Ketamine’s effects tied to opioid system in brain


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Stanford announces:

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Ketamine’s antidepressive effects

tied to opioid system in brain

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“Ketamine’s antidepressive effects require activation of opioid receptors in the brain, a new Stanford study shows. The surprising finding may alter how new antidepressants are developed and administered in order to mitigate the risk of opioid dependence.”

 

 

…”The study enrolled adults with treatment-resistant depression, meaning their condition had not improved after multiple treatment efforts. Twelve participants received infusions of ketamine twice — once preceded by naltrexone, an opioid-receptor blocker, and once with placebo. Neither the study participants nor the researchers were told whether active drug or placebo was administered during each test. The researchers found that ketamine reduced depressive symptoms by about 90 percent for three days in more than half of the participants when administered with a placebo, but had virtually no effect on depressive symptoms when it was preceded by naltrexone.”

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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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Comments are welcome.

This site is not for email, not for medical questions, and not for appointments.

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

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Ketamine for Bipolar Disorder Fear of Harm Phenotype Saved This Man’s Life


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Ketamine has given life back to so many who have been disabled by treatment resistant depression, bipolar disorder or intractable pain. It was approved in 1970 as an injectable anesthetic. It can be prescribed off-label from a compounding pharmacy inexpensively as a nasal spray or sublingual liquid or sublingual tablet for outpatient use or it may be given I.V. in a clinical setting. A patented nasal spray may be available soon (see below) for use only in a clinical setting.

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For many posts on ketamine since May 2009, use search function within this site at top left above small photo.

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NPR Morning Edition news today on ketamine for bipolar disorder “fear of harm phenotype.”

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For six years now, life has been really good for James. He has a great job as the creative director of an advertising firm in New York City. He enjoys spending time with his wife and kids.

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And it has all been possible, he says, because for the past six years he has been taking a drug called ketamine.

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Before ketamine, James was unable to work or focus his thoughts. His mind was filled with violent images. And his mood could go from ebullient to dark in a matter of minutes.

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Ketamine “helped me get my life back,” says James….

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…pharmaceutical companies are testing several new ketamine-related drugs to treat depression. Johnson & Johnson expects to seek approval for its nasal spray esketamine later this year, though the approval would be limited to use in a clinical setting.

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Meanwhile, doctors have begun trying ketamine on patients with a wide range of psychiatric disorders other than depression. And there is now growing evidence it can help people with anxiety, bipolar disorder, post-traumatic stress disorder, and perhaps even obsessive-compulsive disorder.

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“I think it’s actually one of the biggest advances in psychiatry in a very long time,” says Dr. Martin Teicher, an associate professor of psychiatry at Harvard Medical School and director of the Developmental Biopsychiatry Research Program at McLean Hospital.

James found his way to Dr. Demitri Papolos, an associate professor of clinical psychiatry at Albert Einstein College of Medicine.

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“He was like a whirling dervish when he came into my office,” Papolos says. “He was extremely fearful and scanning the environment all the time and he overheated at the drop of a hat.”

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Papolos diagnosed James with a variant of bipolar disorder he calls the “fear of harm phenotype.” It typically appears in childhood and often doesn’t respond to traditional psychiatric drugs.

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But Papolos has found that the condition does respond to ketamine. “It’s been transformational,” he says.

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In January, Papolos published a study of 45 children with the problem. They inhaled a nasal mist containing ketamine about twice a week. Nearly all got dramatically better.

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Scientists still aren’t sure why ketamine works, but there’s evidence that it encourages the brain to rewire, to alter the connections between cells. That process has been linked to recovery from depression. And it may also explain why ketamine helps people who have symptoms associated with several different psychiatric disorders.

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“I think it’s having multiple effects, and that means it’s probably useful for multiple different disorders,” Teicher says.

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One of those effects involves a part of the brain involved in temperature regulation. And that could explain why patients like James usually stop overheating once they are taking ketamine.

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James started taking a ketamine nasal spray every other day. He says his response was dramatic….

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Ketamine Relieves Depression By Restoring Brain Connections

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NPR All Things Considered published on ketamine 3/20/2017:

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Ketamine For Severe Depression: ‘How Do You Not Offer This Drug To People?’

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Gerard Sanacora, a professor of psychiatry at Yale University, has treated hundreds of severely depressed patients with low doses of ketamine, an anesthetic and popular club drug that isn’t approved for depression.

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“If you have patients that are likely to seriously injure themselves or kill themselves within a short period of time, and they’ve tried the standard treatments, how do you not offer this treatment?” he says.

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Why insist someone be suicidal? How do you not offer it to people who have failed all treatments and are disabled by intractable pain or treatment resistant depression? 

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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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Comments are welcome.

This site is not for email, not for medical questions, and not for appointments.

~~~~~

For My Home Page, click here:  

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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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After Ketamine for pain, complaints of depression dropped in half & pain reports were lower


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KPBS Radio highlighted a new study today by UCSD School of Pharmacy

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San Diego Scientists Find Further Evidence A Club Drug Could Treat Depression

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In a new analysis published Wednesday in the journal Scientific Reports, UC San Diego researchers said millions of FDA side effect records reveal that people who took ketamine for pain relief reported lower rates of depression.

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“The occurrence of complaints about depression dropped in half after ketamine administration,” said UC San Diego Skaggs School of Pharmacy professor Ruben Abagyan, who led the study.

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The researchers focussed on the FDA’s Adverse Effect Reporting System, a database that tracks negative side effects among people who take various drugs. But the researchers were not primarily interested in bad outcomes.

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Instead, they looked for a positive outcome: declining rates of depression among people taking drugs not typically thought of as antidepressants.

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They found signs that other common drugs — including Botox, a pain reliever called diclofenac and the antibiotic minocycline — also reduced depression among patients in the FDA database.

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[minocycline is a glial modulator and it can prevent CRPS from spreading.]

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University of Miami psychiatry professor Charles Nemeroff wrote that the study was, “very interesting.”

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“The findings are of considerable interest. However the interpretation of the findings are key,” he wrote, saying it will be important to understand whether ketamine is directly treating depression or simply relieving pain, which can indirectly help people experience less depression.

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The UC San Diego researchers said they controlled for this variable by comparing people who took ketamine with those who took other pain medications. They said they still found a larger drop in depression among those who took ketamine.

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This is the open source (free) article in Nature with brief excerpts below:

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Population scale data reveals the antidepressant effects of ketamine and other therapeutics approved for non-psychiatric indications

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.Isaac V. Cohen, Tigran Makints, Rabia Atayee, Ruben Abagyan

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We found that patients listed in the FAERS database who received ketamine in addition to other therapeutics had significantly lower frequency of reports of depression than patients who took any other combination of drugs for pain (LogOR −0.67 ± 0.034) (Fig. 1c). This reduction in depression is specific to ketamine and is known to be much more rapid than current antidepressants, making this observed effect very promising for treatment of patients with acute depressive or suicidal episodes. These patients cannot afford to wait up to six weeks for reductions in their depressive symptoms. Pain reports were also significantly lower for ketamine patients (LogOR −0.41 ± 0.019) (Fig. 1c).

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The analysis of the whole FAERS database revealed several other unintentional depression reducing drugs among antibiotics, cosmeceuticals and NSAIDS (Fig. 2). Our data supported previous studies that observed the psychiatric polypharmacology of minocycline [my emphasis], a tetracycline antibiotic14 (Fig. 2). The NSAID, diclofenac [that has highest incidence of heart attack and cardiac arrhythmia of any NSAID], was also observed to have some antidepressant properties (Fig. 2). It is theorized that both of these drugs may accomplish antidepressant effects through an anti-inflammatory mechanism. Because of the antidepressant activity of several NSAIDs, we further separated the non-ketamine pain cohort. Ketamine patients were then compared to patients who received any other combination of drugs for pain excluding NSAIDs. It was observed that depression event rates remained low (LogOR −0.56 ± 0.035) (Fig. 2)..The reduction of depression rates in ketamine patient records makes a case for study of ketamine as a psychiatric drug. These results imply that ketamine may be further explored as a monotherapy or adjunct therapy for depression. It should also be noted that FAERS data revealed that ketamine use [may] lead to renal side effects and awareness and caution in patients with renal or hepatic impairment may be warranted (Fig. 1a and b). [my emphasis].

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As an important side note, we also evaluated efficacy and side effects with the use of ketamine for pain management. We found that patients who were on ketamine had reduced opioid induced side effects including constipation (LogOR −0.17 ± 0.023), vomiting (LogOR −0.16 ± 0.025), and nausea (LogOR −0.45 ± 0.034) than patients who received any other combination of drugs for pain indications (Fig. 1d). Our data supports ketamine’s opioid-sparing properties and alludes to the fact that patients may receive benefits of improved pain, reduced requirement of opioids, and ultimately less opioid reduced side effects.

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The results of this study support previous small scale studies’ conclusions that ketamine is a good monotherapy or adjunct therapy for depression. In clinical practice ketamine would be especially useful for depression because of the quick onset of its action compared to existing first line therapies. Regardless of the causative mechanism ketamine appears to have therapeutic potential for TRD. Further, the potential to reduce many of the most complained side effects of opioid treatment makes ketamine adjunct therapy for pain seem desirable.

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Overall, this study demonstrates that the therapeutic potential of ketamine can be derived from appropriate statistical analysis of existing population scale data. This study also outlines a methodology for discovering off label pharmacology of existing approved drugs. This method can be applied to other indications and may reveal new important uses of already approved drugs, providing reliable justification for new indications without large investments in additional clinical trials.

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FDA Adverse Event Reporting System. The FAERS database was created to support FDA’s post marketing surveillance on drugs and biologic therapeutics. It contains adverse reaction and medication error reports sent to the FDA through MedWatch, the FDA Safety Information and Adverse Event Reporting Program. Reporting is voluntary and is done by patients, family members, legal representatives, doctors, pharmacists and other health- care providers. If any party reports an adverse effect to the manufacturer, the manufacturer is legally obligated to forward the report to the FDA. Data is available online in quarterly format for AERS from the first quarter of 2004 to the third quarter of 2012 and for FAERS from the fourth quarter of 2012 to the first quarter of 2016.

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The study used over 8 million adverse event reports from first quarter of 2004 to the first quarter of 2016. All the quarterly files from 2004 to 2016 were combined into a master file which was used as the primary source for analysis. . . .

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Out of 8 million reports, 279,853 reports were used for analysis of ketamine in Fig. 1. Two cohorts for ketamine (K) patients and pain (P) patients with 41,337 and 238,516 patients respectively....

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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.

~~

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!

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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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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.

~~
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!

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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

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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 Chronic Use in Children


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Oral Ketamine for Children with Chronic Pain: A Pilot Phase 1 Study

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From 2013:

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Participants were given 14 days of oral ketamine, 3 times daily, at dosages ranging from 0.25-1.5 mg/kg/dose. Participants were assessed for toxicity and for pain severity at baseline and on day 14 of treatment

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Of these 12 children, 5 experienced improvement in their pain scores, 2 with complete resolution of pain, lasting >4 weeks off ketamine treatment.

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Ketamine for Pain in Adults and Children with Cancer: A Systematic Review and Synthesis of the Literature

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From 2013

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Neurocognitive Changes after Sustained Ketamine Administration in Children with Chronic Pain

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From 2015:

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This prospective, uncontrolled study describes the neurocognitive functioning of 11 children with chronic pain before and after 2 weeks of daily oral ketamine exposure. Neurocognitive assessment was performed at baseline, Week 2, and Week 14.

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Neurocognitive assessment was performed at baseline, Week 2, and Week 14.

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This study did not detect any decline in neurocognitive scores in a small number of children exposed to 2 weeks of oral ketamine therapy. Randomized, controlled studies of the neurocognitive effects of ketamine in children are recommended to further investigate these preliminary findings.

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Pain treatment with ketamine cannot be compared with an untreated control group, that would be inhumane. How do opioids change the brain? And how humane is it to treat severe intractable pain in children by starting opioids for the rest of their life, with monthly visits for opioid medication potentially for decades when we know opioids create pain, create inflammation, not to speak of possible addiction.

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Pain itself no doubt can create cognitive and behavioral changes. Opioids for pain and the many adjuvants may do so as well. Sleep deprivation is often an issue with untreated pain.

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For children with severe behavioral problems, violent, abusive, dangerous and frightening, how can they socialize, how make friends, and how does their brain and behavior develop with such untreated patterns as they are beginning to realize who they are, and realize how they may have permanently damaged everyone they know and love?

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And from today:

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The dark side of opioids in pain management: basic science explains clinical observation

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The Angelic face of Opium is dazzlingly seductive, but if you look on the other side of it, it will appear altogether a Devil. There is so much poison in this All-healing Medicine that we ought not to be by any means secure or confident in the frequent and familiar use of it.Thomas Willis “Medicine in Man’s Body” VII i 128 1848

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Have we all forgotten the dark side of antipsychotics given to children? What does it do to their developing brains and bodies, creating obesity and lipid disease?

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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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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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First Ketamine Patient – Opioids


 

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You must get off opioids to get pain relief, even just to see where you are. I am continuing the conversation started September 2 because I am being attacked for saying get off opioids if you want to try something that may take away your pain. When you tire of pain and tire of monthly visits for opioids the next 30 years, try something better.

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I should have placed this case separately, not at end of note. Here’s the link to that post:

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My First Ketamine Patient 

Ketamine in Outpatient Use

 

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Scroll toward the end of page to read it.

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Opioids cause pain. I’ve said that repeatedly on this site. They trigger pro-inflammatory cytokines in brain and spinal cord which causes more pain. See the links given on home page of this website and repeated below:

 

Please read my posts on May 26, 2009 on low dose naltrexone, dextromethorphan, ketamine and January 2011 on neuroinflammation and the innate immune system in brain and spinal cord to understand some of the new concepts in medicine on which I base my approach. There is much overlap between pain systems and major depression systems, in medications and mechanisms in the brain. Quite often what works for pain will work for depression.

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I am continuing these comments because of continued attacks I am getting. Why attack me for suggesting pain may be treated with something other than opioids, that you must first taper off opiates, for saying opioids don’t work for CRPS?

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That is based on years of clinical experience since the turn of this century. What is your attack all about? If you like where you are at, stay there. America and the internet is full of attacks and rage — tearing so many people apart rather than building something, going forward, working together.

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It’s your choice! Cling all you want to what fails to help. Why attack me? and why expect me to post your attack on this educational site? People come to my office and presumably read those two links on the home page, copied above, and read many many case reports and many pages where I repeat: opioids cause pain. That opioid mechanism is validated research, not something I made up. And sure enough, people can get better after they taper off. But choose carefully what you replace it with.

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Some make an appointment and later are upset in the office when I say I am very mindful of CDC guidelines. If you are on some cocktail or some dose that some doctor has ramped up, do not expect other MD’s to agree with it. Why not stay with that MD? or have they lost their license? Yes, I do prescribe opioids. They may not be the dose you demand, and sadly you will be a patient for life if you take opioids.

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For these last 15 years, this new century, I am seeing patients do better and start to improve only after tapering off opioids. Have I not also defended opioids, railed against CDC opioid dictates? Opioids are all we have for some patients.

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One major obstacle to any alternative is that opioids make billions for pharma so why would pharma be induced to make something that actually relieves pain? I cannot even count how many opioids have been approved by FDA since the turn of this century,

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Stop the personal attacks. Free speech is American – go use it somewhere else. Morons and vicious cranks have taken over the web. Free us from vicious internet attacks that have changed web discourse into no discourse in this country, and now spread to polarized political opposition. Take no hostages. sheesh! Your personal experience is one I have seen thousands of for decades. Failures all. Lifelong use is the best you can hope for. So accept it and stop attacks. I cannot fight CDC. I tried for months to advise, but you don’t think they will stop at the current restrictions do you? Has your insurer already stopped paying for your opioid? That’s next. Why attack me?

 

We are all aiming for freedom. Freedom from pain, freedom in the body; plants are aiming for freedom, animals, social mores are striving for freedom, and we are all aiming for perfection. I hope the work I do continues to be a contribution towards that. It is amazing when it works. But people call to see me, and when I say they must come off opiates in order to do this exciting work, I am personally attacked. Rather than attacking the idea, I am attacked. We cannot move forward until you are ready to try. No one is forcing you to do anything. Stay where you are, find the doctor who will do what you want. Yes, the CDC is pushing everyone; the rules on dosing will get tighter, but they have nothing to offer in its place. Insurance stops paying for drugs that fall out of the CDC range. Congress is not needed to rope in the 80% of the opioids in the entire world that are prescribed in the US. Insurers like saving money on opioids that cost a fortune. $17,000 a month for one patient for one opioid, not counting the other one or two opioids and the many adjuvants these patients are on. See the incentive?

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I have time to report a small part of many years of clinical experience in seeing the amazing possibilities of complete freedom from pain — that occurs only after patients taper off opioids. I have posted case reports on these pages. Give up the attacks and fears. Go for better. No one is forcing you. You don’t have to give it a try. But there’s nothing to lose if you try. You could gain freedom.

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CDC is now getting an inkling, howbeit from a wrong direction, what happens after decades of NIH and congress fail to fund clinical pain research. Clinical research. Failing to ignore the essential discoveries of the innate immune system, how it regulates pain, glia and glial modulators. Medicine ignores science until pharma comes up with medications that modulate glia. But these medications already exist! We are ahead of the process. But it would help to invest in clinical trials on drugs that are glial modulators and a huge help to discover more.

Hello? any scientist or pharmaceutical company  motivated to tear themselves away from the opioid epidemic — what other alternative is there, CDC? We have opioids. Can pharma open the curtain to their money making, and use all those lobbyists hired by pharma to influence politicians, FDA, CDC on better? Can’t government agencies think without being paid tens of millions by pharma lobbyists?

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Consciousness must be wider than opioids. It must include all the science on the innate immune system we have learned since glial research began 1991. Linda Watkins and her lab in Boulder Colorado and the worldwide collaborations form the most exciting thing that has happened to brain research in the last 100 years and it is so dynamic! Fast! It’s not like neurodegenerative diseases that take years or months to evolve before we see change. Glial inflammation is dynamic, instantly evolving and interacting with the brain and master control systems in the body. And the work likely will apply to slower degenerative conditions. Use medications that modulate inflammation in pain and depression to study more interventions.

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This inflammation is created by your innate immune system. We thought glia, these cells, were sort of like glue, holding neurons and structures together or something. Turns out glia are dynamic and we need to study them in vivo, in humans, using pain as an instant feedback mechanism. The rat studies are done. Dog studies done. Papers in place. Professor Watkins and Xalud Therapeutics need $20 million —$20,000,000 —to do the final clinical studies to submit to FDA for approval of the most exciting treatment I could imagine.

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Xalud has the anti-inflammatory cytokine IL-10 in the brain. You may become pain free for 3 months at a time with one injection into the spinal fluid, the CSF. IL-10 restores the anti-inflammatory balance in the brain and spinal cord, the CNS. Chronic pain is caused and/or perpetuated by a super abundance of pro-inflammatory cytokines. Also true of depression in rats, and schizophrenia in young teens who have early signs of schizophrenia.

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Pharmaceutical companies want to make billions in opioids. Fine, and let’s include something that actually helps too. I directly connected one owner of a pharmaceutical company. Small change for this multibillionaire. I failed: zero interest. He was completely invested in opioids for cancer pain. You know they want to seel to 50,000,000 with chronic pain, but FDA approved only for cancer pain. The money in fentanyl is making headlines because of street use. It’s all in the timing. Opioids had been riding a wave of highs, the pun is dead serious, epidemics of death spread like wildfire across the country. Now in the only clinic in North America where addicts can inject safely, they find 90% of the street heroin is contaminated with fentanyl. Fentanyl is 50 times stronger than heroin, your family members and friends are dying from heroin cut with fentanyl. No doubt that happened to Philip Seymour Hoffman, because fentanyl is easier to get on the street, surely it is famous for its high – all opioids are different, but addicts don’t know its power to kill. They don’t have a clue what the dose is. That’s the difference. Knowing its safety profile.

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All I am hoping is that now that fentanyl is riding a rapidly moving down the wave from its high after so many years, that one of the fentanyl making companies invest in glial modulators and hopefully in Xalud Therapeutics. Let’s get this important work off the ground. Professor Watkins has received awards from so many countries. She has been keynote speaker for so many annual medical and scientific meetings. Results are ignored by opioid companies and investors.

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We are ignoring the unharnessed power of the natural, dynamic system in the brain and how to quench the fire that some process has ignited. We can modulate and help to restore balance in the innate immune system. We need to understand so much more. We need glial imaging available only in Australia. All we have are opioids.  I am angry. I want better for all.

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I am simply shocked at the evil of the status quo. The money in fentanyl. The failure of our president and congress to declare an emergency in treating pain and treating substance abuse. Give glial modulators the research it deserves. Stop with all the wars on cancer already. How about a war on cancer pain? We need tools in cancer pain because that applies to all. There is no such thing as cancer pain. Cancer can cause all the same types of pain that osteoarthritis can cause, only the added burden cancer can also kill.

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When I was teaching cancer pain management at MD Anderson Cancer Center, one of the best centers in the world, I saw how serious was our inability to relieve extreme pain when not even the surgical procedures touched pain, not cutting the spinal cord in half, not  alcohol ablation of the lumbo-sacral plexus, not even slicing the small spot in the brain that would turn off the affect toward pain. The patient could feel it, but it did not affect them. They didn’t care about pain. Unfortunately, I hope I never see one of those again. The person was not there anymore. Their entire personality was missing and words fail to describe how awful that was. Obviously these procedures are done only in the last few weeks of life when death is certain and all other procedures failed including opioids.

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This country could fund pain research as part of the new war on cancer. Cancer pain, the one we all dread the most, is nerve pain.  People with cancer have the same types of pain as anyone else, and nerve pain is the most difficult to treat. It has been astonishing for me to literally see intractable nerve pain go into remission. Why for Pete’s sake do I want to waste more of the past 42 years in medicine giving yet another page to someone angry about opioids and attacking me for comments on these pages?

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Gene Wilder once said about why he was so against the acting business, he said: “I like the acting, I don’t like the business.” Pharma is a money making business. Business ethics are not the same as medical ethics. Why should pharma do anything but focus on money  making opioids? They will if CDC cranks down their money making machine even more. And they will, only because they will see it has nothing to do with addicts killing themselves. That’s where we are back to the fentanyl. Heroin laced with fentanyl that’s 50 times stronger than heroin. More and more middle class people will see someone in their family dead from fentanyl on the streets. Kids in grade school passing pills of fentanyl they got on Amazon.

 

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Chronic pain, especially nerve pain, is most difficult to treat. It is never all about medication. Never. You must also learn tools you can use. Even if you pain goes to zero, are you deconditioned? I am certain you’ve got muscles involved and they need help too. You may easily be thinking the pain from those muscle points are nerve pain. Nope. Muscle stuff must be addressed in the language that muscles speak. They don’t speak medicine language.

Work with a psychologist on CBT or DBT. A pain psychologist is not needed to learn tools to make your mind strong. We must all use those tools. We must all be strong. No one can afford to fall apart emotionally because we know that makes pain worse. Learn the tools to use or else pain. There is no surgery, no pill, no Valium or Xanax or Ativan that can make you strong — no crutch. The dark bunny hole will always be there. Nietche’s abyss – we are always walking over the abyss. Do not look down. Look up.

Once we know how to cope, we have tools we can use at any time. Same with muscles that have been inactive for years. Tools we all learn. The entire family together can be taught what it takes for physical therapy. We cannot help all people. Some in pain need family help to bathe and dress and remember home exercises.

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For CRPS especially, we want to prevent spread, mirroring, appearing in the other limb and distant areas. I like to think of treatment like a football game. You’ve failed everything known, that makes it potentially harder. Spinal cord stimulators, nerve blocks, every known pill and high dose opioids. But you’ve got to win this game. You have one guy running down the field with a football, how many guys are you going to send after him? What if 3 or 4 guys only partially help? Add that up and you may have extra 30 or 40% relief. Hit pain hard, use selectively chosen glial modulators and others with mechanisms on these pathways, get pain to zero – or give it the best chance to get it near zero pain. That’s the first goal.

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Nothing is perfect. Nothing in medicine is perfect. It is still an art, not a science. But it is a gift to be able to use these tools that I’ve selected to use together the last 15 years. It’s thrilling to see the science come out explaining even more the power of the innate immune system, the glia.

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Had the practice of medicine evolved, we’d have worked with, not against, the timing of the circadian clock in these cells to prevent postoperative chronic pain, or minimize sending the inflammation into overdrive. That is not happening. Medicine is not tracking with the science. Opioids damage the balance of inflammation in a system already exploding with pain. It would be a miracle if providers and patients ever stop reaching for opioids first. Do they even understand they are doing the opposite of  relieving pain, or care that better choices exist? Perhaps, but it would take a multi-zillion dollar study.

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Pain management is only taught in 3% of medical schools. It loses money. Procedures make money. This is not about procedures. It’s about thinking and using proven mechanisms. Ask any MD and they’ve never heard of glial modulators. We all rely instead  on Pharma and medications approved by FDA to educate on all treatment – that goes for NIH and all medical schools and hospitals too. They teach opioids plus 1960’s pain management. When CDC takes away the opioids, we are treating pain using 1960’s methods plus gabapentin, Lyrica, Cymbalta. And what % of patients did these new drugs help?  one third? Half? No wonder 50 million people have chronic pain. We have 5 different short acting fentanyl products alone. And why is Amazon selling fentanyl when every city and country in the U.S. has people dying from it. Horse and dog fentanyl is same as human fentanyl. Some people think ketamine is a horse tranquilizer, as if it’s shocking to them to think horses and humans would respond differently. Give enough of a sedative, you go into a coma and then you can die. Use medication only under medical supervision.

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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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This site is educational, not for email.

Relevant comments are welcome.

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Advertising on this free website, below, is not endorsed or sanctioned by me.

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Ketamine Prescribed Since 1994 – My Experience


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Ketamine offers an opportunity for normal life unmatched by any medication I know of when given off-label for chronic treatment of intractable pain, treatment resistant depression, bipolar depression, juvenile bipolar disorder. It is one of the safest medications I have prescribed in 41 years of medicine. I have never seen anything more effective – it is not a cure, but remission is highly possible. Please refer to peer reviewed references since 2009 on this website on ketamine and depression or pain. Read elsewhere about street drugs, junkies, addicts and media headlines.

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Never Ketamine Alone

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Ketamine is short acting no matter how it is given.

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I never prescribe ketamine by itself – a fools errand; the religion of ketamine is like the religion of opioids. Decades of intractable conditions and chronic neuroinflammation require more than one short acting drug and usually require a multi-disciplinary approach. I work with psychologists or psychiatrists and other specialists when indicated.

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Entourage effect 

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DRUGS ARE LIKE POLITICIANS. A FAMOUS POLITICIAN MAY WALK UNRECOGNIZED, BUT WHEN YOU SURROUND HIM OR HER
WITH MANY PEOPLE, EVEN OF LESSER STATUS, THE POLITICIAN HAS A FAR MORE POWERFUL EFFECT.

Mechoulam

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1994 – I first prescribed IV when teaching cancer pain at MD Anderson Cancer Center.

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2001 – prescribed for outpatient care of chronic intractable pain

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2011 – prescribed for treatment resistant depression, bipolar depressed, juvenile bipolar/fear of harm phenotype often diagnosed as oppositional defiant disorder.

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2009 – writing about ketamine, neuro-inflammation and glial modulators on this site, with classic references to publications from the foremost peer reviewed journals, including low dose naltrexone, oxytocin.

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Depression, Bipolar Disorder, Juvenile Bipolar/FOH, treatment resistant – may need a dose only twice daily or every 3 days. The dose and frequency of use cannot be predicted – it is idiosyncratic – look up that word.

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Intractable pain – dosing and frequency of medications is very different than for depression.

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My work with these medications, these glial modulators, is too extensive to annotate on these pages. This website since April 2009 has references for context and guidance with active links to peer reviewed publications. Example:

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Clinical experience using intranasal ketamine in the treatment of pediatric bipolar disorder/fear of harm phenotype. D Papolos et al, J Affect Disord. 2013 May;147(1-3):431-6.

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RESULTS:

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.

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CONCLUSIONS:

Intranasal ketamine administration in treatment-resistant youth with BD-FOH produced marked improvement in all symptomatic dimensions. A rapid, substantial therapeutic response, with only minimal side effects was observed. Formal clinical trials to assess safety and efficacy are warranted.

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mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists. R Duman et al, August 2010, Science, Science 2010 Aug: Vol. 329, Issue 5994, pp. 959- 964. [this article free with registration]
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ABSTRACT:

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We observed that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.

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“The resulting protein synthesis and neuronal alterations in the medial prefrontal cortex are the opposite of those produced by chronic stress….”

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Read elsewhere about street drugs, junkies, addicts and media headlines.

If that is you, see an addictionologist, not me.

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Some medications can be drugs of abuse but every patient and every medication that I dispense is followed meticulously. If any sign of misuse or abuse, that unfortunate person is immediately discharged and referred elsewhere.

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For my Home Page, click here: 

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Welcome to my Weblog on Pain Management!

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This site is not for email or medical advice.

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It is not legal for me to give medical advice

unless you are my patient which means I have done a medical history and examination.

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I generally accept only those who have failed most or all known treatments, and only those who I feel I can help.

 

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I interview each patient before accepting.

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Any advertising below is not recommended or condoned by me.

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Migraine remission with ketamine – 20 years constant pain


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Ketamine

Migraine Case Report

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A 65 year old man reported 20 years of constant daily migraine without aura, with nausea, photophonophobia, triggered by barometric changes. Zomig or Imitrex would dull the pain a bit but it was never gone. Oxycontin 50 mg daily 6 months of every year dulled the pain but the nausea of migraine still persisted. He would taper off the opioid every 6 months, enduring weeks of withdrawal symptoms. He had been seen by some of the foremost migraine specialists in the country, and saw other neurologists before seeing me a few months ago.

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We elected to trial ketamine in a nasal spray – it can also be given under the tongue.

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I had never been convinced ketamine would work for migraine and often refer migraineurs to migraine specialists who offer Botox. However, I was encouraged by the report of the UCLA migraine expert, Alan Rapoport, MD, President of the International Headache Society, that injections of ketamine given repeatedly IM in the office,  help status migrainosis.

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The issue encountered with ketamine in treating this patient was side effects. Therefore, I asked him to lower the dose to a one that produces no side effects, repeat that lower dose 3 times per day for 2 or 3 days. That generally allows the body to develop tolerance to side effects so thereafter higher doses can be tested.

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Ketamine has no effect on pain, none whatsoever, until you reach your dose, that is different in everyone. The dose is idiosyncratic, it differs in everyone

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For pain, ketamine at an effective dose relieves pain in 10 to 15 minutes.

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He never reached an effective dose because of side effects. Instead, after a few weeks on a dose he could tolerate without side effects, migraine went into complete remission. Complete remission for months. For at least three months, he’s had no migraine. This is the first time in 20 years he has been headache free. Never free of migraine for even one day.

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Ketamine is a powerful glial modulator. It reduces pro-inflammatory cytokines in the CNS. We tried adding another glial modulator but in two or three days he developed a migraine, stopped the drug, and after another one or two migraines more, he has been migraine free for a few weeks since then. 

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For now, he remains on ketamine three times a day and is now trying twice daily dosing.

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As always, in any patient on medication that could have potential organ toxicity or lead to addiction, I monitor blood and urine regularly.

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This is unique.

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For about 15 years, I have treated patients with ketamine daily for chronic pain, those who have failed all prior medications, procedures, pumps and spinal cord stimulators. But we have always stopped if failing to achieve relief. I have no one who continued sub-therapeutic doses  for 4 weeks or more despite no effect. None. This man did and now has sustained complete remission with no side effects.

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Less is more.

Is that true for other forms of chronic pain?

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It is important not to lock onto one dose if less will work.  If, as research shows, ketamine lowers inflammatory cytokines in brain and cord, then over time, we may need less to maintain effect. At this time, we are very slowly decreasing daily frequency, very slowly, over months, to avoid triggering recurrence. 

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This site is not for email.

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

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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.

It is not a substitute for medical advice, diagnosis or treatment

provided by a qualified health care provider.

Relevant comments are welcome.

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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 educational website is

NOT advocated by me and NOT approved by me.

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Ketamine daily TID did nothing for migraine, but continuing it  at 80 mg TID for weeks – perhaps 2 months, migraine GONE first time in 20 years, for > 2 or 3 months. No sx of migraine at all

then added naltrexone 4.5 mg and triggered migraine!
Stopped LDN  couple days, and he had a couple migraine even after stopping, now none for couple weeks again, on ketamine.

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.

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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.

.

From the Abstract

.

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.

.

Perspective

.
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.

 

.

 

From the Discussion

.

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.

.

.

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.

.

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

.

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

.

From the Conclusion

.

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.

.

.

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.

.

“High failure rates of drugs targeted

to treat neuropathic pain

warrant changes in approaches.”

.

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.

.

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.

.

.

.

.

.

.

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


.

.

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.”

.

~

.

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?


 

.

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.

.

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


.

.

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.

.

~~~

.

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.

.

.

.

 

 

Ketamine for Intractable Pain: 5-Year Study of Efficacy & Safety, A Retrospective


.

.

Efficacy and safety of oral ketamine for the relief of intractable chronic pain: A retrospective 5-year study of 51 patients
European Journal of Pain, 11/25/2014

.

Marchetti F, et al. – This work summarizes the efficiency, failures and adverse effects of oral administration of ketamine at home for intractable pain. Pain was reduced or abolished in two–thirds of patients under ketamine therapy; ketamine was effective for patients taking opioids and resulted in few adverse effects.

.

Methods

.

  • This 5–year retrospective study involved testing ketamine by intravenous in–hospital administration, then a conversion to an oral route, or oral treatment directly administered at home.

  • The daily intravenous dose was increased by steps of 0.5 mg/kg to attain an effective daily dose of 1.5–3.0 mg/kg.

  • Pain was evaluated on a numeric scale from 0 to 10, and evidence of adverse effects was collected every day.

  • The effective daily dose was delivered orally (three to four intakes).

  • If effective, ketamine was continued for 3 months.

  • Short infusions or direct oral treatment began with a 0.5–mg/kg dose, then the daily ketamine dose was increased in 15– to 20–mg increments.

    .

Results

.

  • Among 55 cases (51 patients, neuropathic pain 60%), the mean effective oral dose was 2 mg/kg.

  • Ketamine was effective in 24 patients (44%, mean pain reduction 67±17%), partially effective in 20% (mean pain reduction 30±11%), with a mean opioid sparing of 63±32%, and failure in 22%.

  • Half of the patients experienced adverse effects, but only eight had to stop treatment.

  • For patients with opioid therapy, failure of ketamine was less frequent (7% vs. 36%; p<0.02), with fewer adverse effects (33% vs. 68%; p<0.01).

    .
    >>

  • .

    .

  • .

    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.

    .

    .

Ketamine – small doses work in depression and bipolar disorder


.

.

Everyone is very edgy right now with depression. Media is sensationalizing, which is the worst thing to do. I even hesitate to write this now.

.

Ketamine really does work

.

Small doses may be all that’s needed. Even large doses are safe.

.

Two Cases

.

I hate to play on emotion that is strong right now, but Robin Williams might be alive today if his doctors prescribed ketamine nasal spray.

.

Every one, doctors and patients alike, worry about ketamine. It sells newspaper headlines and distorted media coverage that then overtakes the life saving stories of its profound safety when used under good medical supervision. Experience helps.

.

Two cases from yesterday and today really must be shared. These two patients would not be alive today if they did not have ketamine nasal spray for their depression.

.

I don’t mean to say every one will respond to these extremely tiny doses, but it’s always exciting to hear the effective dose is simply so small.

.

These details would make good case reports if time permitted, but there is never enough time. I wanted simply to say a few things now because these two patients were seen.

.

**1**

.

In May 2014, saw a fifty-ish woman who is now responding to 20 mg (4 nasal sprays) given as one dose every 48 hours. She has been treated at well known university psychiatry departments, failed ECT 9 or 10 times – memory loss was so bad she got lost in her own neighborhood. Received IV ketamine once or twice weekly for one year before I saw her.

.

Diagnoses:  dysthymia as long as she can remember, and 25 years of Major Depressive Disorder, PTSD, anxiety, etc. Olympic level athlete —

.

.

**2**

.

Second patient now in late teens, Juvenile Bipolar Disorder/Fear of Harm phenotype, profound thermoregulatory changes respond in seconds to ketamine, 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. She was so violent before treatment that she had been hospitalized 7 times in 2-1/2 years. Doing very very well. And the low dose naltrexone, by the way, is involved in thermoregulation.

.

I should mention, no side effects whatsoever. I have never seen toxicity. I watch kidney and bladder function meticulously, and patients with massive pain on very high doses have never had any organ toxicity.

.

.

NEURO-INFLAMMATION AND GLIA – brain on fire.

.

I mention Olympic athlete because so many people I see with Complex Regional Pain Syndrome – the pain that so often leads to suicide, seems to occur more often in top level athletes, either state or national level, professional or sponsored in their teens. Yes, they occur in others, but there is a striking predominance in athletes for unknown reasons.

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Glia are triggered by trauma, then they become activated and produce pro-inflammatory cytokines. Inflammation is out of balance. Ketamine profoundly reduces the pro-inflammatory cytokines, and so does low dose naltrexone. I write about these mechanisms with more frequency that anything else. This is what we must address – the brain is essentially “on fire.” And this inflammation, these pro-inflammatory cytokines, are involved in almost every known disease: Alzheimer’s disease, Parkinson’s disease, ALS, chronic pain, major depressive disorder, cancer, autoimmune disease, and atheroscloerosis.

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Inflammation kills. Unfortunately this new research on glia and inflammatory diseases, these diseases could be called gliopathies, all based on new research since the turn of the century. We now know glia are your innate immune system in brain and spinal cord. They need a balance the anti-inflammatory cytokines with the pro-inflammatory cytokines. Inflammation may be lifesaving when you have caught a virus, but not as a steady diet. Give the brain a break or it leads to hyperexcitable glutamate that triggers calcium flooding into the neuron, cell death, brain atrophy and memory loss. Seen in people with Major Depression and those with chronic low back pain.

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Do doctors know about the innate immune system? or the receptor that won the Nobel Prize 2 and 1/2 years ago? or glia?

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Answer: no.

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

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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.

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Dr. Papolos’ video on treatment points out, ketamine nasal spray is off-label

for Bipolar Disorder. And I add, ketamine is off-label for pain and for major depression.

He posts this:

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PUBLIC WARNING

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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 it is FDA approved for another purpose, but he prescribes it for Juvenile Bipolar Disorder. I would add that in qualified hands, ketamine is one of the safest medications we have in our formulary.

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More later, as time permits.

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PUBLIC WARNING

reprinted with permission of Demitri Papolos, MD
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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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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.

~~~~~

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.

.

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

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Ketamine Nasal Spray for Major Depression – The First Randomized Controlled Trial


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A Randomized Controlled Trial of Intranasal Ketamine in Major Depressive Disorder

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Psychiatrists from Mt. Sinai in New York this month have published the first randomized controlled trial of intranasal ketamine showing it is safe, well tolerated, and rapidly effective in treating symptoms of depression in persons with Major Depressive Disorder.

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This is a small study of 18 patients with treatment resistant depression showing a significant antidepressant effect occurred as early as 40 minutes in some. 44% responded after 24 hours compared to 6% placebo. Ketamine was significantly different from placebo at 40 minutes, 240 minutes, and 48 hours, but not separable from placebo at 72 hours or 7 days thought they were still better. And ketamine was significant at improving anxiety symptoms at 24 hours. There were no clinically significant changes in heart rate or blood pressure and all changes resolved in four hours. “No serious adverse events occurred.”

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“Intranasal ketamine was well tolerated with only very minimal increases in dissociation, psychosis-like symptoms or hemodynamic parameters.” They felt these very minimal behavioral side effects and insignificant changes in blood pressure and pulse were consistent with the lower blood levels of ketamine compared to the higher doses used in studies of IV ketamine. Bioavailability via intranasal route is reported to range from 25% to 50%.

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Their sample had an average of 4.1 ± 3.9 treatment failures, compared to 5.7 and 5.1 in previous studies – those required a minimum of 2 to 3 treatment failures to enroll. Other clinical characteristics did not differ including “duration of illness, length of current depressive episode, and history of ECT.” They allowed ongoing treatment of psychotropic medication.

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They chose a 50 mg dose based on a previous study and on the dose used in persons with a chronic pain disorder (Daniel Carr, et al 2004). It is a lower dose than the 0.5 mg/kg dosage commonly given intravenously. They point out one limitation of the study was the use of the single dose and a standardized protocol, which did not allow them to study optimal dosing. Future study is needed to address optimal dosing, relapse prevention and scheduling of treatment.

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The minimal side effects shown in their study correlates well with my experience. I find the effective dose of ketamine is idiosyncratic. That means it is unpredictable and specific only to that individual. Large males may need only the smallest dose, and tiny elderly females may require far higher doses. That may account for the higher response rate that I believe I am seeing, however, I have not tracked percentage of responders. I have not seen toxicity in years of prescribing either for intractable pain or treatment resistant depression. Importantly, in my opinion, relapse prevention must address not only different neurotransmitters but also neuroinflammation, pro-inflammatory cytokines.

 

 

 

 

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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.

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

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Ketamine Inhaler – Bipolar Child NPR – Review of Ketamine for Depression


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NPR reported yesterday on the beneficial effects of ketamine for depression, this time reporting on a ketamine inhaler prescribed by Demitri Papolos, MD.

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Dr. Papolos is Associate Professor of Clinical Psychiatry at the Albert Einstein College of Medicine and Director of Research of the Juvenile Bipolar Research Foundation.

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He “is one of a handful of psychiatrists in the world who began to see and to speak out about the possible deleterious effects of antidepressants and stimulants in the population of children within the bipolar spectrum.”

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This NPR report described a syndrome Dr. Papolos has identified of Bipolar children & adolescents consumed by fear. They described a boy who had extreme attacks of rage for decades, and horrific violent nightmares.

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The boy had attempted suicide at age 5. He was hospitalized in a psychiatric unit at age 12 and strapped down in a padded room, terrified. He failed many medications for years, some made him worse, and he was literally never able to complete a meal at table with the family without flying off in a rage or someone leaving.

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in 2010, the boy tried Dr. “Papolos’ ketamine treatment. He says he’ll remember the day for the rest of his life. ‘I think we did two puffs, and I remember I sat up and I just started laughing,’ he says. Then his mother picks up the story: ‘You said you had an internal feeling of calm that you had never had before in your life. And when we came home that night, that was the first night that we ever all had dinner at the table without somebody leaving.'”

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This boy, George McCann, now at age 22 is finally able to begin a more normal life. He needs the medication only every third day. “Papolos has treated about 60 young people with ketamine so far and says all but two have had dramatic responses.”

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“The number of patients treated so far is small, and the approach is so new it hasn’t been tested by other researchers yet. Papolos says he’s hoping a study he published late last year will help persuade other researchers to try the drug on other children.”

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“In the meantime, George McCann continues to inhale a prescribed dose of ketamine every third day. The fear and anger that once dominated his life are gone, he says, adding that his mind is free now to work….”

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The relief with ketamine from the prison of mood disorders is deeply important. Severe mood disorders such as Major Depression and Bipolar Disorder can destroy the lives of patients and their loved ones. At worst, they can be lethal.

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A review of published cases of intravenous ketamine for depression asks : “Ketamine for depression: where do we go from here?

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I think the answer is we need to simplify the method of treatment using inhaled ketamine and begin to give their lives back to the patients we see. It is one of the safest medications I have ever prescribed. It does not cause weight gain or loss. It does not cause sexual dysfunction. And although it may increase sedation when used in combination with other sedating medications, at the low doses needed to treat mood disorders, I do not see ketamine interfere with other medication.

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Ketamine can relieve depression from one second to the next. And this young man needs the medication every third day. Is that too much to ask to gain a life?

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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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~

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

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

~

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

~
~

RSD/CRPS, Multiple Sclerosis, LDN & Ketamine


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It is rare for me to see a patient who is not complex.

They have failed so many treatments for so many years before they call.

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This is the report of a lovely woman in her early 70’s with progressive Multiple Sclerosis for 30 years and paraplegia that has forced her to use an electric scooter the last 5 years, and power wheelchair the last 2o years. Because of total paralysis of the right lower limb, she fell and shattered her femur, the thigh bone, in August 2009. Tragically, and all too often, the surgeon failed to diagnose Complex Regional Pain Syndrome [CRPS], even failed to visit her in the hospital. CRPS increased the fatigue she had already had from Multiple Sclerosis.

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Thankfully a physical therapist suggested the diagnosis.

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Why is pain management not a required subject for physicians?

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I have written elsewhere that the American Pain Society discovered that our National Institute of Health, NIH, devotes less than half of 1% of their research dollar to pain research. Of 28 NIH institutes, none for pain, three for addiction. This will not change soon. The only hope is that RSDSA.org will succeed in collaborating with all pain organizations, groups with dystonia, chronic fatigue in order to give a voice and research dollar to advances.

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Before seeing me in September, she had 11 sympathetic blocks with no benefit.

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Does it make you wonder why 11 were done?

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How does insurance authorize 11 when 10 had no benefit? I have just learned that a doctor must indicate at least 50% relief before another will be authorized. That explains it.

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Then she was given opioids including tramadal and Butrans patch which rendered her a “zombie,” sedated, poor memory, unable to function. She tried 4 or 5 treatments of Calmare with no benefit but was advised she needed a clear neural pathway for it to work. That was not possible due to the Multiple Sclerosis.
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Lyrica caused severe edema. Gabapentin 1400 mg/day caused weight gain, increased her appetite  more than usual, but she remained on it. She craves sweets more than usual, at times uncontrollably. Perhaps it can be slowly tapered now. Advil 600 mg gave some benefit but caused ulcers that required Nexium.

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Since her initial visit a few weeks ago, she became 60% better during her two week stay.

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I will highlight only two of the new medications started.

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It may also be said that opioids are not the answer.

Opioids may perpetuate pain.
They may produce paradoxical pain or opioid induced hyperalgesia or windup.

They may block the effect of ketamine and other adjuvants that would otherwise lower pain.

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Of importance is that she was not able to tolerate clothing on her right lower limb for three years, not even a sheet, and now she is able to sleep through the night without pain for the first time in three years and able to wear a skirt. This allows her to go out with family to restaurants and even to enjoy shopping with her daughter. Her dose of ketamine is very small relative to most of my patients and she uses it only once or twice a day since most of the new medications have brought her pain down.

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At her first visit one month ago, she rated pain from 6 to 8 on a scale of 10, average 7/10. Now 60% better, ranging from zero to 7, average 4. Yes zero pain, sleeping through the night without pain and waking without pain. She had not been able to tolerate touch to the right thigh or foot and would pull her skirt above the thigh, removing her shoe.

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Now she indicates pain continues to improve.

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Of interest, despite an abundance of concern that low dose naltrexone [LDN] may flare her Multiple Sclerosis, we were easily able to increase the dose to triple what is usually called “LDN.” This did not flare her condition and may be one of the most effective medications she is taking for pain.

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What is LDN?

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The FDA has sanctioned its use in the USA only in doses of 50 to 400 mg for addiction to opioids and alcohol.

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Low dose naltrexone [LDN] is a fascinating medication. It has been used in low dose in persons with Multiple Sclerosis since 1985 when a Harvard trained neurologist in New York City, Dr. Bihari, first discovered that it relieved all disability in some patients with Multiple Sclerosis and prevented recurrent attacks. Since then, doctors in Scotland, where they have the highest incidence of Multiple Sclerosis, find that one of the earliest signs of recovery in this population is relief of neurogenic bladder. It is said that persons with Multiple Sclerosis must remain on LDN for 1.5 years before they might fully assess its value.

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 Multiple Sclerosis may be flared unless very small doses of LDN are used.

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Many with Mulitple Sclerosis cannot tolerate more than 2 or 3 mg, perhaps due to spasticity. There is a great deal of dogma on the web about its mechanism, dosing and timing for off label use. Use the search function on this site to review the prior discussions I posted on LDN, MS, CRPS.

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Naltrexone is a glial modulator.

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What’s that?!

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By serendipity, four years ago I discovered naltrexone in low dose may relieve chronic intractable pain. I had been using it for perhaps eight years in microgram doses but I found in milligram doses it is even more profound.

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The mechanism of naltrexone and a wee bit of glial research is discussed here. The Nobel Prize was awarded last year for the discovery that these glia are your innate immune system. They are profoundly important in many diseases including chronic pain, Major Depression, Multiple Sclerosis, Alzheimers, Parkinsons Disease, ALS, Autism. They produce inflammatory cytokines that lead to inflammation.

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Now that she has been home for two weeks, on a number of medications that I started, not just the ketamine and LDN, I hope she will comment on her experience and her progress since flying back to the east coast after her brief visit here.

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It is often essential to taper off opioids to allow other medication to work.

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I feel she was able to benefit from these low doses of medication because she tapered off all opioid medication prior to her visit, thus allowing her system to recover and respond to these medications. We will know more in the next few months as she slowly titrates up on some of the medications that were started.

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Next year on her return, we may be able to withdraw some of the medications depending on how well she is doing.

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Finally, ketamine does cause her to have brief side effects. Her husband likens the effect the same as half a glass of wine: “She’s really cute.” Thankfully, most people have no side effects and if they do, they rarely last more than 20 minutes.

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She sends an update below, 80 to 90% better. Hopefully this will continue to improve over the next months as she slowly increases the medication we started. And ketamine has an additive effect in some. It is anti-inflammatory.

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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.

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

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

~~~~~

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

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Ketamine Rapidly Relieves Depression by Restoring Brain Connections


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This research is one of the most dramatic findings in the field of depression and mood disorders. It was published in Science by researchers from Yale and the National Institute of Mental Health, discussed by PBS here.

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The speed with which ketamine can relieve major depression is deeply moving to witness. In my experience prescribing nasal ketamine it works almost 100% of the time. I have discussed ketamine and previous publications on it for Major Depression and PTSD. It is also effective for suicidal and bipolar depression patients.

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Ronald S. Duman, PhD, the lead scientist, reviews his group’s research in this 2011 video:

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Stress and depression leads to structural changes in the brain and these structural changes are reversible.

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Depression affects 17% of the population, almost one in five of the population. Only one third of patients are effectively treated by existing antidepressants, even after many weeks. Nerve growth factors, in particular BDNF, are decreased by stress, with a very significant loss in depressed patients. BDNF produces antidepressant behavior in rodent models of depression.

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BDNF is important for influencing the survival and function of neurons.

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There are certain neurogenic zones in the brain that produce new neurons. Stress decreases the number of new neurons. Chronic antidepressant use increases the numbers and proliferation of these new neurons. Antidepressant treatment increases neurogenesis and this is dependent upon BDNF, this neurotrophic factor.

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[His slide shows] Exercise, Prozac, ECT, antipsychotics, antidepressants increase neurogenesis.

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Not only are there more synapses made by ketamine, but they are a larger size which is indicative of ones that are more functionally connected. Antidepressants take many weeks. A single dose of ketamine rapidly reverses depressive behaviors and loss of connections and completely reverses the decrements that had occurred over several weeks.

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In suicidal patients given ketamine at Yale in the Emergency Room, within a matter of hours, the suicidality is completely reversed. These people are better for weeks after a single dose of ketamine treatment. [emphasis mine]

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Therapeutically ketamine is even more rapidly acting than ECT.

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Ketamine increases BDNF. But research shows its effects are blocked in mice that are deficient in BDNF. Riluzole also influences BDNF, but the side effect profile is so serious that I would not consider prescribing it without more data on safety.

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Safety concerns are often raised in publications regarding chronic ketamine use. Most of my patients have no side effects at all. It is one of the safest medications we have and only a small percentage experience transient side effects. The favorable side effect profile, simplicity and low cost is key. The results for nasal ketamine are not 100%, neither is IV ketamine, but I have patients who respond to nasal spray when they failed IV ketamine. More importantly, they can carry it in their pocket and use as needed.

 

My experience prescribing ketamine goes back almost to the year 2000 for persons with chronic pain who have used ketamine several times daily, and since Spring 2012 for Major Depression. Its effect for depression lasts longer than for chronic intractable pain where it is short lasting. In the past, I prescribed it orally, by mouth, but since late 2011 I have prescribed it in a nasal spray and that form works for depression.

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The neuroprotective action of ketamine has been published since at least 1988.

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Patients can use nasal ketamine as needed. Schedules vary, everyone is different. It is short acting, but it does not stop working.

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However, the use of other adjuvants, such as glial modulators, in treatment of depression is essential to understand, and is now work in progress. The role of inflammation and glia in the pathogenesis of depression has been well established since 2000, and discussed here.

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Does ketamine also restore brain connections in patients with chronic pain? Chronic pain and major depression both lead to brain atrophy and memory loss. Both cause the same imbalance in glial cytokines. Both may respond to glial modulators, e.g. low dose naltrexone among others that have worked in some patients.

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“The original link between ketamine and relief of depression was made at the Connecticut Mental Health Center in New Haven by John Krystal, chair of the department of psychiatry at Yale, and Dennis Charney, now dean of Mt. Sinai School of Medicine, who helped launch clinical trials of ketamine while at the National Institute of Mental Health,” reported by Yale  here.

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I hope to add new approaches to treatment of anxiety that has failed to respond to other interventions.

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The material on this site is for informational purposes only, and is not a substitute

 for medical advice, diagnosis or treatment provided by a qualified health care provider.

~

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

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

~

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

~

~

~

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Ketamine IV vs Nasal Spray or Sublingual


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Patients ask me to compare IV ketamine to other routes of administration such as intranasal or sublingual. No one has done comparisons. Even if they had, every person is different and may have several pain syndromes.

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I have outlined one case below. One disadvantage of IV ketamine is the cost and the need to schedule for an IV treatment with your physician often weeks in advance. For some, this may mean setting aside two weeks to travel and make other arrangements. The alternative is carrying this low cost medication in your pocket and using as needed to relieve pain when you have pain, or to prevent pain when you know your activity will flare it.

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Ketamine is an important medication for pain.  It is considered a third line choice for pain relief, but it is almost a first line choice for Complex Regional Pain Syndrome, CRPS  – the old term is RSD. And I prescribe it for other conditions that have been refractory to treatment. But, far more than any other pain syndrome, pain from CRPS can be flared by emotional stress or minor injury and it can spread to other areas.

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Ketamine is a short acting medication. It is both analgesic and anti-inflammatory.

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Opioids create pain; ketamine not only relieves pain, it also relieves inflammation. In fact, opioids may prevent ketamine from helping at all.

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A small number of pain specialists in the USA, most at university centers, provide IV ketamine for CRPS. Not all people respond. A lucky few may get months of pain relief, but may require monthly boosters, i.e. it may be a short acting medication only during the infusion or it may offer relief for weeks or months but not years. I do not believe anyone has published comparisons showing duration of effect.

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I view ketamine as a short acting medication that requires other combination medications to “clamp” the relief and prevent pain from recurring.

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Here is a case report posted a few years ago of my patient who had 8 months of relief from IV ketamine. It was given 24 hours/day for 5 days in May 2007, followed by four hour IV boosters two days every month. Unfortunately all ketamine stopped having any effect after 8 months. I then added multiple medications that were selected because of specific mechanisms — no opioids, no ketamine — and she has been pain free since December 2009 on a single drug.

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CASE REPORT

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Today was the 5th visit in the last two weeks with an out of state patient who has had CRPS since 1999. She also has sciatic neuropathy, chronic lumbar pain after 360 degree spinal fusion, shoulder pain, and two types of headache. Medications are now significantly helping all pain syndromes.

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Before seeing me, she had had a total of 9 infusions of IV ketamine most of them given at doses of 300mg/hr — a very high dose. She had no side effects from ketamine. One of those infusions was given for 6 days over 4 hours each day. She had failed a lidocaine infusion at high dose. A spinal cord stimulator was reprogrammed 10 times, but only made pain worse.

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I then started her on a combination of medications. With addition of the first new medication, she had 50% improvement in the first 24 to 36 hours, that lasted beyond the relief from nasal ketamine that was also started. Unfortunately, on day 8, she and another family member, came down with a virus that causes headache and severe vertigo. Nevertheless, all pain is markedly better.

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With ketamine she is able to reduce pain down to 1 on a scale of 10 for a few hours. Best of all she can carry it with her and use it as needed. She no longer needs to take two weeks out of her life to schedule IV ketamine infusions.

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It will take almost 3 months to slowly increase the other medications we started. Hopefully this combination will “clamp” the pain and prevent it from increasing so that she may become pain free without needing ketamine.

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After that, if she is able to become pain free, the plan is that we will then be able to slowly remove most of the new medications we started this week and still maintain relief of pain. I will see her again in the future.

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Sierra wildflowers

Click to embiggen

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~~~~~

The material on this site is for informational purposes only,

and is not a substitute for medical advice,

diagnosis or treatment provided by a qualified health care provider.

.

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

If you wish an appointment, please telephone my office.

.

~

For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

~

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Depression, Ketamine, Naltrexone, Glia and Inflammation – A Case Report


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Current antidepressant therapies are only modestly effective, may have significant side effects and do not provide universal efficacy.

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The role of inflammation and immune systems in the pathogenesis of depression has become well-established since 2000. Immune system activity is mediated by pro-inflammatory cytokines that change behavior.

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This 2012 review is the first to summarize genetic variants of the inflammatory system involved in immune activation and Major Depressive Disorder, Major Recurrent Depression, Dysthymia, Childhood Onset Major Depression and Geriatric Depression: The role of immune genes in the association between depression and inflammation: A review of recent clinical studies. They reviewed 52 papers of which 27 are case-controlled studies. 

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Pro- and anti-inflammatory cytokines are produced by glial cells in the central nervous system (CNS). Glial cells make up 90% of the cells in the CNS; 10% are nerve cells, neurons. When glia are activated, they produce cytokines that lead to inflammation. Glia and inflammatory cytokines play a role in infection, stroke, trauma, chronic pain, Multiple Sclerosis, Alzheimer’s Disease, Parkinson’s Disease, ALS and Major Depression. The Nobel Prize was awarded in 2011 for discoveries of the innate immune system, in particular the mammalian Toll-like receptor 4 (TLR-4) which is the receptor for naltrexone. That discovery incidentally was made by Bruce Beutler at Scripps Research Institute.

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You can read more about glia and the inflammatory response posted January 2011: Pain and the Immune System – It’s Not Just About Neurons – Naltrexone. This is not specific to pain but also relates to some with major depression.

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Ketamine is a major anti-inflammatory and glial modulator. Naltrexone is a glial modulator that I have prescribed for chronic pain in low dose for almost four years in patients who are not taking opioids, and in ultra low microgram dose for more than eight years in patients who are on opioids for pain. Some of those case reports are posted on this site.

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Low dose naltrexone, LDN, may be effective for Autism, Multiple Sclerosis, and some autoimmune diseases. Jarred Younger at Stanford has shown fibromyalgia symptoms are improved by LDN; Jill Smith at Pennsylvania State University, Hershey, has shown remission in Crohn’s Disease with LDN; and Bruce Cree at UCSF has shown improved quality of life in a small study of Multiple Sclerosis that he is pursuing with larger multi-center studies.

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Case Report

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This week I saw a young man who traveled from Northern California for me to possibly treat major depression with nasal ketamine. Depression prevented him from working for the last two years. He scored 34 on the Hamilton Depression Rating Scale. Scores over 24 indicate severe depression. On June 4, 2012, we started his treatment using ketamine nasal spray. The daily dose was increased but has not yet reached an effective level. In my experience of prescribing ketamine for pain and depression in the last eleven years, the dose differs for everyone and is not related to age, gender or body weight.

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As conveyed by him to me, his progress thus far:

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ON JUNE 7, 2012, early morning, he used 40 mg of ketamine by nasal spray. He reported feeling dizzy, experiencing spinning sensation for two hours and then was his usual self, i.e. he felt bad the rest of the day as his usual self but vision was better. His strabismus (lazy eye) usually depends on better mood, but mood was unchanged.

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At 3:00 pm, he took naltrexone, a very low dose approximately 4 mg.

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ON JUNE 8th: approximately 12 hours later, he woke at 2 AM. He later told me that he was feeling “extremely sharp! I felt great! Clear in mind, quiet and calm. I didn’t realize how noisy my mind is till everything felt calm.” He returned back to sleep.

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He woke again at 6 AM feeling great! Not thinking negative thoughts, but no other change, i.e. did not like or love activities or people anymore than in recent years with his depression.

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At 1:15 PM, in the office his self-rated improvement of depression was 40% due to the low dose of naltrexone taken yesterday afternoon. He had no effect from ketamine as yet, and had not used any in more than 24 hours.

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My plan has been to trial low dose naltrexone for persons with treatment resistant depression. If it is effective, then ketamine is not needed. Ketamine is a short acting medication and may pose issues such as tolerance, whereas low dose naltrexone is simple, once daily, used with few side effects and has never caused tolerance in my clinical experience.

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It is very possible that with such rapid improvement overnight and continued treatment, his depression will continue to improve over coming weeks and months.

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~~~~~

The material on this site is for informational purposes only,

and is not a substitute for medical advice,

diagnosis or treatment provided by a qualified health care provider.

.

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

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

~

~

For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

.

.

Glia a Promising Target for Neuropathic Pain – Ketamine Acting on Glia More Than on Neuronal NMDA Receptors?


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 Three important new articles from March, August and November 2011, show ketamine acts on glia.

Emphasis within articles is mine.

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

Abstract

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

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Ketamine depresses toll-like receptor 3 signaling in spinal microglia in a rat model of neuropathic pain.

Abstract

Reports suggest that microglia play a key role in spinal nerve ligation (SNL)-induced neuropathic pain, and toll-like receptor 3 (TLR3) has a substantial role in the activation of spinal microglia and the development of tactile allodynia after nerve injury. In addition, ketamine application could suppress microglial activation in vitro, and ketamine could inhibit proinflammatory gene expression possibly by suppressing TLR-mediated signal transduction. Therefore, the present study was designed to disclose whether intrathecal ketamine could suppress SNL-induced spinal microglial activation and exert some antiallodynic effects on neuropathic pain by suppressing TLR3 activation. Behavioral results showed that intrathecal ketamine attenuated SNL-induced mechanical allodynia, as well as spinal microglial activation, in a dose-dependent manner. Furthermore, Western blot analysis displayed that ketamine application downregulated SNL-induced phosphorylated-p38 (p-p38) expression, which was specifically expressed in spinal microglia but not in astrocytes or neurons. Besides, ketamine could reverse TLR3 agonist (polyinosine-polycytidylic acid)-induced mechanical allodynia and spinal microglia activation. It was concluded that intrathecal ketamine depresses TLR3-induced spinal microglial p-p38 mitogen-activated protein kinase pathway activation after SNL, probably contributing to the antiallodynic effect of ketamine on SNL-induced neuropathic pain.

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Microglial Ca(2+)-activated K(+) channels are possible molecular targets for the analgesic effects of S-ketamine on neuropathic pain.

Abstract

Ketamine is an important analgesia clinically used for both acute and chronic pain. The acute analgesic effects of ketamine are generally believed to be mediated by the inhibition of NMDA receptors in nociceptive neurons. However, the inhibition of neuronal NMDA receptors cannot fully account for its potent analgesic effects on chronic pain because there is a significant discrepancy between their potencies. The possible effect of ketamine on spinal microglia was first examined because hyperactivation of spinal microglia after nerve injury contributes to neuropathic pain. Optically pure S-ketamine preferentially suppressed the nerve injury-induced development of tactile allodynia and hyperactivation of spinal microglia. S-Ketamine also preferentially inhibited hyperactivation of cultured microglia after treatment with lipopolysaccharide, ATP, or lysophosphatidic acid. We next focused our attention on the Ca(2+)-activated K(+) (K(Ca)) currents in microglia, which are known to induce their hyperactivation and migration. S-Ketamine suppressed both nerve injury-induced large-conductance K(Ca) (BK) currents and 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS1619)-induced BK currents in spinal microglia. Furthermore, the intrathecal administration of charybdotoxin, a K(Ca) channel blocker, significantly inhibited the nerve injury-induced tactile allodynia, the expression of P2X(4) receptors, and the synthesis of brain-derived neurotrophic factor in spinal microglia. In contrast, NS1619-induced tactile allodynia was completely inhibited by S-ketamine. These observations strongly suggest that S-ketamine preferentially suppresses the nerve injury-induced hyperactivation and migration of spinal microglia through the blockade of BK channels. Therefore, the preferential inhibition of microglial BK channels in addition to neuronal NMDA receptors may account for the preferential and potent analgesic effects of S-ketamine on neuropathic pain.

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The material on this site is for informational purposes only,

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.


For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

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.

.

.

.

Ketamine Intranasal for Rapid Relief of Pain and Depression


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Poorly managed pain can evolve into chronic disease of the nervous system

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Ketamine is an important analgesic, more important than opioids. It can dramatically reduce pain, and rapidly relieve depression and PTSD.  Please read my earlier posts here and here. And the NPR report here just after I posted this (skip to their last section). Yes, it is FDA approved and legal. One woman said:

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 ‘It was almost immediate, the sense of calmness and relaxation.

‘No more fogginess. No more heaviness. I feel like I’m a clean slate right now. I want to go home and see friends or, you know, go to the grocery store and cook the family dinner.’

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NPR again reports ketamine’s rapid relief of depression. A 28 year old man whose refractory depression began at age 15, after ketamine, says:

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‘I Wanted To Live Life’

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Stephens himself has vivid memories of the day he got ketamine. It was a Monday morning and he woke up feeling really bad, he says. His mood was still dark when doctors put in an IV and delivered the drug.”Monday afternoon I felt like a completely different person,” he says. “I woke up Tuesday morning and I said, ‘Wow, there’s stuff I want to do today.’ And I woke up Wednesday morning and Thursday morning and I actually wanted to do things. I wanted to live life.”.
.
Since then, they treated him with Riluzole that is FDA approved for ALS and has one of the dirtiest side effect profiles I have ever seen in medicine with serious organ toxicity. Ketamine rarely causes mild transient side effects, usually none. It appears the concern is how ketamine is used on the street with potential for abuse. I do not see ketamine abuse in my patients, some of whom are on opioids for pain or Valium family medicines from their psychiatrist. All of those have a greater potential for abuse, also not occurring in my patients. Pain and/or depression can lead to suicide.
.
About 18 months ago, researchers at Yale found a possible explanation for ketamine’s effectiveness. It seems to affect the glutamate system in a way that causes brain cells to form new connections.
.
Researchers have long suspected that stress and depression weaken some connections among brain cells. Ketamine appears to reverse the process.

.

It would be of interest to see a case report of the bladder problems they mention. Is this in a single drug addict who used many unknown medications on the street? Several physicians have infused IV ketamine for persons with pain for many years, in far higher doses than I prescribe, with no report of any but transient minor symptoms.

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David Barsook’s 2009 review, reference below, describes changes that cause memory loss and brain atrophy with chronic pain, in particular, Complex Regional Pain Syndrome (CRPS), and they also occur with chronic depression:

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With the onset of chronic pain (including CRPS) a number of changes in brain function occur in the human brain including but not limited to: (1) central sensitization ; (2) functional plasticity in chronic pain and in CRPS; (3) gray matter volume loss in CRPS ; (4) chemical alterations; and (5) altered modulatory controls. Such changes are thought to be in part a result of excitatory amino acid release in chronic pain. Excitatory amino acids are present throughout the brain and are normally involved in neural transmission but may contribute to altered function with excessive release producing increased influx of calcium and potentially neural death.

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Brain atrophy and memory loss has also been shown in chronic low back pain as well as in chronic depression.

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Barriers to management of chronic pain are many:

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Although opioids are effective for acute pain, effective treatment of chronic pain is often daunting, particularly neuropathic pain.

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Opioids have been shown to create pain causing imbalance in the glial cytokines that favor pain rather than relief of pain. Opioids carry the risk of opioid-induced hyperalgesia which is a severe pain sensitivity. They affect the brain and endocrine system. Opioids may fail to offer significant relief, fail to improve function, and risk misuse, abuse, diversion and death. Their costs are astronomic, insurance coverage is increasingly limited, the potential for complications may be life threatening in a hectic medical setting, side effects can be lethal, lack of physician training in use of opioids and alternatives to pain control lead to increasing deaths, addiction and diversion. It has become a national emergency and a trillion dollar war on drugs.

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Complications can be greatly reduced through use of a scrupulous history and physical examination, but reimbursement is directly proportional to the shortest time spent with a patient. Will that help assessment and care?

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Individuals may have dramatically different responses to opioid therapy; some may not tolerate any, and relief must be balanced with side effects that increase as the dose increases. Patient status may change and require IV, rectal or tube delivery instead of oral formulas; drug-drug interactions may require rapid changes, and disease of kidney, liver or brain may require modifications or stopping altogether. They may increase risk of falls and cause central sleep apnea with drop in oxygen because the brain fails to give a signal to breathe.

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Chronic pain can lead to loss of sleep, hopelessness, depression, anger and other mood disorders such as panic, anxiety, hypochondriasis and post traumatic stress disorder [PTSD]. Treatment of mood disorders are shown to profoundly reduce pain perception and/or ability to cope with pain.

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Ketamine is anti-inflammatory and can reduce the need for opioid use, thus reducing the pain and side effects caused by opioids.

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Nasal ketamine is more effective than oral ketamine for pain relief; oral dosing has no effect on depression.

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Nasal delivery of ketamine is now possible due to advances in metered nasal sprayers that deliver a precise dose. No needle is required, no IV access, no travel to a specialist needed.

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You can carry pain relief with you and use it as directed when it is needed.

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Ketamine is an NMDA antagonist: it antagonizes the NMDA receptor which plays a profound role in pain systems and centralization of pain.

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Ketamine is neuroprotective and it can help other disease states as noted by Barsook, 2009:

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Besides improvement in pain, “there may be lessons from other diseases that affect the brain; it is noteworthy that acute ketamine doses seem to reverse depression and ketamine decreased prevalence of post-traumatic stress disorder (PTSD) in soldiers receiving ketamine during their surgery for treatment of their burns. In addition ketamine attenuates post-operative cognitive dysfunction following cardiac surgery that has been known to produce significant changes in cognition. [emphasis mine] The data suggest that the drug can alter or prevent other conditions based on its NMDAR activity where other drugs NMDA receptor antagonists are perhaps not as effective in these or pain conditions. Lastly, NMDA antagonists have been used in degenerative disease (and pain may be considered a degenerative disease as defined by loss of gray matter volume, see above) with mixed effects perhaps relating to how they act on specific NMDA subtypes. Taken together, ketamine may act not only on sensory systems affecting pain intensity, but also on a constellation of brain regions that are involved in the pain phentype. [sic, phenotype]”

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Side Effects

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Ketamine is more frequently used in babies and children than in adults because high doses of ketamine can induce hallucinations in the adult. Importantly, it is used in high dose in adults for treatment of Complex Regional Pain Syndrome.

Low doses, cause little or no side effects in adults. If present, they are transient and often resolve in 20 minutes. Patient who respond to ketamine report good acceptance as they find the relief of pain and/or depression far outweighs any short term minimal discomfort.

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Pain care reform is urgently needed.

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Research funding for pain is less than half of one percent of the NIH budget. More research is needed, but research on low dose ketamine for treatment of pain and depression has gone on for twenty years.

The public health crisis of untreated pain, which often results in disability, parallels the country’s struggle to halt the cost of health care. The longer a person remains with untreated pain, the less likely they are to return to work or to be employable.

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Conclusion

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Pain control requires urgent attention. It is past time to put into practice the use of this valuable medication so people can get on with life instead of being mired in chronic pain that for many risks suicide and ensures continuing decades of disability. Academic studies are usually limited by defining a predetermined dose rather than clinically titrating to effect. Thus no surprise, they find no effect as every patient will have no response until they reach their dose. And that dose, in my experience, falls into a bell shaped curve. One size does not fit all. Some respond at very low dose, others require much more, and the majority fall between.

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In my experience prescribing ketamine for ten years, only a rare person has problems. Almost all find it has returned function or significantly relieved pain. Some have been able to entirely eliminate opioids that did nothing for their pain for decades, though they dutifully returned to the MD every month to chronicle that pain. Pain continued to be rated ten on a scale of ten; patient always compliant despite side effects of constipation and often depression. My patients find the benefits of nasal ketamine far outweigh the relief of oral ketamine and at much lower doses with fewer side effects.

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Further, while the pain relief may be short lived, some find it gets better with repeat dosing, and relief of depression may last one to two weeks with a single dose.

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References

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http://www.wjgnet.com/1007-9327/10/1028.asp  Ketamine suppresses intestinal NF-kappa B activation and proinflammatory cytokine in endotoxic rats.

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CONCLUSION: Ketamine can suppress endotoxin-induced production of proinflammatory cytokines such as TNF-a and IL-6 production in the intestine. This suppressive effect may act through inhibiting NF-kappa B.

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http://informahealthcare.com/doi/abs/10.1080/J354v16n03_03  Ketamine as an Analgesic Parenteral, Oral, Rectal, Subcutaneous, Transdermal and Intranasal Administration

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Ketamine is a parenteral anesthetic agent that provides analgesic activity at sub-anesthetic doses. It is an N-methyl-D-aspartate (NMDA) receptor antagonist with opioid receptor activity. Controlled studies and case reports on ketamine demonstrate efficacy in neuropathic and nociceptive pain. Because ketamine is a phencyclidine analogue, it has some of the psychological adverse effects found with that hallucinogen, especially in adults. Therefore, ketamine is not routinely used as an anesthetic in adult patients. It is a frequently used veterinary anesthetic, and is used more frequently in children than in adults. The psychotomimetic effects have prompted the DEA to classify ketamine as a Schedule III Controlled Substance. A review of the literature documents the analgesic use of ketamine by anesthesiologists and pain specialists in patients who have been refractory to standard analgesic medication regimens. Most reports demonstrate no or mild psychotomimetic effects when ketamine is dosed at sub-anesthetic doses. Patients who respond to ketamine tend to demonstrate dramatic pain relief that obviates the desire to stop treatment due to psychotomimetic effects (including hallucinations and extracorporeal experiences). Ketamine is approved by the FDA for intravenous and intramuscular administration. Use of this drug by the oral, intranasal, transdermal, rectal, and subcutaneous routes has been reported with analgesic efficacy in treating nociceptive and neuropathic pain.
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http://www.ncbi.nlm.nih.gov/pubmed/15109503  Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study  Daniel Carr, et al, 2004
Crossover, 20 patients. Ketamine reduced breakthrough pain within 10min of dosing, lasting up to 60min
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http://www.ncbi.nlm.nih.gov/pubmed/15288418  Safety and efficacy of intranasal ketamine in a mixed population with chronic pain
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The intranasal route for ketamine administration has been applied only for pain of dressing changes in a single case study (Kulbe, 1998). In this patient, oxycodone and acetaminophen were ineffective to control pain during burn dressing changes in a 96-year-old woman cared for at home. She tolerated the burn dressing changes after three intranasal sprays of 0.1 ml each, in rapid succession, each containing 5 mg ketamine (15 mg total) (Kulbe, 1998).
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http://www.acutepainjournal.com/article/S1366-0071%2807%2900167-2/abstract  Safety and efficacy of intranasal ketamine for acute postoperative pain
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Ketamine delivered intranasally was well tolerated. Statistically significant analgesia, superior to placebo, was observed with the highest dose tested, 50 mg, over a 3 h period. Rapid onset of analgesia was reported (<10 min), and meaningful pain relief was achieved within 15 min of the 50 mg dose. The majority of adverse events were mild/weak and transient. No untoward effects were observed on vital signs, pulse oximetry, and nasal examination. At the doses tested, no significant dissociative effects were evident using the Side Effects Rating Scale for Dissociative Anaesthetics.
The safety profile following treatment with ketamine was comparable to that seen with placebo.
Although patients did report side effects of fatigue, dizziness and feelings of unreality more often following treatment with ketamine than following treatment with placebo, no patient reported hallucinations and the side effects were generally reported to be of mild or moderate severity, and transient. No serious adverse events were reported and the incidences of associated adverse events were comparable for ketamine and placebo. Although study medication was administered intranasally, nasal signs and symptoms were few and inconsequential. A distinctive taste, however, was reported more often following treatment with ketamine than following treatment with placebo.In conclusion this randomized, placebo-controlled, double-blind study, in 20 patients, has demonstrated that intranasal ketamine is safe and effective for BTP [breakthrough pain]. Our findings augment an early but promising literature documenting the effectiveness of nasal administration of a variety of opioids for pain management in adults (Dale et al., 2002) .
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~http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2875542/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2875542/  Ketamine and chronic pain – Going the distance, David Barsook, 2009

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This important paper covers essential points not mentioned by many, thus quoted at length below:

“Ketamine, brain function and therapeutic effect – neuroprotective or neurotoxic

With the onset of chronic pain (including CRPS) a number of changes in brain function occur in the human brain including but not limited to: (1) central sensitization ; (2) functional plasticity in chronic pain and in CRPS; (3) gray matter volume loss in CRPS ; (4) chemical alterations ; and (5) altered modulatory controls. Such changes are thought to be in part a result of excitatory amino acid release in chronic pain. Excitatory amino acids are present throughout the brain and are normally involved in neural transmission but may contribute to altered function with excessive release producing increased influx of calcium and potentially neural death. Here lies the conundrum the use of an agent that potentially deleteriously affect neurons that may already be compromised but may also have neuroprotective properties by mechanisms that include reducing phosphorylation of glutamate receptors resulting in decreased glutamatergic synaptic transmission and reduced potential excitotoxicity . Alternatively, ketamine may affect glia regulation of glutamate and inhibit glutamate release within glia. However, by whatever mechanism ketamine acts on CRPS pain, there does seem to be a dose/duration effect in that longer doses at levels tolerated by patients seem to prove more effective in terms of the duration of effects.

So what could be happening in the brain and what is required to alter brain systems and reverse the symptomatic state? Ketamine may diminish glutamate transmission and “resets” brain circuits, but it seems that a minimal dose and/or duration of treatment is required. Alternatively, ketamine may produce neurotoxicity and damage or produce a chemical lesion of affected neurons. These two issues are important to be understood in future trials. Reports from patients who have had anesthetic doses have included prolonged pain relief for many months. While the authors did not address issues such as the effect of dosing duration or repetitive dosing at say 6weeks, they did show a level of efficacy based on NNT that equals or betters most drug trials for this condition.”

….

“Conclusions

As a community we have a major opportunity to define the efficacy and use of a drug that may offer more to CRPS (and perhaps other) patients than is currently available. This is clearly an opportunity that needs urgent attention and a number of questions remain to be answered. For example, is ketamine more effective in early stage disease? How does ketamine provide long-term effects? Further controlled trials evaluating dose, duration, anesthetic vs. non-anesthetic dosing are needed. Few of us really understand what it is like to suffer from a chronic pain condition such as CRPS. Ketamine therapy may be a way forward that can be brought into our clinical practice through further controlled studies that will allow for appropriate standards for use in patients.”

 

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

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

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

~
~
For My Home Page, click here:  Welcome to my Weblog on Pain Management!
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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. A 28 year old man whose refractory depression began at age 15, after ketamine, says:

    .

    ‘I Wanted To Live Life’

    .
    Stephens himself has vivid memories of the day he got ketamine. It was a Monday morning and he woke up feeling really bad, he says. His mood was still dark when doctors put in an IV and delivered the drug.”Monday afternoon I felt like a completely different person,” he says. “I woke up Tuesday morning and I said, ‘Wow, there’s stuff I want to do today.’ And I woke up Wednesday morning and Thursday morning and I actually wanted to do things. I wanted to live life.”.
    .
    Since then, they treated him with Riluzole that is FDA approved for ALS and has one of the dirtiest side effect profiles I have ever seen in medicine with serious organ toxicity. Ketamine rarely causes mild transient side effects, usually none. It appears the concern is how ketamine is used on the street with potential for abuse. I do not see ketamine abuse in my patients, some of whom are on opioids for pain or Valium family medicines from their psychiatrist. All of those have a greater potential for abuse, also not occurring in my patients. Pain and/or depression can lead to suicide.
    .
    About 18 months ago, researchers at Yale found a possible explanation for ketamine’s effectiveness. It seems to affect the glutamate system in a way that causes brain cells to form new connections.
    .
    Researchers have long suspected that stress and depression weaken some connections among brain cells. Ketamine appears to reverse the process.

    .

    It would be of interest to see a case report of the bladder problems they mention. Is this in a single drug addict who used many unknown medications on the street? Several physicians have infused IV ketamine for persons with pain for many years, in far higher doses than I prescribe, with no report of any but transient minor symptoms.

    .

    Memory loss and brain atrophy occur with chronic depression, reported by the National Institute of Mental Health ~2001. The mechanism is described by Barsook referenced here.

    ~

  • You do not need to be hospitalized.

  • A single low dose ketamine treatment, given nasally, may reduce core symptoms of PTSD and depression. It can save your life.

  • Relief of depression may occur in 2 minutes to 2 hours and may last 1 to 2 weeks.

  • National Institute of Mental Health published 100% relief in a group with depression refractory to all treatment that failed as long as 43 years.

  • You cannot anticipate when suicidal thoughts occur, but you can carry ketamine with you for instant relief.

  • Ketamine is not toxic, not expensive, side effects if any are transient – usually none. It is compounded by pharmacy.

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  • I can help. I’ve prescribed this medication for 11 years, spoken with some of the world’s foremost psychiatrists. Some of my patients with profound pain/depression travel to Germany for high dose ketamine coma treatment of RSD/CRPS and tolerate those doses. Ketamine is safe even in babies and children. Very few MD’s prescribe ketamine, and even fewer have much experience with it.

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  • I need to examine you in person.

  • I can meet with you at my office and it is essential that you meet with my colleagues, a psychologist and psychiatrist.

  • Time is of the essence because we may need to adjust the concentration of ketamine. We need to determine your comfort level with its use.

  •  This must be a team approach.

  •  Please ask your psychiatrist to call me with your diagnoses and speak with me in person.

  • If you live long distance, this team should include your local psychiatrist, or one nearby, who will prescribe ketamine for depression.

  • Alternately, I will need to see you in my office every few months to renew the medication.

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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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    References
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    http://emedicine.medscape.com/article/2013085-clinical#aw2aab6b3b3
    Suicide Clinical Presentation

http://www.ptsd.va.gov/professional/pages/ptsd-suicide.asp The Relationship Between PTSD and Suicide  

PTSD alone out of six anxiety diagnoses was significantly associated with suicidal ideation or attempts. Anger and impulsivity have also been shown to predict suicide risk in those with PTSD.

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Articles, below, support use of ketamine for rapid relief of depression, even for resistant bipolar depression. The lead author of the first three studies is Carlos Zarate, M.D., Chief of the Mood and Anxiety Disorders Research Unit of the National Institute of Mental Health, NIMH:

http://www.ncbi.nlm.nih.gov/pubmed/20673547   Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder

100% response in persons with refractory depression: 29% went into remission, another 71% were responders.

http://archpsyc.ama-assn.org/cgi/content/full/67/8/793  A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression It even works for resistant bipolar depression

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726824/figure/F1/  Ketamine and the next generation of antidepressants with a rapid onset of action

Potential targets for ketamine and similar agents induce rapid and sustained antidepressant effects. A diagram scientists and physicians will find useful for mechanisms. “Notably, ketamine’s rapid antidepressant effects have been shown to be modulated by AMPA relative to NMDA throughput. Excessive glutamate also stimulates the extrasynaptic NMDA receptors, which antagonizes the activation of neurotrophic cascades. The potential sustained (sub-acute) antidepressant effects of ketamine are hypothesized to be mediated by increases in CREB and BDNF expression, as well as the anti-apoptotic protein Bcl-2.”

https://www.sciencemag.org/content/329/5994/959.abstract mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

“The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications….Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.”

http://psychiatry.jwatch.org/cgi/content/full/2010/1008/5 Ketamine’s quick antidepressant actions

“The resulting protein synthesis and neuronal alterations in the medial prefrontal cortex are the opposite of those produced by chronic stress….”

 

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The material on this site is for informational purposes only, and is not a substitute

 for medical advice, diagnosis or treatment provided by a qualified health care provider..

~

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

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

~

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

~

~

~

Ketamine


Ketamine for persons with severe pain

cancerIn special circumstances, I may suggest a trial of low dose oral ketamine. It is formulated by a compounding pharmacist as an oral suspension. It is safe to use without significant adverse effects, though you may experience transient symptoms lasting 20 to 40 minutes after the first few doses. For most people, it may relieve pain when all other methods have failed, possibly including total pain relief with no side effects in patients who have then been able to discontinue all opioids.

Keep all your medicine, opioids and ketamine, in a lock box to prevent abuse by others. This is a Schedule III drug like Vicodin.

Achieving control of chronic pain requires a partnership

based upon trust and effort

Requirements: I will work closely with you on ketamine and ask you to keep a log of pain before each dose and 30 minutes after. In addition, for the first week I ask that you log blood pressure and heart rate before each dose and 30 minutes after. This requires that you see me in the office one week later. If you have any questions or problems, I ask that you call me the same day, whether it be weekend or holiday. If you are unable to keep these logs before and after the dose, and the appointment one week later, the trial will be discontinued. You have no authority to continue without my consent.

Blood Pressure: Usually no change occurs in blood pressure. Some have reported that ketamine lowers their blood pressure and they are lightheaded when they stand up. If your blood pressure drops or if you are lightheaded, be very cautious as that may lead to fainting and brief loss of consciousness. Anytime a person faints, that could result in potentially serious injury such as hip fracture, other fractures, bleeding or brain injury if you strike your head. Your blood pressure should be above 100 when standing.  Ketamine has been reported to increase blood pressure and pulse, but I have not found that to occur with these doses.

Side Effects: Ketamine has a very narrow therapeutic window for pain control. This means that once you find the dose that relieves pain, a very slight increase in dose may produce intolerable side effects. Unfortunately some patients reach a dose that produces side effects before they experience any pain relief.

Most patients have no side effects with the low doses used by this protocol, though some may have mild symptoms lasting up to 40 minutes. If you do, then try decreasing the dose a small amount.

It is possible but rare that you may experience severe, frightening hallucinations or may feel you are outside the body observing it do things, called a dissociative reaction.

These side effects are dose related and have been short lasting, usually no longer than 40 minutes.  The antidote is Ativan.

Steps to follow: Read all steps carefully before you begin

  • Take ketamine 30 minutes prior to your other pain medication
  • For the first dose, remain seated or lie down for 20 minutes after you take the dose to avoid risk of falling. Do not take the dose and walk around.
  • A few persons have had severe imbalance lasting 10 or 20 minutes. This has resolved after the first few doses in those persons. It may not happen to you, so test with caution. If it has not occurred at the first dose, it is unlikely to occur at all.
  • Follow the dosing guidelines in the log I give you and which I repeat in this next step:
    Begin with 0.25 mL and increase by increments of 0.25 mL every 6 hours or longer than 6 hours, until you have some pain relief. Do not increase that dose or dosing interval.

Example: begin 0.25 mL, then 0.5, next 0.75, 1.0, 1.25, 1.5, 1.75, 2.0

If you have had no effect on pain by 2.0 mL, schedule an appointment for further instructions.
If your pain decreases only 1 or 2 points, that is your dose.  It will NOT get better by increasing the dose.  Stop increasing.

  • If you have intolerable side effects, you may use 1 or 2 Ativan tablets immediately as an antidote, and every 30 minutes, up to 5 of them.
  • CAUTION: Be alert to the opioid-sparing effects of ketamine!

This means that if ketamine relieves your pain, you do not need to take the opioid as that would be an opioid overdose and may cause serious side effects.

Reduce or temporarily stop your opioid medication if pain is gone after using ketamine.

This is why you take ketamine 30 minutes before the opioid. Some people have been able to completely stop all opioid medication due to pain relief from ketamine alone.

  • CAUTION: Do not drive for 6 hours after a dose.

This is for the protection of you and others. You may not be aware of very subtle side effects.

  • You may take a dose every 6 hours, or longer than 6 hours. Less is more.

If ketamine loses its effect, stop use for 2 or 3 days, then resume. It can be a fickle drug.  That is why increasing the dose causes loss of effect.

Some take ketamine only before sleep. If you do that, use it 30 minutes before sleep in order to log its effect and take blood pressure/pulse before and after. Continue this initially until further changes are approved.

Ketamine was approved for use as an anesthetic by the FDA in 1970

It’s use for pain is “off label” as it was approved only in high doses for anesthesia. It has been used safely in babies. Unlike opioids, it does not depress breathing or bowel function, and usually does not depress cardiovascular function. Since the late 1980’s, numerous scientific articles have been published on its use as a third line choice for some pain conditions; there are few double blind control studies, one is listed below. If you search ketamine on various internet search engines you find it is abused by addicts just as other drugs are. You find medical articles when you search the literature using Google Scholar or PubMed in the National Library of Medicine. If you find a medical article with adverse effects, let me know. I have spoken to leading brain and psychiatric researchers who have verified there are no lasting side effects from its use.

Many publications on ketamine use multi-day infusions at much higher dosages than the oral dosages in my protocol. Drexel University has treated over 3,000 patients with infusions of 40 mg/hour for 5 days with no lasting adverse effects. Even higher doses than that are used for surgical anesthesia. Ketamine is a powerful tool for treating pain.

Medical Publications


You can click and download each reference in blue below

High dose ketamine improves neurological outcome after stroke in rats, Reeker et al, Canadian J Anesth 47:572-578, 2000

Ketamine, Pasero C, McCaffery M, Amer J Nursing, 105:60-64, 2005
An excellent review, more clinical, easier to read than some more technical papers

Ketamine in Chronic Pain Management: An Evidence Based Review, Hocking & Cousins, Anesth Analg, 97(6):1730-1739, 2003This nine page article is the best comprehensive review of ketamine’s use in almost every known pain condition including post stroke pain.  Easier to read; a catalogue of pain syndromes and references.

Ketamine Stops Aura in Familial Hemiplegic Migraine, Neurology, 55:139-141, 2000 Two mechanisms may account for this. First, ketamine can increase cerebral blood flow, which may counteract the marked hypoperfusion induced by cortical spreading depression, as observed in migraine with aura. Second, in experimental animals, ketamine accelerates the  restitution of neuronal function after hypoxia.

Ketamine oral use in 8 chronic pain patients, Canadian J. of Anesthesia, 2004


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The Reflex Sympathetic Dystrophy Association library has many articles on RSD, CRPS and ketamine. Remember most of the articles are written for scientists and physicians.

From their library I particularly recommend the first article, below.  The last two are very technical but important new research.


Expectations of Pain: I Think, Therefore I Am, Jones-London M, National Institute of Neurological Disorders and Stroke

For pain mechanisms, read
Beyond Neurons: Evidence that Immune and Glial Cells Contribute to Pathological Pain States, Watkins L and Maier SF, Physiology Review. 2003;82:981-1011.

For pain mechanisms, read
Complex Regional Pain Syndrome (CRPS): Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy),  Oaklander AL et al., Pain. 2006;120:235-243.

There is no link to the following double blind controlled research publication:

Mercadante S, Arcuri E, Tirelli W, Casuccio A. Analgesic effect of intravenous Ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study. J Pain Symptom Manage 2000;20:246-252. Mercadante et al compared intravenous infusions of Ketamine (0.25 and 0.5 mg/kg) with placebo in a double-blind, crossover study of 10 cancer patients with neuropathic pain.

Please note that the free Adobe Acrobat Reader is needed to read some references.

You can download the free reader now.

~~~~~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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