ve been to my share of pain conferences lately that people are really talking about, “Okay, well there’s come a realization that opioid-only, drug-only therapy, is really not going to work to the best majority of this population.  It doesn’t [mean] that opioids should be ignored and we’ll get into that later, but that they’re going to work in isolation and should never been expected to.  And then they start advocating things that are a lot like supportive and cognitive behavioral therapy and to be practiced basically by the primary care physician or the pain doctor.  And the idea that, to me that’s in a way comical because as a psychologist myself, we’re dealing with the system wherein cognitive behavioral therapists can’t even get paid to do cognitive behavioral therapy.  And so, I think something’s got to give, and I think one of the main obstacle is that – and this really gets into the next question as well but I’ll come back to that more specifically – but when people have a set of whatever chronic condition that involves psychiatric motivational, lifestyle, spiritual as well as nociceptive elements, and we put a premium only on what you do to people, prescribed to people, put in people, take out of people, and then that’s only going to relegate the other kinds of treatment or the other kinds of ways in which a caring physician and treatment team would spend time with the patient to the very poorly reimbursed category.  You’ll always going to have a problem with people being treated with the kind of respect that should go along with treating that kind of an illness and it’s not unique even to chronic pain.  I’ve seen treatment scenarios with people who are taking care of people with pancreatic cancer, have an afternoon clinic that has 45 people in it.  I mean how you – something’s got to give in our healthcare systems and I do think that patients are going to have to stand up and say, “I don’t want to be on a conveyor belt.  I want to spend some time and make a connection with the people that are taking care of me and it’s not just about the piece paper in my hands, for a prescription or that I walk out the door with.”

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Clematis Blue.

 The New York Times article further says:

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…This is the smallest proportional and absolute gap in mortality between blacks and whites at these ages for more than a century,” Dr. Skinner said. If the past decade’s trends continue, even without any further progress in AIDS mortality, rates for blacks and whites will be equal in nine years, he said….

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…Not many young people die of any cause. In 2014, there were about 29,000 deaths out of a population of about 25 million whites in the 25-to-34 age group. That number had steadily increased since 2004, rising by about 5,500 — about 24 percent — while the population of the group as a whole rose only 5 percent. In 2004, there were 2,888 deaths from overdoses in that group; in 2014, the number totaled 7,558….

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…For young non-Hispanic whites, the death rate from accidental poisoning — which is mostly drug overdoses — rose to 30 per 100,000 from six over the years 1999 to 2014, and the suicide rate rose to 19.5 per 100,000 from 15, the Times analysis found….

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…For non-Hispanic whites ages 35 to 44, the accidental poisoning rate rose to 29.9 from 9.6 in that period. And for non-Hispanic whites ages 45 to 54 — the group studied by Dr. Case and Dr. Deaton — the poisoning rate rose to 29.9 per 100,000 from 6.7 and the suicide rate rose to 26 per 100,000 from 16, the Times analysis found….

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…Eileen Crimmins, a professor of gerontology at the University of Southern California, said the causes of death in these younger people were largely social — “violence and drinking and taking drugs.” Her research shows that social problems are concentrated in the lower education group.

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The material on this site is for informational purposes only.

It is not a substitute for medical advice,

diagnosis or treatment provided by a qualified health care provider.

Relevant comments are welcome.

If any questions, please call the office to schedule an appointment.

This site is not email for personal questions.

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

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Please be aware any advertising on this free website is

NOT advocated by me and NOT approved by me.

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Be the change you wish to see – or walk away. Money at NIH

 

 

A Turning Point

 

$$$$$ MONEY $$$$$

 

at NIH

 

May not come this way again

 

NIH developing

5-year NIH-wide Strategic Plan

 

 

 

Donate to organizations, below

They can provide feedback to NIH via the

RFI Submission site


 

 

 

John C. Liebeskind, 1935 – 1997, distinguished scholar and researcher, past president of the American Pain Society, had the radical idea that pain can affect your health.

 

Research decades ago by an Israeli team at UCLA and others had shown “that pain can accelerate the growth of tumors and increase mortality after tumor challenge.” Decades ago Professor Liebeskind lectured all over the country: Pain kills.

 

He wrote an editorial in 1991, summarizing a life’s work:

 

“Pain and stress can inhibit immune function.”

 

 

Quoting John Bonica, the father of modern pain management, he wrote:

 

“Bonica has long argued that the term ‘chronic benign pain’ (used in distinction to pain associated with cancer) is seriously misleading.  Chronic pain is never benign, he contends; “it is a ‘malefic force’ that can devastate its victims’ lives and even lead to suicide.”

 

 

Liebeskind continues, “It appears that the dictum ‘pain does not kill,’ sometimes invoked to justify ignoring pain complaints, may be dangerously wrong.”

 

Pain mediates immune function

 

Importantly

 

  Opioids mediate the suppressive effect of stress on natural killer cells,

 

 published in 1984, immune system.

 

Alcohol increases tumor progression, 1992, immune system.

 

It used to be news.

He did not live to see change.

 

People just want to go on doing what they’re doing.

They want business as usual.

 

 

After 1991, we saw the great discoveries of neuroinflammation, pioneered by Linda Watkins, PhD, the early understanding of the innate immune system, its involvement in chronic pain and depression, and a few weeks ago, a British team showed neuroinflammation in teens with early signs of schizophrenia and DNA markers.

 

 

Major Depression has the same neuro-inflammation found in chronic pain, often responding to same medications, in particular glial modulators – immune modulators. Now, perhaps early schizophrenia will respond to glial modulators, reducing inflammation seen on scan in teens, before they become homeless and burned out by antipsychotic drugs

 

Inflammation out of control destroys neurons

 

Fire on the brain

 

 

We must be the change we wish to see

 

It’s not just the Bern. It’s been starting. Forces are finally coming together. We want change. It’s been too much. Too long.

 

We won’t take it anymore.

 

I figure if I tell you about it, you might just mention it to someone to pass it on. That is all. One small action may lead to change. Activate inputs to the NIH strategic plan.

 

 

~ Action needed ~

 

Prices of drugs becoming unaffordable

No new drugs for pain or major depression

Research to repurpose existing drugs

Expose the politics destroying our compounding pharmacies

 

Above all

The #1

Major Priority:

Request NIH to solicit priority call for research on

Glial modulators of the

Innate immune system

 

 

Why?

 

Glia modulate

chronic pain, major depression

and almost every known disease

 

Glia are your innate immune system

 

Inflammation kills

 

 

 

 Stress kills. Inflammation kills.

 

 

Pain kills

 

In the 1970’s, Professor Liebeskind and an Israeli team at UCLA injected cancer cells to two groups of rats that had sham surgery. Cancer spread much faster and killed far sooner in the group with poor treatment of surgical pain.

 

 

~ Pain kills ~

 

He lectured all over the country

 

Forty five years ago

 

 

I’m gonna be dead before I see this country do anything but unaffordable opioids and the magical ineffective trio of gabapentin, Lyrica, Cymbalta to treat chronic pain. The devastating, blind, nationwide emphasis does nothing to address the cause: inflammation, the innate immune system gone wild.


 

 

Innate immune system in action

 

Untreated pain suppresses the hormone systems too.

 

Untreated depression – same inflammation kills lives.

 

Where’s the money?

 

We are the change we wish to see. It’s pitiful I am so lazy. Suddenly, too late, we may need something, but, aha, no new drugs in the pipeline.

 

 

 

~ Make a joyful cry to NIH ~

 

They are soliciting input from professional societies

 

If your condition has failed all known drugs for pain or major depression, then make a joyful cry to NIH, now, before they give away all that nice new $$$$$money$$$$$.

 

 

Follow and join

 

American Pain Society

 

 

International Association for Pain

celebrating 40 years of pain research

 

 

Reflex Sympathetic Dystrophy Syndrome Association

help for CRPS/RSD  

 

 

 

The key to CRPS/RSD pain will apply to all forms of chronic pain, in particular the most difficult form, neuropathic pain. RSDSA funds research into all forms of chronic pain, not only Complex Regional Pain Syndrome (CRPS/RSD). Their scientific board members are not funded by opioid money.

 

 

 

Exactly

what is the annual cost of care

as fraction of GDP

for the growing population of Americans on opioids

for one year, for lifetime?

 

 

People are dying from prescription opioids and those who need them find they don’t work well enough. Prescriptions opioid costs must be a huge fraction of the medical costs in the United States GDP. You are required  to see a doctor every single month each year, often lifelong, just for one opioid, 12 months a year x 30 years x tens of millions of people and increasing – a growth industry. Not even counting $600 a day for the opioid, what the cost of monthly visits for 30 years? Not counting the army of DEA, FDA, CDC agents watching the opioids like a hawk. We all have to be sharp, addiction is growing. Addiction aside, deaths from prescription opioids are shaking up the CDC forcing urgent change this coming month.

 

 

 

Opioids do not work well for chronic pain

We need better

It’s not just the $600/day price

They just don’t work

 

 

donate

 

 

Raise a joyful noise at NIH now or write back at us readers with comments and better suggestions. Tell others what you’d like to see. Which politicians do you know would be most interested in this at national levels and organizations?

 

You may never see this change unless you do it now. Other forces will get this new money.

 

 

Turning point now

May not return

 

 

We are at a turning point and we will fail to catch the sail that’s coming fast to carry all research money in their shiny big stem cell direction. They never look back.

 

 

There is so many medications we can use today, FDA approved drugs that can be re-purposed and applied to recent cutting edge science. Someone must pay to do the work to study this.

 

 

Re-purpose old drugs

 

 

Stanford just showed a popular generic drug improved recovery of stroke paralysis in mice to begin at 3 days rather than 30. Old drug, new purpose, of course more years of testing to confirm in humans. Brilliant team applying new science.

 

 

Request
NIH to solicit a

Special Invitation

for 30 good protocols to

repurpose old drugs

 

 

Hundreds of old drugs, already approved, could be involved in mechanisms we have recently learned about. Speak up or money will go to shiny new stem cells. None for chronic pain or major depression. No company will find this profitable – it must be funded by NIH. A popular generic sleeping pill can bring astonishing return from stroke paralysis.

 

 

Congress has not opened this new money to NIH in many long years. How often will there be extra money?

 

 

donate

 

 

Lawrence A. Tabak, D.D.S., Ph.D.
Principal Deputy Director, NIH, solicits you to

Review the NIH Strategic Initiative Plan and their

Request for Information (RFI) and the NIH website

and provide your feedback via the RFI Submission site

 

 

This is for “stakeholder organizations (e.g., patient advocacy groups, professional societies) to submit a single response reflective of the views of the organization/membership as a whole. We also will be hosting webinars to gather additional input. These webinars will be held in early to mid-August.

 

 

 

Be the change you wish to see

Donate to those organizations

to solicit the change you wish to be

 

 

 

Happy New Year

Rejoice!

There’s money at NIH

 

 

 

 

 

 

The material on this site is for informational purposes only.

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

Relevant comments are welcome.

If any questions, please schedule an appointment with my office.

This site is not for email.

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

 

 

 

 

Ketamine Pathway for Antidepressant Response – Ventral Hippocampus-Medial Prefrontal Cortex

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Molecular Psychiatry , (1 December 2015) | doi:10.1038/mp.2015.176

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

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F R Carreno, J J Donegan, A M Boley, A Shah, M DeGuzman, A Frazer and D J Lodge

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This is an excellent model for studying Alzheimers Dementia and may explain why my patient with Alzheimers has been so stable for so many years. Yale with NIMH had published that ketamine rapidly creates synapses, that led to treating a senior with Alzheimers. This should encourage further research on memory and dementias.

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The material on this site is for informational purposes only.

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

Relevant comments are welcome.

If any questions, please schedule an appointment with my office.

This site is not for email.

~~~~~

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

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Analgesic Response to Ketamine Linked to Circulating microRNA in Complex Regional Pain Syndrome

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Analgesic Response to Intravenous Ketamine

Is Linked to a Circulating microRNA Signature

in Female Patients

With Complex Regional Pain Syndrome

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The ability to measure Micro RNS’s (miRNA) in blood looks like it may become an important tool someday once it is available for the clinic. It could be used to predict if your condition will respond to various medications.

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MicroRNAs are emerging as important modulators of various psychiatric (schizophrenia, bipolar disorder) and neurological conditions including pain, epilepsy, cognitive dysfunction, neuronal development, structure and function. “MicroRNAs are small, non-coding RNAs that act as post-transcriptional regulators of gene expression.  miRNA’s can be affected by morphine and affected by other drugs. It is hoped that complex clinical phenotypes may be profiled in assays of peripheral blood and may predict response to treatment such as in this study. Ketamine is given for selected patients that have failed to respond to standard treatment.

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This research was published in Pain, June 2015, by Professor Schwartzman’s group at Drexel University. Seven of his patients with Complex Regional Pain Syndrome were ketamine responders and 6 were poor responders. They note that, “Although [ketamine] treatment is generally effective, approximately 30% of patients have an inadequate response to ketamine.”

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“Stability in circulation and dysregulation in disease state are 2 features making extracellular miRNAs useful candidates for biomarker discovery. Alterations in miRNA profiles have been reported for rheumatoid arthritis and systemic lupus erythematosus as well as for painful conditions such as irritable bowel syndrome, chronic bladder syndrome, endometriosis, and migraine. Cerebrospinal fluid from patients with fibromyalgia showed differential expression of 9 miRNAs.”

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Quoting directly from the article:

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Highlights

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•We studied ketamine treatment–induced miRNA alterations in blood from patients with CRPS.
•Differential miRNA expression was observed in whole blood before and after treatment.
•Before therapy, 33 miRNAs differed between responders and poor responders.
•Lower pretreatment levels of miR-548d-5p may contribute to higher UDP-GT activity.
•Circulating miRNAs can be potential biomarkers in predicting treatment response.

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From the Abstract

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Investigation of the mechanistic significance of hsa-miR-548d-5p downregulation in poor responders showed that this miRNA can downregulate UDP-glucuronosyltransferase UGT1A1 mRNA. Poor responders had a higher conjugated/unconjugated bilirubin ratio, indicating increased UGT1A1 activity. We propose that lower pretreatment levels of miR-548d-5p may result in higher UDP-GT activity, leading to higher levels of inactive glucuronide conjugates, thereby minimizing the therapeutic efficacy of ketamine in poor responders.

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Perspective

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This study suggests the usefulness of circulating miRNAs as potential biomarkers. Assessing miRNA signatures before and after treatment demonstrated miRNA alterations from therapy; differences in miRNA signature in responders and poor responders before therapy indicate prognostic value. Mechanistic studies on altered miRNAs can provide new insights on disease.

 

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From the Discussion

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Ketamine is also considered to be the prototype for a new generation of glutamate- based antidepressants that can alleviate depression within hours of treatment. Several biological measures have been explored to characterize treatment response and to gain insight into mechanisms underlying the rapid antidepressant effects of ketamine. A plasma metabolomics study in patients with bipolar depression suggested that the basal mitochondrial b-oxidation of fatty acids differed between responders and nonresponders to ketamine. Other studies have shown differences in baseline plasma concentrations of D-serine, serum levels of interleukin 6, and plasma levels of Shank3, a postsynaptic density protein involved in NMDA receptor tethering and dendritic spine rearrangement.

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Differences in the ability to metabolize ketamine because of interindividual differences and pharmacogenetic factors have been proposed to contribute to the varied responses to ketamine therapy and its clinical outcome. Similar conclusions have been drawn for patients with depression; plasma from patients with treatment- resistant bipolar depression who had undergone a single 40-minute infusion of a subanesthetic dose of ketamine showed that although NK is an initial metabolite, it is not the major circulating metabolite. This again suggests that other downstream metabolites of ketamine may play a role in the pharmacological effects of the drug. It is also known that (2S,6S)-hydroxynorketamine is an active and selective inhibitor of the a7 subtype of the nicotinic acetylcholine receptor; this activity was shown to contribute to the pharmacological responses associated with the antidepressant activity of (R,S)-ketamine. We postulate that in patients with CRPS, 1 factor contributing to resistance is an altered pharmacokinetic profile produced by enhanced elimination of active metabolites downstream of NK, which is mediated by hsa-miR-548d-5p. However, because we have relied on indirect evidence of a higher percentage of direct/indirect bilirubin in poor responders, indicating increased UDP-GT enzyme activity, additional studies investigating hydroxynorketamine and its downstream metabolites along with their glucuronide conjugates in plasma and urine will provide direct evidence for the role of miR-548d-5p in mediating response to ketamine therapy in responders and poor responders.

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They noted a significant difference in body weight between responders and nonresponders (heavier), but not in duration of disease and analgesic response to ketamine. Toward that end, they will publish separately upon

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… investigating the link between miR-34a, which showed 28-fold reduction in poor responders relative to responders (Table 2), and the neuroendocrine system….

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From the Conclusion

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Our studies showed that miR-548d-5p can regulate UDP-GT but not CYP3A4, suggesting that UDP-GT activity in responders and poor responders may be mediated by differences in the level of circulating miR-548d-5p. Lower levels of miR-548d-5p in poor responders before treatment could result in higher UDP-GT activity, leading to the production of more inactive glucuronide conjugates and faster elimination of active ketamine metabolites downstream of NK. Thus, the levels of hsa-miR-548d-5p could minimize the therapeutic efficacy of ketamine and pain relief. Differences in miRNA signature can thus provide molecular insights distinguishing responders from poor responders. High failure rates of drugs targeted to treat neuropathic pain warrant changes in approaches. Studies targeting well-defined patient populations for clinical trials will play a crucial in developing drugs that may be efficacious in a subset of patients. Extending this approach to other treatment and outcome assessments might permit stratification of patients for maximal therapeutic outcome.

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How frustrating it is for patients and family who must cope with an intractable condition such as pain or Bipolar Disorder or treatment resistant Major Depression that has failed all commonly prescribed medications. For all of them, we need changes in approach.

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“High failure rates of drugs targeted

to treat neuropathic pain

warrant changes in approaches.”

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Perhaps scientists reading this would comment upon how it may relate to tolerance as it differentially occurs in those receiving intermittent ketamine vs continuous intravenous infusion.

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Dysregulation of miRNA’s has been shown in psychiatric disorders including depression and schozophrenia, neurodevelopmental disorders, cognitive dysfunction,  epilepsy, chronic pain states with implication for the cause and treatment of these disorders.

.

Research targeting miRNA’s as novel treatment for depression has shown that chronic fluoxetine, repeated electroconvulsive shock therapy, and acute ketamine have the capacity to alter hippocampal miRNA levels.

.

It is hoped these tests may be available someday clinically as the cost of off-label treatment not covered by insurance is a great burden for those already disabled by intractable pain or treatment resistant depression.

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.

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PUBLIC WARNING

warning reprinted with permission of Demitri Papolos, MD
.
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.

.

.

.

.

.

.

.

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.

~~
This site is not for email and not for appointments.

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

~~~~~

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

.

Please ignore the ads below. They are not from me.

.

.

.

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.

S-Ketamine for Patients with Neurological Injury – Revising a Dogma

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.

Continueing on yesterday’s discussion of S-Ketamine, here, there is an interesting Anesthesia & Analgesia review article 2005, entitled:

.

Revising a Dogma: Ketamine for Patients with Neurological Injury?

.

Money quote:

.

“In the laboratory, ketamine has neuroprotective, and S(+)-ketamine additional neuroregenerative effects, even when administered after onset of a cerebral insult. However, improved outcomes were only reported in studies with brief recovery observation intervals. In developing animals, and in certain brain areas of adult rats without cerebral injury, neurotoxic effects were noted after large-dose ketamine. These were prevented by coadministration of GABA receptor agonists.”

.

~

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If we are to use ketamine in the setting of intractable conditions, because nothing else works at all or works better, we must begin to have more data. Its effects on the brain seen in animals has specifically never been proven to occur in humans. We need more data in humans after chronic use.

..

Those who are disabled, deserve the choice to continue what works for desperate situations. At the same time, much needed research should be done on both racemic and S-ketamine. The affordable racemic ketamine, generic, off patent, and the S-Ketamine yet to be on market. S-Ketamine may be so strictly defined by FDA indications as to restrict its use considerably.

.

And for chronic depression, outside of emergency, insurers may not  cover without step therapy and prior authorization. That and cost will severely limit its use.

.

 .
..

.

.

.

.
PUBLIC WARNING

reprinted with permission of Demitri Papolos, MD
.
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.

.

.

.

.

.

.

.

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.

~~
This site is not for email and not for appointments.

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

~~~~~

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

.

Please ignore the ads below. They are not from me.

.

.

.

.

S-Ketamine – What’s That?

.judg

.

W-H-A-T’s  T-H-A-T?

.

..

S-Ketamine nasal spray is undergoing clinical trials in a few countries in Europe for treatment of Major Depressive Disorder. It may have fewer side effects and be effective at a lower dose than the FDA approved racemic ketamine we now have in the U.S.

.

Racemic means it has equal amounts of left-and right-handed enantiomers of a chiral molecule. Google those words if you wish, or just look at your left and right hand. They are not the same. That’s the point, and that’s why FDA must approve new clinical studies on S-Ketamine nasal spray which, I understand, is being fast-tracked by the FDA for Treatment Resistant Depression.

.

S-ketamine has twice the affinity for the NMDA receptor (compared to racemic), it’s a 4-times more potent dopamine re-uptake inhibitor, and there’s quicker elimination from body too. However, it still may have a hallucinogenic effect related to enhanced glucose metabolism in prefrontal cortex . . . . But not due to effect on sigma receptors, because it doesn’t have much affinity for those; and it may still elevate liver enzymes.

.

I will be very interested if that’s true of liver enzymes. It is extremely rare in my experience.

.

I am told that Thomas Insel, MD, the Director of the National Institute of Mental Health, NIMH, says ketamine is the most important new drug in psychiatry.

.

I hope my patients could feel that level of support from their local treating doctors. In my experience it is one of the safest medications I have prescribed in 40 years of medicine. I saw patients with intractable status epilepticus, chronic pain, cancer pain and treatment resistant depression. There is simply nothing comparable to ketamine. These conditions can be highly refractory.

.

Further, Dr. Insel “Acknowledges That Antipsychotics May Worsen Long-Term Outcomes.” I have seen psychiatrists who prescribe antipsychotics all their lives, now discharge patients now normal on ketamine at long last after decades of treatment resistant depression that has ruined their lives, their finances and their families.

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Why? Because it works? Because it’s generic and there are no drug representatives who come every week to offer free dinners? I hate to think that but the wall of resistance is awful for these patients.

.

..

I am deeply concerned that S-ketamine nasal spray

may be allowed only

for use in Emergency Departments.

.

~

.

That means the dose will

likely not be individualized.

.

.

It should be made available not just for Emergency Departments but also for outpatient use to physicians specially trained in the simple technique of how to start low, go slow, as we do in medicine to find an effective dose with fewest side effects. We have taught that at UCLA Epilepsy Center since the early 1980’s. And we use ketamine IV for Status Epilepticus – it works in emergency when nothing else works, and it’s a lot safer than many other drugs that induce coma: No effect on breathing. Of course, we are not inducing coma for depression or pain. We only use high-dose ketamine to do that for anesthesia in the Operating Room or for Status Epilepticus in the ICU. It is wonderful for pain when all else fails, including continuous infusion for cancer pain or Complex Regional Pain Syndrome.

.

Outside of emergencies, start low, go slow works for ketamine as well as it does for epilepsy medication and for strong opioids like fentanyl spray for rapid changes in cancer pain.

.

Going fast in high dose increases the potential for injury, even dreaded side effects or death. Yes, in an emergency we may consider the use if benefit exceeds the risk. That is best done in special facilities or ICU. The Benefit: Ketamine may allow suicidal ideation to resolve in ten minutes. But if the untrained ER doctor gives a high dose in a big man who needs a tiny dose – and yes, I have large male patients who respond to tiny doses – why give an unnecessarily high-dose to a person who has already suffered black suicidal thoughts that very night and almost killed him or herself?

.

When you start low, go slow, one does not need to rush for suicidality to be gone in minutes. We can wait 1 or 2 days if need be. But it can still resolve in 10 minutes in some, and at most one or two days in almost everyone. Breathe . . . . . . . easy. . . . . . like new life, a return of life, dawning.

.

I’ve seen cancer patients who had such severe hallucinations from Narcan that instantly reversed their opioid, slamming their body into acute withdrawal, that they literally saw the devil. They would never go near drug that again if in their power. Trembling fear. That could potentially happen with ketamine when given in a dose too high, the “one formula fits all.”

.

Hallucinations: The other day I saw a patient who had a history of hallucinations with Lyrica, Cymbalta, and now with ketamine after he slowly increased the dose to a non-effective low dose of 20 mg. He vividly remembers the hallucination. But his neuropathic pain is so extreme, and he had failed everything else, he was willing to try it again after specific instructions. Hallucinations did not recur. Yes, there is a method: Teach the body how to develop tolerance to the drug and the side effect will not continue; now you are able to push the dose to the effective level for depression or, in far higher doses, for neuropathic pain.

.

.

Persons with Major Depressive Disorder

respond to

far lower doses of ketamine

than persons with severe neuropathic pain.

.

.

Ketamine is unique for its rapid onset relief, and, when it is administered in an individualized way, it has fewer side effects. Many physicians and lay persons are likely afraid of rare side effects, and they may shun this valuable drug. Even now, everyone is started with the same sudden high IV dose: BHAM a big dose! Thus, when S-ketamine is FDA approved for use in a nasal spray the need to limit that method to emergency settings is very reasonable: the high dose BHAM! for S-ketamine spray in Emergency. Ketamine can be rapidly effective.

.

But for chronic severe forms of Major Depressive Disorder when there is no sudden emergency, I know of no better way to teach the use of ketamine nasal spray than we do now when we teach the use of rapid onset fentanyl spray under tongue. Simply teach how to begin treatment, slowly, at home, to reach the effect in one or two days.

.

I urge the FDA approve home use of S-ketamine for chronic conditions. There is very little difference between the use of rapid onset fentanyl spray under tongue for severe cancer pain and the use of ketamine nasal spray. I teach that to patients and doctors. It is humane and easily within our reach to address intolerable suffering.

.

With use of medication at home rather than Emergency Room, the patient is given control of a chronic intractable condition that fails to respond to other remedies. As always, physicians must assess past records and the entire history, the risk of addiction and drug abuse, and follow the patient at reasonable intervals for potential toxicity.

.

The main difference between ketamine and high dose opioids is that ketamine does not affect breathing, whereas we know what does, and its making headlines: death from prescription opioids. Any drug could potentially cause death, that’s why we use utmost caution and best judgement. Read about all the street addicts you want, and the sad thing is ketamine is now the #1 drug of abuse in China, but how different is that from opioids even on our streets? Yet, if you had an intractable condition, name the top drugs you would want to take home with you.

.

Here I discussed more about my experience with the drug for Treatment Resistant Depression.

 

.

.
PUBLIC WARNING

reprinted with permission of Demitri Papolos, MD
.
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.
.

.

.

.

.

.

.

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.

~~
This site is not for email and not for appointments.

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

~~~~~

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

.

Please ignore the ads below. They are not from me.

.

.

.For

Intranasal Ketamine in Major Depressive Disorder

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.

Physicians at Icahn School of Medicine at Mount Sinai, New York, studied intranasal ketamine in 18 patients with Major Depressive Disorder, published in 2014:

.

A Randomized Controlled Trial of

Intranasal Ketamine in Major Depressive Disorder

.


Conclusions

.

“This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression.”

.

I have previously posted more detail on this study. They report a significant antidepressant effect occurred as early as 40 minutes in some. I have seen some respond in seconds. But the dose is unique and specific to each person and there is no response until that dose is reached.

.

~~~

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It is hoped that more studies will be funded, though that seems unlikely since congress slashed the NIH budget in 2010 by the unthinkable 30%, never done in history.

.

Entire generations of scientists are now lost forever.

.

Ketamine Safety

.

Ketamine is one of the safest medications I have prescribed in 40 years of medicine. And I meticulously obtain laboratory studies at least twice a year to verify any potential harm as it has been reported in addicts that it may affect bladder, kidney, liver or biliary system. I first prescribed ketamine about 14 years ago for intractable pain rated 10 on a scale of 10 for 30 years; and prescribed ketamine since Spring 2012 for Major Depression. For years I searched to find a spray with a metered dosing system. Thus since late 2011, intranasal has been the delivery I find most useful. When given as nasal spray or under the tongue, not swallowed, it goes straight to the bloodstream, bypassing the liver, and works for depression because the liver does not convert it to a different metabolite.

.

Nevertheless, it is important to stress that ketamine must be monitored for any possible adverse effects including toxicity and/or addiction. I require long distance patients to be followed by a psychiatrist or psychologist regularly while on ketamine. So far, my returning patients have been stable for years.

.

Further, when given by the nasal or sublingual route, I do not see the side effects that my anesthesiology colleagues see after I.V. infusion. I’ve been in board meetings with some of the finest anesthsiology pain specialists in the country sharing and comparing experience. I don’t see those complications. But that is what is published and I.V. is how it is given in the few centers where ketamine is used for treatment of Major Depression or Bipolar Depression.

.

Ketamine is a short acting medication whether it is given I.V. or nasally or under the tongue. But it is quite bitter and most prefer nasal delivery.  Review the case study of the professional who traveled out of state once or twice weekly for one year to receive I.V. ketamine. She had failed ECT 9 or 10 times – memory loss was so bad she got lost in her own neighborhood. She now does very well on a small dose every 48 hours given nasally. In the same post, I reported the patient with Juvenile Bipolar Disorder, Fear of Harm phenotype whose profound thermoregulatory abnormalities respond in seconds to ketamine, with a very small dose of 10 mg nasal spray every 3 days. That’s it! Temperature responds in seconds, and the depression responds in 10 minutes in her case.

.

Unfortunately research protocols require the study of fixed dosages in order to be a cost effective study for one sample size at one dose to be even slightly meaningful, even then 18 patients studied at Mt. Sinai is a small study at the one dose they used.

.

The principle that I have always used is “start low, go slow.” That allows for the discovery that some large men may require the tiniest dose and some tiny 90 pound seniors may require some of the largest doses I’ve seen. It cannot be predicted by body weight. Anesthesiologists generally think in terms of mg/kg body weight, for example the 0.5 mg/kg I.V. generally used for depression. But ketamine’s dosage variance is unrelated to weight. That likely explains why some develop frightening symptoms when given IV, and others do not respond. One size does not fit all. That method either under-doses or overdoses.

.

There are case reports on this website giving examples of some individuals I have seen with Major Depressive Disorder. One man is unusual in needing a small dose only every 6 to 8 weeks, but most use the nasal spray daily or every second or third day. I suspect that after initially starting ketamine on a daily basis for one or two weeks, the frequency of dosing may be lowered to every two or three days. Less is more.

.

Professor David Feifel at UCSD guesstimates that ketamine helps 70% of persons with Major Depression. I think that’s a fair statement given that we are unlikely even to see the unknown number who remain at home, forever feeling they are unable to leave their confinement. We know that effects of ketamine are blocked in mice that are deficient in BDNF. We may speculate that when ketamine fails in persons with Major Depression, that may be due to lack of BDNF. We know exercise helps Major Depression and exercise increases BDNF. Much more research is needed.

.

The use of ketamine is essentially a first line drug for Complex Regional Pain Syndrome (CRPS). That may never be said in publications, but that has been the case for years in persons with CRPS who have failed all other medications. I specialize in CRPS, a form of neuropathic pain that leads to suicide more often than any other pain syndrome.

.

For pain, intranasal ketamine is far shorter lasting, typically three hours, rarely six. And requires doses far higher than for Major Depression or Bipolar Depression. Even then, when used for pain six times daily in very high doses, it has proven to be profoundly safe with few if any side effects that last less than half an hour, if present at all.

.

.

Inflammation

.

The role of inflammation and glia in the pathogenesis of depression has been well established since 2000, and discussed here. The study of ketamine has taken on new life with the discovery that it profoundly lowers pro-inflammatory cytokines produced by microglia. Inflammatory cytokines have been shown to be elevated in chronic pain and in Major Depression. That is why I feel it is important to prescribe adjuncts that also lower inflammatory cytokines. And patients with Major Depression and Bipolar Depression have reported the adjuncts make ketamine stronger and last longer. Some don’t even need ketamine after awhile, but remain on the adjuncts.

.

Ketamine is not a cure and I find it is best used with adjunct medication. In my experience, ketamine and adjunct medications are likely to help as long as prior to treatment, patients are still able to function, to work at least somewhat. I do have 4 patients in the last four years who have not left their home or their bed for many years, and they failed to respond. Sadly, one older woman had to be institutionalized for life, her melancholic depression was so deep. When ketamine is even partially effective, I have patients who had been too fatigued to work before treatment, yet who are able to return to graduate school for a PhD and do well for years on a stable dose. It is immensely rewarding to be a part of this unique therapy, to see them regain life and function after years of misery and disability.

 

.

.

Studies

.

S-Ketamine

.

It is my hope to be able to compare S-ketamine, that is not yet FDA approved, with the racemic* ketamine that we now have, that was FDA approved in 1970 in high dose as an anesthetic. Obviously we do not use high anesthetic doses for control of pain or Major Depression. I understand unfortunately that when clinical studies are completed, S-ketamine will be available only in emergency departments.

.

*Racemic means the molecule has equal amounts of left and right-handed enantiomers (mirror images) of a chiral molecule (meaning, you cannot superimpose the left hand with the right hand. They mirror but do not superimpose). Thus both left and right racemic ketamine mixture has been FDA approved, but the S-ketamine, the left sided molecule is considered a different drug, and must be FDA approved.

.

Without FDA approval, ketamine can be studied with FDA permission that provides an Investigational New Drug (IND) application.

.

Given the lack of funding for almost any research in this country, I would consider doing a patient-funded study if patients showed interest. It would be modeled on the intranasal study published in the Mt. Sinai study, above, i.e. short term, randomized, double blind, placebo controlled.

.

It is reported that S-ketamine may be more effective with fewer side effects. This must be proven and cannot be taken at face value without several studies. Shockingly, some publications in recent years have been fabricated and woven into mythology.

.

.

Finally, ketamine is off-label for pain and for major depression.

.

Papolos et al have published Clinical experience using intranasal ketamine in the treatment of pediatric bipolar disorder/fear of harm phenotype

..

“Ketamine administration was associated with a substantial reduction in measures of mania, fear of harm and aggression. Significant improvement was observed in mood, anxiety and behavioral symptoms, attention/executive functions, insomnia, parasomnias and sleep inertia. Treatment was generally well-tolerated.”

.

 

.
PUBLIC WARNING

reprinted with permission of Demitri Papolos, MD
.
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.

.

.

.

.

.

.

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.

~~

This site is not for email and not for appointments.

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

 

~~~~~

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

.

Please ignore the ads below. They are not from me.

.

.

.

 

 

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