Stephen Colbert: “I love the thing that I most wish had not happened.”

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Excerpt from a recent interview of Stephen Colbert by Joel Lovell:

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“…he is the youngest of eleven kids and … his father and two of his brothers, Peter and Paul, the two closest to him in age, were killed in a plane crash when he was 10.”

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The interview ends with the realization he had of their deaths.

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….I love the thing that I most wish had not happened.

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I asked him if he could help me understand that better, and he described a letter from Tolkien in response to a priest who had questioned whether Tolkien’s mythos was sufficiently doctrinaire, since it treated death not as a punishment for the sin of the fall but as a gift. “Tolkien says, in a letter back: ‘What punishments of God are not gifts?’ ” Colbert knocked his knuckles on the table. “ ‘What punishments of God are not gifts?’ ” he said again. His eyes were filled with tears. “So it would be ungrateful not to take everything with gratitude. It doesn’t mean you want it. I can hold both of those ideas in my head.”

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He was 35, he said, before he could really feel the truth of that. He was walking down the street, and it “stopped me dead. I went, ‘Oh, I’m grateful. Oh, I feel terrible.’ I felt so guilty to be grateful. But I knew it was true.

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“It’s not the same thing as wanting it to have happened,” he said. “But you can’t change everything about the world. You certainly can’t change things that have already happened.”

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Consider that this is coming from a man who millions of people will soon watch on their televisions every night—if only there were a way to measure the virality of this, which he’ll never say on TV, I imagine, but which, as far as I can tell, he practices every waking minute of his life.

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The next thing he said I wrote on a slip of paper in his office and have carried it around with me since. It’s our choice, whether to hate something in our lives or to love every moment of them, even the parts that bring us pain. “At every moment, we are volunteers.”

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‘What punishments of God are not gifts?’ Tolkien

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“So it would be ungrateful not to take everything with gratitude. It doesn’t mean you want it.

I can hold both of those ideas in my head.”

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 It’s our choice, whether to hate something in our lives or to love every moment of them,

even the parts that bring us pain. “At every moment, we are volunteers.”

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

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Analgesic Response to Intravenous Ketamine

Is Linked to a Circulating microRNA Signature

in Female Patients

With Complex Regional Pain Syndrome

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

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

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

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

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Quoting directly from the article:

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Highlights

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

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From the Abstract

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

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Perspective

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

 

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From the Discussion

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

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

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

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

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From the Conclusion

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

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

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“High failure rates of drugs targeted

to treat neuropathic pain

warrant changes in approaches.”

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

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

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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.

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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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PUBLIC WARNING

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

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S-Ketamine – What’s That?

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W-H-A-T’s  T-H-A-T?

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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.

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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.

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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.

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

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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.

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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.

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

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

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I am deeply concerned that S-ketamine nasal spray

may be allowed only

for use in Emergency Departments.

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That means the dose will

likely not be individualized.

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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.

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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.

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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?

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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.

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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.”

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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.

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Persons with Major Depressive Disorder

respond to

far lower doses of ketamine

than persons with severe neuropathic pain.

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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.

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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.

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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.

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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.

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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.

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

 

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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.
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The material on this site is for informational purposes only.
.
It is not legal for me to provide medical advice without an examination.

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

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

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

~~~~~

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

.

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

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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
.
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

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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.

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Ketamine really does work

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

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Two Cases

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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.

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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.

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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.

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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.

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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.

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**1**

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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.

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

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**2**

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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.

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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.

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NEURO-INFLAMMATION AND GLIA – brain on fire.

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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.

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

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Do You Have Depression? Are you the one who runs into snow wearing shorts?

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Since you were a baby, thermoregulation may be the source of the problem

that triggers your depression or the depression of someone you know.

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You may be a candidate for a research study if you have other key characteristics.

Treatment may help.

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Contact the Juvenile Bipolar Research Foundation.

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OR

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Demitri Papolos, MD, is the psychiatrist who, in collaboration with many others, has discovered that body temperature appears to be at the origin of this condition:

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Juvenile Bipolar Disorder, Fear of Harm phenotype.

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Dr. Papolos has written many publications and has published a book, with Janice Papolos, describing this serious disorder. “The Papoloses were the first to sound a national alarm about the dangers of using antidepressant and stimulant drugs with this population of children.”

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Either the link to Dr. Papolos or the Research Foundation, above, can give you further information on treatment.

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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

..

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 he posts this

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PUBLIC WARNING

.

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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I am not affiliated with Dr. Papolos, but wish to call attention to the dedicated academic work they have been doing for this devastating mood disorder. .

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Of interest, thermoregulation appears to be modulated by low dose naltrexone (LDN).

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It has been anecdotally reported to relieve heat intolerance in persons with Multiple Sclerosis.

I have seen a response with Juvenile Bipolar Disorder/Fear of Harm, and

severe postmenopausal hot flashes were completely reversed by LDN.

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Naltrexone blocks the TLR4 receptor. There is a strong literature on TLR4 and temperature regulation. This raises the interesting question whether anyone has done objective studies to show that low dose naltrexone may be modulating temperature in patients. If you have experience with this, please add your comments below.

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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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