Ketamine’s effects tied to opioid system in brain


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Stanford announces:

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Ketamine’s antidepressive effects

tied to opioid system in brain

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

 

 

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

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The material on this site is for informational purposes only.

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

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

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Comments are welcome.

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

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

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Cannabidiol (CBD) FDA Approved for Epilepsy – May Help Pain, Mood – Costs Review


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Epidiolex from GW Pharmaceuticals, is a cannabidiol (CBD) recently approved by FDA for treatment of epilepsy. Others have found CBD helpful for pain, migraine, and mood disorders. CBD is one of the more than 80 known cannabinoids in the cannabis plant, the marijuana plant. It has no psychoactive effect, that means it does not make anyone “high”. But urine drug tests will be positive for marijuana and anyone may risk losing their job if their employer checks – some drug tests do not specify marijuana.

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Medications can be prescribed off-label by your doctor for conditions other than the FDA approved epilepsy in this case, and hopefully covered by healthcare insurance. Below are costs of the Epidiolex brand reviewed by O’Shaughnessy’s newsletter, the newsletter originally for California cannabis doctors.

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FDA approval means CBD now has accepted medical use and should be no longer classified as Schedule I, though the ruse will likely be continued by congress.

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GW Pharmaceuticals PLC said it plans to charge about $32,500 per patient annually in the U.S. for its new treatment for rare forms of epilepsy, the first prescription drug derived from the marijuana plant.

Chief Executive Justin Gover said in an interview Wednesday that the company set the price to be in line with other brand-name epilepsy drugs, such as H. Lundbeck A/S’s Onfi. He noted that the FDA designated the product an “orphan drug,” meaning it treats rare conditions, and that some other orphan drugs carry higher prices.

Out-of-pocket costs for patients taking Epidiolex could range from $5 to $10 a month for those in state Medicaid programs to as high as $200 a month for some private insurance plans, Julian Gangolli, president of the company’s North America unit, said on a conference call with analysts Tuesday. Uninsured patients may qualify for receiving the drug free.

Dr. Jacqueline French, chief scientific officer of the Epilepsy Foundation, said there are low-cost generic epilepsy drugs on the market, but many patients with the rare forms of the disease have already tried them and the drugs didn’t help much.

Dr. French said Epidiolex improved symptoms for many children in clinical trials, and she is happy the price isn’t significantly higher.

The company expects to make the drug available after the U.S. Drug Enforcement Administration assigns it a controlled-substance classification, a decision expected by late September. GW Pharmaceuticals will distribute the drug through specialty pharmacies that ship directly to patients and caregivers.

FDA approval of a CBD extract means that cannabidiol now has an acknowledged medical use and therefore doesn’t fit a key criterion of Schedule I status. DEA rescheduling is supposed to follow as day follows night. Logically, the DEA resked should apply to cannabidiol, the molecule. But fixisin.com says CBD will remain on Sked I, with an exception created for CBD in an FDA-approved pharmaceutical.”

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The material on this site is for informational purposes only.

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

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

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Comments are welcome.

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

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

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Memantine for Neuropathic Pain & Complex Regional Pain Syndrome, CRPS


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Neuropathic pain syndromes show an over-expression of NMDA receptors in the brain in animal models. Ketamine blocks the NMDA receptor. Another medication with the same mechanism, but in pill form is memantine. This report on six patients of the use of memantine for Complex Regional Pain Syndrome (CRPS) from 2007 in the Clinical Journal of Pain, six months after treatment with memantine, showed significant decrease in pain, improved motor symptoms and autonomic changes, and fMRI changes on the affected side improving, comparable to the unaffected side of the brain.

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It was approved for Alzheimer’s dementia gradually titrating to a dose of 28 mg/day, but for decades has been very useful off label for neuropathic pain including but not limited to CRPS, at a dose of 55 mg/day, and in recent years often prescribed for migraine.

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Ketamine is highly successful also for treatment resistant depression, and one patient, a psychiatrist disabled from the unfortunate triad of intractable neuropathic pain, migraine and treatment resistant depression, while slowly titrating to a dose of 55 mg/day, a process that takes almost 3 months, found depression relieved for the first time in decades at the dose of 35 mg. It was highly effective as one component of the multi-pronged approach for all three conditions.

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This life is a hard fact. We all need all the help, encouragement and positive attitudes we can get. Complex intractable pain and/or depression requires rational polypharmacy, selectively chosen based upon well known mechanisms, neurotransmitters, receptors, hormones, stress reduction, cognitive behavioral therapy, physical therapy, occupational therapy, nerve blocks, and spiritual understanding, etc. Several choices were summarized almost two years ago here.

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In my experience, memantine is very well tolerated with few if any side effects but covered by insurance only for mild to moderate dementia. Thus, not only is it highly challenging to treat neuropathic pain, but important to creatively meet the challenges of our backwards medical system that barely recognizes the needs of those with chronic pain.

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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.

~~

Comments are welcome.

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

~~~~~

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

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


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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Ketamine Relieves Depression By Restoring Brain Connections

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

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

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

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

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

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The material on this site is for informational purposes only.

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

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

~~

Comments are welcome.

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

~~~~~

For My Home Page, click here:  

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Welcome to my Weblog on Pain Management!

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Please IGNORE THE ADS BELOW. They are not from me.

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Oxytocin for Pain, Treatment Resistant Depression and Bipolar Disorder


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Recent publications on Oxytocin are listed below. It is a very effective hormone made by the brain. It is NOT the opioid oxycodone and NOT oxycontin.

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Use search function top left above photo to see previous postings on oxytocin since 2013. It can be extremely important in the treatment of intractable pain, treatment resistant depression, bipolar disorder or anxiety.

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Once you titrate to the proper dose for each person —from 10 to 100 u’s, relief is quite astonishing, with rapid onset in a few minutes when given under the tongue – only after reaching that person’s dose, simple, without side effects. May use as needed 3 or 4 times per day. There is no withdrawal.

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Avoid use if polycystic ovary syndrome (PCOS). 

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Oxytocin must be made by a compounding pharmacy. Healthcare insurance refuses to reimburse for any compounded medications though they are far less expensive even than gabapentin that fails to help so many with pain, and oxytocin is far more effective. 

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Every time you hug someone, you are giving each other oxytocin. When your dog and you stare at each other, oxytocin is being stimulated. Having discussed that with one of my patients, he came back one month later to say he and his wife had fallen in love again after almost 50 years of marriage because they’ve been hugging every day: hugs stimulate oxytocin. 

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Behavioral effects of oxytocin are highly context- and person-dependent. You are not going to fall in love with someone you do not like. 

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Rash, JA, et al: Oxytocin & Pain, A Systematic Review & Synthesis of Findings. Clin J Pain 30(5):453-462, May 2014.

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Xin Q et al: The Analgesic Effects of Oxytocin in the Peripheral and Central Nervous System. Neurochemistry Intl 103:57-64, 2017.

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Paloyelis Y et al: The Analgesic Effect of Oxytocin in Humans: A double-blind, placebo-controlled, cross-over study using laser-evoked potentials. 

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MacDonald K, Feifel D. Oxytocin’s role in anxiety: a critical appraisal. Brain Res 2014; 1580: 22–56.

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Churchland PPS, Winkielman P. Modulating social behavior with oxytocin: how does it work? What does it mean? Horm Behav 2012; 61: 392–399.

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Bethlehem, R A I  et al: Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women, Translational Psychiatry, 2017, 7, 4, e1099 ********excellent********

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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.

~~

Comments are welcome.

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

~~~~~

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


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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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The material on this site is for informational purposes only.

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

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

~~

This site is not for email and not for appointments.

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

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

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Naltrexone in Low Dose Reduces Pain & Depression


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We’ve known LDN helps pain since the turn of the century. Stanford could really shake the research world if they trialed LDN for Major Depressive Disorder, not the depression that improves with less pain, or in Multiple Sclerosis clinics or the Parkinson’s or Inflammatory Bowel Disease clinics. Is it too much to ask for better quality clinical research, not just results of patients responding by click or touch on a computer touch pad?

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The astonishing promise of low dose naltrexone (LDN) research remains in its infancy since 1984, 33 years ago, when it was discovered to offer profound clinical relief for multiple sclerosis and other serious conditions. I have prescribed naltrexone in ultra low and low dose since 2003, and discussed its central anti-inflammatory glial modulating mechanisms in 2009:

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Low dose naltrexone, or LDN, has been prescribed “off label” for persons with many conditions including intractable pain, chronic fatigue syndrome, complex regional pain syndrome, RSD, Multiple Sclerosis, Parkinsons Disease, IBS, inflammatory bowel disease, autoimmune diseases and Crohn’s Disease to mention only a few. Low dose naltrexone is not a cure but may be potentially helpful for selected persons with these conditions. It appears to have little or no toxicity at this low dose – a few persons report transient insomnia, nausea or vivid dreams.

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The same year in 2009, soon after my post on LDN, Drs. Younger and Mackey of Stanford Pain Center reported a double blind study of low dose naltrexone in persons who had fibromyalgia more than 10 years and showed 30% improvement in pain and fatigue.

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In 2016, five Stanford authors including Dr. Mackey published a poster presentation. At least the 2009 study was double blind; not this one. It was open label.

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A novel glial cell inhibitor, low dose naltrexone, reduces pain and depression, and improves function in chronic pain: A CHOIR study

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Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 418.

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Authors: K. Noon,  J. Sturgeon, M. Kao, B. Darnall, S. Mackey

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Stanford University Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford, CA

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Funding received from NIH and the Redlich Pain Endowment

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NIH funding should lead us forward, not back to a single open label study. One would hope Stanford would do the larger study they recommended 7 years ago. This adds to the CV of five researchers, but

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  • does it help millions with chronic intractable pain?

  • does it add to the growing body of clinical LDN experience worldwide?

  • when will the mechanism and uses of LDN, the TLR4 receptor and the powerful innate immune system be taught by healthcare providers in academia, in practice, and in pharmacies, not just in basic science?

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The poster highlights the Stanford CHOIR Information Registry (discussed below), but provides almost nothing new despite the computing power of CHOIR that likely cost small fortunes. Patients are asked to enter clinic data into a convenient handheld click- or touch-based input device. What could be easier? We look forward to better studies from Stanford’s CHOIR devices and we long for the days when doctors publish better data that addresses the disabling pain, depression and needs of millions of our patients with chronic intractable pain.

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Stanford’s CHOIR Information System

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“We modified and implemented an existing, web-based system that administers computer-adaptive PRO questionnaires, called the Collaborative Health Outcomes Information Registry (CHOIR).  Next, we developed a messaging interface to send PRO results from CHOIR to the UF Health Epic EHR.

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The CHOIR system was developed at Stanford University by a team of informaticists and physicians who provided a no-cost license for our implementation. CHOIR utilizes a client-server architecture with web-based clinician and patient interfaces that use open source technologies, including jQuery mobile and Google Web Toolkit. Users can access CHOIR via web browsers on desktop or mobile devices. The primary patient user function is the completion of computer-adaptive PRO assessments using a click- or touch-based input device ( Figure 1 ).  Clinical user functions include registering patients to complete a PRO assessment, reviewing individual and summary PRO assessment results, longitudinal outcomes tracking, and clinical decision support through the aggregation of PRO result sets.”

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.The material on this site is for informational purposes only.

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

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

~~

This site is not for email and not for appointments.

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

~~~~~

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

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