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


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

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Revising a Dogma: Ketamine for Patients with Neurological Injury?

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Money quote:

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

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

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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.

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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.

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

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

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This site is not for email and not for appointments.

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

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

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

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Intranasal Ketamine in Major Depressive Disorder


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

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A Randomized Controlled Trial of

Intranasal Ketamine in Major Depressive Disorder

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Conclusions

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“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.”

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

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

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Entire generations of scientists are now lost forever.

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Ketamine Safety

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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Inflammation

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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.

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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.

 

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Studies

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S-Ketamine

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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.

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*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.

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

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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.

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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.

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

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

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

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This site is not for email and not for appointments.

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

 

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

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

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Ketamine 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.

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

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

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

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Spine Fusions: No Better Than Cognitive Behavioral Therapy & Exercise


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Spine Fusions: no better than Cognitive Behavioral Therapy and Exercise

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This reportfrom the Academy of Neurology may help guide you in decision making: 

Deaths, Complications, Higher Costs Accompany Increase in Complex Spine Fusions Among Elderly.

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“Fusion is usually performed for degenerative disc disease for chronic low back pain, but a number of studies have shown that their outcomes are no better than a combination of graded exercise and cognitive behavioral therapy.”

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Tragically, dementia can result from extensive spine surgery. Many factors can contribute to that. If I were having spine surgery, I would look at the data of dementia following open heart surgery and the protective benefits of ketamine given prior to surgery. Ketamine can spare neuronal function. It is neuroprotective. I link to a publication on that in this post. The problem may be that so few physicians are willing to provide ketamine as they may lack information on its use, yet it is one of the safest medications we have, nontoxic and neuroprotective.

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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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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.”.
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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.
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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.
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Researchers have long suspected that stress and depression weaken some connections among brain cells. Ketamine appears to reverse the process.

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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.”

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“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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