Curcumin-like Drug Slows Aging, Reverses Memory Deficits

Drug Slows Aging, Reverses Memory Deficits

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Possible Alzheimer’s & Parkinsons Drug

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Roll over and click on BOLD links above and below to open article – unable to indicate color blue.

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“…potential Alzheimer’s drug works by reducing the rate of aging at the molecular level, according to a new study led by Salk Institute scientists.

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The study explains how the drug both improves cognition and reduces the rate of aging, when given to very old mice.

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Study authors say a drug that inhibits aging may succeed where drugs specifically aimed at Alzheimer’s have failed.

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Getting the drug into human clinical trials will require a little over $1 million.”

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 The study was published in the journal Aging Cell….

The mitochondrial ATP synthase is a shared drug target for aging and dementia

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 Salk Institute News

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….“This really glues together everything we know about J147 in terms of the link between aging and Alzheimer’s,” says Dave Schubert, head of Salk’s Cellular Neurobiology Laboratory and the senior author on the new paper. “Finding the target of J147 was also absolutely critical in terms of moving forward with clinical trials.”

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Schubert’s group developed J147 in 2011, after screening for compounds from plants with an ability to reverse the cellular and molecular signs of aging in the brain. J147 is a modified version of a molecule (curcumin) found in the curry spice turmeric. In the years since, the researchers have shown that the compound reverses memory deficits, potentiates the production of new brain cells, and slows or reverses Alzheimer’s progression in mice. However, they didn’t know how J147 worked at the molecular level.

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In the new work, led by Schubert and Salk Research Associate Josh Goldberg, the team used several approaches to home in on what J147 is doing. They identified the molecular target of J147 as a mitochondrial protein called ATP synthase that helps generate ATP—the cell’s energy currency—within mitochondria. They showed that by manipulating its activity, they could protect neuronal cells from multiple toxicities associated with the aging brain. Moreover, ATP synthase has already been shown to control aging in C. elegans worms and flies.

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“We know that age is the single greatest contributing factor to Alzheimer’s, so it is not surprising that we found a drug target that’s also been implicated in aging,” says Goldberg, the paper’s first author.

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Further experiments revealed that modulating activity of ATP synthase with J147 changes the levels of a number of other molecules—including levels of ATP itself—and leads to healthier, more stable mitochondria throughout aging and in disease.

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“I was very surprised when we started doing experiments with how big of an effect we saw,” says Schubert. “We can give this to old mice and it really elicits profound changes to make these mice look younger at a cellular and molecular level.”

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The results, the researchers say, are not only encouraging for moving the drug forward as an Alzheimer’s treatment, but also suggest that J147 may be useful in other age-associated diseases as well.

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“People have always thought that you need separate drugs for Alzheimer’s, Parkinson’s and stroke” says Schubert. “But it may be that by targeting aging we can treat or slow down many pathological conditions that are old-age-associated.”

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Metformin

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From WebMD, March 29, 2017:

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“Doctors have prescribed metformin, the most common drug to treat type 2 diabetes, for about 60 years. But it’s received new attention as a possible anti-aging drug after researchers in Britain found that people with diabetes who took it outlived some of their peers who did not have the disease by 15%.

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“They compared them to a whole bunch of people who were matched for weight and smoking and [other factors] but who didn’t have diabetes,” says Steven Austad, PhD, chairman of the biology department at the University of Alabama at Birmingham. “It turned out the diabetics on metformin were living longer than the non-diabetics who were not on metformin. … It was very, very intriguing.”

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Austad is a bio-gerontologist and scientific director of the American Federation for Aging Research….

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Scientists believe the drug works in the mitochondria, the powerhouses in the body’s cells that convert sugars like glucose into energy. Austad says metformin makes those powerhouses run more efficiently, reducing the release of substances known as free radicals. Free radicals can damage cells, hurting their ability to reproduce and causing defects.”

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….Resveratrol, a compound found in grapes and nuts, may reduce stress that leads to cell aging. Research shows it can extend life span in yeast, worms, and fish, but these effects haven’t been demonstrated in humans yet.”

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

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Dementia, Memory Loss, Brain Atrophy – not always Alzheimer’s Disease. We are all at risk.

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Dementia

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Alzheimer’s Disease

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Sustained Reversal Published by UCLA

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If you have a medical problem that involves the brain, this may apply to you.

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In a major breakthrough, Dale E. Bredesen reported that 9 of 10 patients with Alzheimer’s Disease were able to return to full time work. His report appeared in the journal Aging, September 2014. A PDF can be downloaded. He is UCLA Augustus Rose Professor of Neurology, director of the UCLA Easton Center Center for Alzheimer’s Disease Research.

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He used a 36 point holistic approach based on published neuroscience research. There is no drug. .

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There is No Magic Bullet – Highly Individualized

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Dementia is the third leading cause of death in the U.S. behind cardiovascular disease and cancer. It affects roughly 25 to 30 percent of the population over 80, with 70 percent of those having Alzheimer’s Disease.

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The number of cases doubles every 5 years in people over 65. By age 85, almost half of all people are afflicted. A family history of Alzheimer’s increases risk. Five percent have onset early in age.

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In other words, once we pass 60, we are all at risk for this disease, but may occur as young as 30 in rare cases.

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What to do?

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1. See a good neurologist for a proper diagnosis. If  dementia, there are at least 9 causes, Alzheimer’s is 40% of those [N.B. source, verify].

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Some are treatable, such as deficiency of vitamin B12 or thyroid. Remember, do not take folic acid unless you are taking adequate B12 as folate will mask B12 deficiency and lead to neurological problems that may be severe.

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2. Read the Alzheimer’s Disease In-Depth Report in the New York Times. It gives clear and comprehensive advice for the patient and the caregiver. It is not a diagnosis.

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3. Memory loss can be reversed and sustained. Dr. Bredeson reports, “Improvements have been sustained, and at this time the longest patient follow-up is two and one-half years from initial treatment, with sustained and marked improvement.”

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He points out the failure of the so called Alzheimer’s drugs, that help little or not at all. Instead, he uses a 36 point metabolic approach, discussed in more detail below. He said the findings are “very encouraging,” but he added that the results are anecdotal, and a more extensive, controlled clinical trial is needed.

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Alzheimers has the potential to devastate the economy worldwide in the near future. The Bredesen report is a first. Ideally it may revolutionize medical research, fiscal budgets, dietary guidelines, policy changes, school lunches, advertizing and foods that promote all the wrong changes in brain. But it involves changing behavior and even simple school lunch programs that improve cognitive function and health have been mercilessly attacked.

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Alzheimer’s Disease is relentless. The causes are not known and there is no cure. Changing behavior is dificult.

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There are three hallmarks of the diagnosis of Alzheimer’s Disease:

• amyloid plaques

• neurofibrillary tau tangles, the primary marker

• loss of connections in the brain

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Plaques and tangles may be present for years and may appear quite early in life, without ever developing Alzheimer’s. We do not have a specific marker for diagnosis, but we can exclude treatable conditions. More importantly, doctors and families need a better tool to monitor cognitive decline so that we may intervene early before the devastating and costly disease captures the lives and finances of patients, caregivers and families alike.

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Risk Factors For Alzheimers Are The Same As For Heart Disease

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Obesity, inactivity, smoking, diabetes, hypertension, hyperlipidemia, low Vitamin D – serum level of 50 ng/mL is ideal.

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Benzodiazepines increase risk of Alzheimers 50%, reported in 2014, particularly with long acting forms (Valium, clonazepam) or long term use. They are widely prescribed for insomnia or anxiety, yet almost 50% of older adults continue to use these drugs. It is unrealistic to think they can be eliminated – they are habit forming after all, but a Quebec study showed that a brochure alone helped 27 percent of elderly users taper down and discontinue their drug in six months. Another 11 percent reduced dosage. Do taper off slowly with proper guidance. Informed consent can help each person to choose the risk or the taper. If the brochure doesn’t scare you, I don’t know what will.

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Systems Approach – No Silver Bullet

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The small trial published by Dr. Bredesen showed reversal of cognitive decline using an individualized 36 point ‘systems approach’ to memory disorders. Results started to be seen after 3 to 6 months.

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In the UCLA Newsroom interview, he says: “The existing Alzheimers drugs affect a single target, but Alzheimers disease is more complex. Imagine having a roof with 36 holes in it, and your drug patched one hole very well, he said. The drug may have worked, and a single hole may have been fixed, but you still have 35 other leaks, and so the underlying process may not be affected much.”

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It “involves comprehensive diet changes, brain stimulation, exercise, sleep optimization, specific pharmaceuticals and vitamins, and multiple additional steps that affect brain chemistry.” Though each target may be affected in a modest way, the overall effect may be additive or even synergistic.

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The downside is its complexity. No one was able to stick to the entire protocol. The side effect was improved health and improved body mass index. Successful candidates did lose weight. He emphasizes that this small study needs to be individualized and replicated on a large scale. The program for one patient included:

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• eliminating all simple carbohydrates, gluten and processed food from her diet, and eating more vegetables, fruits and non-farmed fish

• meditating twice a day and beginning yoga to reduce stress

• sleeping seven to eight hours per night, up from four to five

• taking melatonin, methylcobalamin, vitamin D3, fish oil and coenzyme Q10 each day

• optimizing oral hygiene using an electric flosser and electric toothbrush

• reinstating hormone replacement therapy, which had previously been discontinued.

• fasting for a minimum of 12 hours between dinner and breakfast, and for a minimum of three hours between dinner and bedtime

• exercising for a minimum of 30 minutes, four to six days per week

 

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Diet

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We have known that calorie restriction reverses amyloid deposition.

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One diet was developed by nutritional epidemiologist Martha Clare Morris, Ph.D., of Rush University in Chicago, and her colleagues.

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According to the findings, the MIND diet was able to lower the risk of AD by as much as 53 percent in participants who strictly adhered to the diet, and by about 35 percent in those who followed it fairly well. It was compared to the DASH diet and Mediterranean diet.

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“To follow the MIND diet, a person should eat at least three servings of whole grains, a salad and one other vegetable every day —  along with a glass of wine —  snack most days on nuts, eat beans every other day or so, eat poultry and berries at least twice a week, and eat fish at least once a week.

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However, a person should limit consumption of the designated unhealthy foods, especially butter (less than one tablespoon a day), cheese, and fried or fast food (less than a serving a week for any of the three), to have a real shot at avoiding the devastating effects of AD, according to the study.

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Berries are the only fruit included in the MIND diet. “Blueberries are one of the more potent foods in terms of protecting the brain,” Morris said, and strawberries have also performed well in past studies of the effect of food on cognitive function.”

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I recommend that my patients Google pro and anti-inflammatory foods and move their diet in the direction of lowering the burden of inflammation.

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Supplements

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CurcuViva or Longvida is a special formulation of curcumin, the active ingredient in turmeric spice that is able to cross through the blood brain barrier and reach the brain. I posted on it here and it is reviewed in more detail here. Turmeric does not enter the brain. It was developed by researchers at UCLA Alzheimer’s Research Center showing the relationship between pre-tangle tau, brain cell death, and cognitive function. Full memory was restored in mice that had dysfunction caused by tau tangles. It has been shown to help Alzheimers and joint pain.

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WARNING: Do not take CurcuViva if ulcers or gallbladder disease.

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Supplements Can Harm – Caution Toxic

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Supplements can cause great harm. Many are toxic and deplete the brain of essential nutrients or cause irreparable harm.

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Always research the value and harm of every supplement put into your body. The best site on herbs and botanical I have found is updated regularly by the expert in integrative medicine and alternative therapies at Memorial Sloan Kettering Cancer Center. They research supplements and herbs to show efficacy and how they interact with prescription medications to verify if they may help or harm. Ask, does this drug – yes, vitamins and supplements are drugs but unregulated and untested – cause toxic increase in medication or rapid loss (speeded metabolism) of prescription medications resulting in less effective serum levels and no benefit.

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Metabolism of drugs and drug-drug interactions is critical to know.We do not have enough data on supplements. We ignore behavioral changes such as diet, exercise, stress reduction at our peril in favor of unregulated, unproven, costly silver bullets.

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Reflecting the importance of my interest in supplements since the majority of Americans take so many, one of the first things I did in starting this website is to post on benefit and harms of vitamins and supplements.

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In addition to that detailed list, use the search box just above my photo top left to find other posts on frequently used supplements mentioned below.

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The Good, The Bad and The Ugly

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• Vitamin B6 in excess can cause irreversible neurological disease – know the safe dose because it is now overdosed in many things.

• Heavy NSAID use increases risk of Alzheimers.

• Zinc blocks copper that is essential for every cell in the body.

• Vitamins A and E have no proven benefit and serious risks.

• CoQ-10 is essential for every cell. Statins deplete CoQ-10. It is essential in the electron transport chain to make ATP, the energy used by every cell. Research has shown it helpful for mitochondrial diseases such as migraine and Parkinsons Disease though very high doses for the latter. I do not know of any publications for its use in Alzheimers.

• Fish oil can reduce triglycerides 45%. Adjust dose based upon level of triglycerides – elevated levels increase risk of Alzheimers.

• Hormones affect function of many organs including brain. If low, then restore at least to low normal. If high, rule out tumor.

• Low vitamin D doubles the risk of dementia and Alzheimers.

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Low Vitamin D Doubles Risk of Dementia & Alzheimers Disease

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That was published in the journal Neurology, August 2014. Vitamin D is a special category and I have posted on its anti-inflammatory and analgesic benefit many times, its effect on the immune system, on pain relief, and on depression. It is important for five cancers, heart disease. Again, use the search function top left by my photo for details.

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WARNING: Make sure before taking any Vitamin D that your MD checks PTH and then if normal, recommend a dose of D3 based upon serum levels of 25(OH)D. I maintain my patients on a serum level of ~50 ng/mL, not more, not less, in accord with the most recent research.

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B Vitamins

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Brain atrophy occurs in those with aging as well as with Major Depression or Chronic Pain and with aging. They were able to prevent 90% atrophy of the hippocampus and areas targeted by Alzheimers Disease with specific doses of B vitamins, below. The OPTIMA (Oxford Project to Investigate Memory and Ageing) at Oxford University, March 2013. I disagree with their dose of Vitamin B6 as I have seen tragic toxicity in patients that takes at least one year to reverse, if ever.

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These are the doses I suggest:

• .B12 500 mcg/day

• Folic Acid 800 mcg/day

• B Complex —-B6 not to exceed 2 mg ! B6 is one of the vitamins in B Complex and it

  can be toxic to nerve. It is being overdosed in many supplements and energy drinks.

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Inflammation

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If you haven’t gathered by now, the focus is on inflammation. The brain and spinal cord has an innate immune system different than the immune system in the rest of your body. The cells of the innate immune system are called glia, and they produce many chemicals, in particular, microglia and astrocytes produce cytokines. Anti-inflammatory and pro-inflammatory cytokines. They must be in balance.

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Inflammatory cytokines are shown to be involved in almost every known disease including Alzheimers, Parkinsons, ALS, MS, autoimmune disease, chronic pain, major depression, cancer, atherosclerosis.

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Pro-inflammatory drugs: opioids and alcohol for example.

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Anti-inflammatory drugs: low dose naltrexone, dextromethorphan, ketamine, amitriptyline, Vitamin D, melatonin. Again, use the search function above photo for the many posts including case studies. It would be helpful to see more medications studied to show if they are pro- or anti-inflammatory, and to see studies on these medications in persons with memory difficulty. That will not happen since they are generic, low cost.

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Living Wills & Healthcare Power of Attorney

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Be aware of the changing laws in your state. In the event dementia prevents you from choosing your care, if you have asked that no food or water be given, medical staff are not legally permitted to follow that directive. Legal precedent directs that if you reach for food or water, that indicates your intent to be fed, regardless of written requests made when you were of sound mind. It behoves us all to change behavior now.

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Summary

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• Use an Alzheimers self test for early detection. This is not a diagnosis.

• Obtain a neurological evaluation.

• Be aware of the importance of the 36 step metabolic approach.

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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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Radical experiment in managing pain without narcotics – Validation of years of work

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Read this story in the New York Times Business Day, May 10, 2014.

 

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It is the story of one veteran who had severe injuries. His wife now says when she sees other patients: “I can go in there and I can immediately spot people that are on narcotics or on drugs.”

 

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A Soldier’s War on Pain

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Many thanks from my heart to Barry Meier for his research into these rare pain specialists who are managing pain without narcotics, and the story of how this veteran did it.

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This validates so much of the work I’ve been toiling over since the turn of the century. This has nothing to do with blame. There is a whole new paradigm to the understanding of treating pain. But the article mentioned only those things my patients have failed, that were done before use of opioids. Physical therapy alone dates back to Greek culture and Hippocrates’ influence as the father of Western medicine and in Europe during the 1500’s. But another point was made and is important to emphasize: these therapies don’t work while someone continues taking opioids.

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Where are we now and what are the questions?

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-Only a few doctors are mentioned. We need more.

-Physicians are taught the first thing: Do no harm. But we are in a very difficult place right now. We are taught to use opioids. Little attention has been paid to research on how to treat patients once off opioids, after they have failed gabapentin, Lyrica, Cymbalta, opioids, Elavil.

-Patients don’t know that when asking for more opioids, they are actually creating more pain.

-There is less pain when you taper off opioids. That alone is often enough to help, but often more must be done.

-Who does better with a new approach?

-Insurance companies must be taught not to tie doctor’s hands with denials.

-Do we need to allow PA’s and NA’s to write their own opioids without doctor’s supervision?

-Or do we need to teach everyone, doctors and patients included, how to treat pain without opioids?

-None of us has the data that gives us greater certainty. Until then trillions of dollars are wasted creating disability and pain unknowingly.

-No I am not taking away grandmum’s small dose that she has been on for years and has been shown to improve function.

-Acute pain definitely and usually requires treatment with opioids. But chronic pain? How long do we prescribe opioids in the acute situation before we taper?

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Monster in the system – personal doctor ratings

Translation: job and hospital ratings – by the insurance system and the internet’s phoney doctor “ratings” — all those ratings partly depend on giving opioids and that colors the patient’s opinion of the doctor.

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Doctors who push opioids are more highly rated by patients. Is that what we want as a society?

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 Patients can’t be faulted.

How can they know better?

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Doctors do what they are trained to do, unaware that the opioids they prescribe actually cause more pain,  reinforcing the demand to give more opioids.

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I see better pain relief without opioids

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I will add much more on this page in the next few days, and even later adding remarkable case reports, and covering other medications seldom used, often compounded, but I wanted to get this out urgently. This is such a vast area. We all need to learn from those who are doing this work.

 

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 report, from 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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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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“Heavy NSAID Use Linked to Higher Dementia Risk” – Exercise, Antidepressants Both Help Neurogenesis

NSAIDs are anti-inflammatory drugs used to treat pain, inflammation, or fever.  The only NSAIDs that are NOT associated with increased risk of heart attack or arrhythmia are naproxen (Aleve) or aspirin.  Taking high doses of aspirin has a greater risk of GI bleed than naproxen, which is why I usually recommend naproxen.

Background:

Several past studies have shown NSAIDs delay or prevent dementia, but there have been contradictory results.  Last year Neurology published a study of 49,349 patients’ usage ranging from ≤1 year to ≥7 years done at Boston University and Bedford VA. They showed long term use of NSAIDs protects against Alzheimers:

Compared with no NSAID use, the relative risk of Alzheimer’s disease decreased from 0.98 for ≤1 year of use (95% CI 0.95 to 1.00) to 0.76 for >5 years of use (95% CI 0.68 to 0.85).

Among patients who specifically cited use of ibuprofen, the risk of Alzheimer’s disease declined from 1.03 (95% CI 1.00 to 1.06) to 0.56 (95% CI 0.42 to 0.75).

Ibuprofen came out ahead in that study perhaps because it is the most commonly used.

They also sought to answer whether NSAIDs known to suppress Aβ1-42 amyloid would more likely protect .  Aβ1-42 amyloid is a major component of plaques found in Alzheimer’s Disease.

Aβ1-42 amyloid suppressors include ibuprofen, diclofenac, flurbiprofen — but as for suppressing Alzheimer’s, these were found to be no different than other NSAIDs, putting that theory to rest.

Risk of dementia and Alzheimer’s Disease with prior exposure to NSAIDs in an elderly community-based cohort:

This new study by Breitner  et al, from the University of Washington School of Medicine was published online April 22, 2009, before the print edition in Neurology.  

Their outcome contradicts earlier protective studies possibly because they started with an older cohort, healthy adults 65 and older, which “could be enriched for cases [of Alzheimer’s] that would otherwise have appeared earlier.”

They prospectively followed 2,736 persons in a Seattle health plan.  Before starting the study, they reviewed pharmacy records as much as 17 years earlier.

Findings:

12.8% of the study participants [were] heavy NSAID users at baseline. Heavy use was defined as taking 500 or more standard daily doses over a two-year period.

Another 3.9% of participants became heavy users during follow-up.

Ibuprofen, naproxen, indomethacin, and sulindac accounted for about 80% of all NSAIDs used.

Through follow-up, 476 participants developed dementia; for 356 of them, it was Alzheimer’s disease.

After controlling for age, gender, education, APOE status, hypertension, diabetes, obesity, osteoarthritis, and physical activity, the risk of developing all-cause dementia was 66% higher among heavy users than among those with little or no NSAID use (HR 1.66, 95% CI 1.24 to 2.24).

The risk of developing Alzheimer’s disease was 57% higher (HR 1.57, 95% CI 1.10 to 2.23).

Strengths of the study: the community-based sample, biennial assessment of dementia, rigorous exposure classification, and large numbers of dementia cases, outweigh the limitations.

Limitations:  lack of generalizability to a younger patient population, the lack of exact dosing information, and the possibility of bias from unmeasured confounders.

Can we draw conclusions on one study alone? We know that exercise is protective against Alzheimer’s Disease and pain may have prevented this older age group from being active. Though they did control for that, this research needs to be supported by further studies. What is helpful is to remain as active as you can.  Keep and maintain every bit of function you can and get help for depression and anxiety as they may profoundly affect memory, morbidity and mortality.  For a review of the literature on the morbidity and mortality of stress and mood, refer to my post on Cognitive Behavioral Therapy and the importance of a positive outlook.

The brain makes new neurons – neurogenesis.  I will write more in the future on exercise, mood, stress, brain atrophy and memory loss.   Exercise improves depression and anxiety, and exercise stimulates neurogenesis.  It appears that the action of antidepressants also may be to stimulate neurogenesis.  Chronic low back pain has been reported to cause brain atrophy.  Chronic depression leads to brain atrophy and memory loss with atrophy occurring in the hippocampus, the area essential for memory.  This important publication from Vancouver reviews the topic in great detail and proposes a hypothesis:  Antidepressant effects of exercise: Evidence for an adult-neurogenesis hypothesis?

Further medication is being tested to reduce neuronal cell death that leads to Alzheimer’s Disease, using a very simple compound that blocks free radicals and inflammation.  More on this later.

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!

Vitamin D – A Steroid Hormone, Anti-inflammatory

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The Sunshine Vitamin Controversy

What should normal values  be for calcium homeostasis?

My attention was drawn to Vitamin D several years ago when a review appeared in the journal Neurology, published by the Academy of Neurology, that linked low levels of Vitamin D to Multiple Sclerosis.  The article was unusual for its length and the breadth of research cited over several decades.  More recently, a Johns Hopkins article published “the most conclusive evidence to date” that Low Vitamin D Levels Pose Large Threat to Health.

New publications on Vitamin D seem to appear every week with the focus on levels of 25-hydroxyvitamin D, also written as 25(OH)D. Its half life in serum is ~ 10 days to 3 weeks.

The biologically active form 1,25-dihydroxyvitamin D, written as 1,25(OH)D²,  is made in the kidneys and has a much shorter serum half-life of ~ 4-6 hours, thus making it less useful as a serum marker for measuring.

Sources & Metabolism: Vitamin D is a fat soluble vitamin that’s absorbed in the small intestine from  foods such as egg yolks, fatty fish, fish liver oils, fortified milk, margarine, and cereals.  Bile salts are required for absorption.  Sunlight stimulates the skin to synthesize vitamin D, but exposure of hands and face as little as 15 minutes may not be sufficient and it is not as effective for everyone.  It won’t work in winter months, it won’t work for the aged, for those who have pigmented skin, and it won’t work for those who cover their skin.

Vitamin D Metabolism

The Controversy –  How Do We Determine Normal Values?

Surprisingly, in a well designed multicenter study of healthy young Hawaiians in their 20’s who were exposed to at least 29 hours of sun per week, 51% were found to have vitamin D deficiency using the usual cut off of 30 ng/ml for normal.  This study from 2007 found the mean concentration of 31.6 ng/ml, and the highest of 62 ng/ml.  It raises the question whether

“it seems prudent to use this value [60 ng/ml] as an upper limit when prescribing vitamin D supplementation,”

rather than the generally published normal range of 30 to 80 ng/ml or even 100 ng/ml quoted in some labs.  This study is important in discussing the controversial question of what normal values should be for calcium homeostasis and reviews several possible explanations for inadequate production of D3 including genetic differences.

They note the highest reported values in “Nebraska outdoor workers… were between 81 and 84 ng/ml” but the assay system differed compared to theirs and results in a higher value.   Reviewing this study that was published in the Journal of Clinical Endocrinology & Metabolism has allowed me just now to readjust my own patient practice.

Laboratory Testing:  results can differ from one laboratory to another.  My hospital sends specimens to ARUP for testing, whereas Quest has acknowledged errors in laboratory testing and problems with standardization as reported by the New York Times here.

Function:  It is important for absorption of calcium and phosphorous from the small intestine, for bone health, osteoporosis, risk of falls, certain cancers(colon, breast, prostate), and possibly 6 to 7 years of longevity.  Deficiency of vitamin D is associated with suboptimal health and possibly increased pain; it is linked to infections, gum disease, hypertension, diabetes, coronary disease, neurological diseases such as Multiple Sclerosis, Parkinson’s Disease, dementia and Alzheimer’s Disease though it may not be causal. Its receptor is found all over the body including the brain.

I recommend this review by one of the best web resources at Memorial Sloan Kettering Cancer Center Herbs & Botanicals.

They quote a reference showing it reduces postmenopausal weight gain and “In adults with impaired fasting blood glucose, giving calcium and vitamin D reduced increases in plasma glucose and insulin resistance….”

It is the only vitamin that is a steroid hormone, and my interest increased on learning that it functions as an anti-inflammatory.  But as I tested blood levels for 25(OH) vitamin D and parathyroid hormone (PTH), I discovered more than 90% of my patients had vitamin D deficiency and a few had hyperparathyroidism.  There are four parathyroid glands next to the thyroid, and for some reason doctors have rarely tested their hormone levels.

***Persons with hyperparathyroidism should NOT take calcium or vitamin D.

It may lead to kidney stones and bone pain:  stones, bones and groans.***

Evidence for Optimizing Vitamin D Concentrations

On the other hand, if vitamin D is low, there is some evidence that replacement with vitamin D3 so that blood levels are in the high normal range, may help pain.  That is, it may raise the pain threshold and possibly have other benefits for health and longevity. It is desirable to avoid toxic levels of D as it causes hypercalcemia with depression, drowsiness, weakness, headache, polydipsia,  bone loss, and metastatic calcifications of many organs, soft tissues and blood vessels.  The generally quoted range of normal for 25(OH) vitamin D is 30 to 80, that varies with the lab.

Doesn’t that photo of the Great Western Divide make you want to get outside into the sun?

Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes was reviewed by Heike Bischoff-Ferrari et al, in 2006,  though it has been superseded by much additional work since then.

To quote from their article:

This review summarizes the evidence for optimal serum  25(OH)D concentrations. The endpoint selection for this review was based the strongest evidence to date—ie, that from RCTs [randomized controlled trials], consistent evidence from prospective and cross-sectional epidemiologic studies, and strong mechanistic evidence or dose response relations.  BMD [bone mineral density], fracture prevention, lower-extremity function, falls, oral health, and colorectal cancer met these criteria. Weaker evidence exists of a beneficial effect of vitamin D on other diseases, including multiple sclerosis (15), tuberculosis (16), insulin resistance (17, 18), cancers other than colorectal (19 –22), osteoarthritis (23, 24), and hypertension (25–27), but these diseases are not considered here.

They did not review pain studies.  I would add that “weaker” evidence merely means that it must be confirmed by more studies, not that it excludes those conditions.  There is an epidemic of vitamin D deficiency in the country, and the incidence is very high in pain clinics as reported in several studies.

A new multi-center epidemiology study  “Demographic Differences and Trends of Vitamin D Insufficiency in the US Population, 1988-2004”  by Ginde, et al, in 2006,  “demonstrate a marked decrease in serum 25(OH)D levels from the 1988-1994 to the 2001-2004 NHANES data collections.”  And like others before them, they point out:

“Current recommendations for vitamin D supplementation are inadequate to address the growing epidemic of vitamin D insufficiency.”

Summary:

Make sure your doctor checks both your 25(OH)Vitamin D and parathyroid hormone level (PTH) – not thyroid – to determine if you have hyperparathyroidism or if you have normal or low vitamin D.  That will determine if you need replacement or if you should stop using calcium and D as it will cause kidney stones and calcium deposits on your bones leading to pain.

If vitamin D levels are low it may result in increased physical pain and may cause or aggravate many medical conditions.

If PTH levels are high indicating hyperparathyroidism it will cause new painful conditions.

Intake does vary with the patient, the season, the age, but the recommended daily allowance may perhaps be double what it is now.  It is unclear when the federal government will adjust that dosage.   As always, your physician’s recommendation will be based upon blood levels of 25(OH)D and PTH.

Do not make changes in your dosage without careful evaluation.

Could this possibly be one of the most important areas of research this century?

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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