Metformin – Nerve Pain & Microvascular Pain (angina)


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Metformin & Pain

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A diabetes drug used for many who have no diabetes. Recent discussion on metformin here and here.

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Metformin “can lead to a long-lasting reversal of pain hypersensitivity even long after treatment cessation, indicative of disease modification.” [ref below]

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References:

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A successful case of pain management using metformin in a patient with adiposis dolorosa.

International Journal of Clinical Pharmacology and Therapeutics

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In this case report, we describe a patient with Dercum’s disease who was successfully managed with metformin. The administration of metformin reduced pain intensity from 9/10 to 3/10 and favorably affected the profile of inflammatory cytokines (i.e., TNF a, IL-1β, IL-6, and IL-10), adipokines (i.e., adiponectin, leptin, and resistin), and β-endorphin. Because each variable was affected moderately by the drug, in the range of 20 – 30%, it follows that these effects are additive, i.e., they act independently of each other. However, taking into account advances in the pharmacology of metformin, it seems that other phenomena, such as modulation of synaptic plasticity, activation of microglia, and autophagy of the afferents supplying painful lipomas should be taken into consideration. Nonetheless, metformin deserves further exploration in the biology of pain.

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The use of metformin is associated with decreased lumbar radiculopathy pain

Journal of pain [2013], from University of Arizona Tucson, Ted Price’s lab, and USC

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Abstract:

Lumbar radiculopathy pain represents a major public health problem, with few effective long-term treatments. Preclinical neuropathic and postsurgical pain studies implicate the kinase adenosine monophosphate activated kinase (AMPK) as a potential pharmacological target for the treatment of chronic pain conditions. Metformin, which acts via AMPK, is a safe and clinically available drug used in the treatment of diabetes. Despite the strong preclinical rationale, the utility of metformin as a potential pain therapeutic has not yet been studied in humans. Our objective was to assess whether metformin is associated with decreased lumbar radiculopathy pain, in a retrospective chart review. We completed a retrospective chart review of patients who sought care from a university pain specialist for lumbar radiculopathy between 2008 and 2011. Patients on metformin at the time of visit to a university pain specialist were compared with patients who were not on metformin. We compared the pain outcomes in 46 patients on metformin and 94 patients not taking metformin therapy. The major finding was that metformin use was associated with a decrease in the mean of “pain now,” by −1.85 (confidence interval: −3.6 to −0.08) on a 0–10 visual analog scale, using a matched propensity scoring analysis and confirmed using a Bayesian analysis, with a significant mean decrease of −1.36 (credible interval: −2.6 to −0.03). Additionally, patients on metformin showed a non-statistically significant trend toward decreased pain on a variety of other pain descriptors. Our proof-of-concept findings suggest that metformin use is associated with a decrease in lumbar radiculopathy pain, providing a rational for larger retrospective trials in different pain populations and for prospective trials, to test the effectiveness of metformin in reducing neuropathic pain.

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The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model.

PLoS One [2014] from MD Anderson Cancer Center

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Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) characterized by loss of sensory sensitivity and pain in hands and feet is the major dose-limiting toxicity of many chemotherapeutics. At present, there are no FDA-approved treatments for CIPN. The anti-diabetic drug metformin is the most widely used prescription drug in the world and improves glycemic control in diabetes patients. There is some evidence that metformin enhances the efficacy of cancer treatment. The aim of this study was to test the hypothesis that metformin protects against chemotherapy-induced neuropathic pain and sensory deficits. Mice were treated with cisplatin together with metformin or saline. Cisplatin induced increased sensitivity to mechanical stimulation (mechanical allodynia) as measured using the von Frey test. Co-administration of metformin almost completely prevented the cisplatin-induced mechanical allodynia. Co-administration of metformin also prevented paclitaxel-induced mechanical allodynia. The capacity of the mice to detect an adhesive patch on their hind paw was used as a novel indicator of chemotherapy-induced sensory deficits. Co-administration of metformin prevented the cisplatin-induced increase in latency to detect the adhesive patch indicating that metformin prevents sensory deficits as well. Moreover, metformin prevented the reduction in density of intra-epidermal nerve fibers (IENFs) in the paw that develops as a result of cisplatin treatment. We conclude that metformin protects against pain and loss of tactile function in a mouse model of CIPN. The finding that metformin reduces loss of peripheral nerve endings indicates that mechanism underlying the beneficial effects of metformin includes a neuroprotective activity. Because metformin is widely used for treatment of type II diabetes, has a broad safety profile, and is currently being tested as an adjuvant drug in cancer treatment, clinical translation of these findings could be rapidly achieved.

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Proteomic and functional annotation analysis of injured peripheral nerves reveals ApoE as a protein upregulated by injury that is modulated by metformin treatment

from Mol Pain [2013], from University of Arizona

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Abstract

BACKGROUND:

Peripheral nerve injury (PNI) results in a fundamental reorganization of the translational machinery in the injured peripheral nerve such that protein synthesis is increased in a manner linked to enhanced mTOR and ERK activity. We have shown that metformin treatment, which activates adenosine monophosphate-activated protein kinase (AMPK), reverses tactile allodynia and enhanced translation following PNI. To gain a better understanding of how PNI changes the proteome of the sciatic nerve and ascertain how metformin treatment may cause further change, we conducted a range of unbiased proteomic studies followed by biochemical experiments to confirm key results.

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CONCLUSIONS:

These proteomic findings support the hypothesis that PNI leads to a fundamental reorganization of gene expression within the injured nerve. Our data identify a key association of ApoE with PNI that is regulated by metformin treatment. We conclude from the known functions of ApoE in the nervous system that ApoE may be an intrinsic factor linked to nerve regeneration after PNI, an effect that is further enhanced by metformin treatment.

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Volume 107 of the series Experientia Supplementum [2016] from University of Texas Dallas

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Abstract:

Chronic pain is a major clinical problem that is poorly treated with available therapeutics. Adenosine monophosphate-activated protein kinase (AMPK) has recently emerged as a novel target for the treatment of pain with the exciting potential for disease modification. AMPK activators inhibit signaling pathways that are known to promote changes in the function and phenotype of peripheral nociceptive neurons and promote chronic pain. AMPK activators also reduce the excitability of these cells suggesting that AMPK activators may be efficacious for the treatment of chronic pain disorders, like neuropathic pain, where changes in the excitability of nociceptors is thought to be an underlying cause. In agreement with this, AMPK activators have now been shown to alleviate pain in a broad variety of preclinical pain models indicating that this mechanism might be engaged for the treatment of many types of pain in the clinic. A key feature of the effect of AMPK activators in these models is that they can lead to a long-lasting reversal of pain hypersensitivity even long after treatment cessation, indicative of disease modification. Here, we review the evidence supporting AMPK as a novel pain target pointing out opportunities for further discovery that are likely to have an impact on drug discovery efforts centered around potent and specific allosteric activators of AMPK for chronic pain treatment.

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Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain.

Mol Pain [2011] from University of Arizona

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Abstract

Neuropathic pain is a debilitating clinical condition with few efficacious treatments, warranting development of novel therapeutics. We hypothesized that dysregulated translation regulation pathways may underlie neuropathic pain. Peripheral nerve injury induced reorganization of translation machinery in the peripheral nervous system of rats and mice, including enhanced mTOR and ERK activity, increased phosphorylation of mTOR and ERK downstream targets, augmented eIF4F complex formation and enhanced nascent protein synthesis. The AMP activated protein kinase (AMPK) activators, metformin and A769662, inhibited translation regulation signaling pathways, eIF4F complex formation, nascent protein synthesis in injured nerves and sodium channel-dependent excitability of sensory neurons resulting in a resolution of neuropathic allodynia. Therefore, injury-induced dysregulation of translation control underlies pathology leading to neuropathic pain and reveals AMPK as a novel therapeutic target for the potential treatment of neuropathic pain.

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Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice.

Age [20124, from University of Arizona

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Abstract:

The chronic and systemic administration of rapamycin extends life span in mammals. Rapamycin is a pharmacological inhibitor of mTOR. Metformin also inhibits mTOR signaling but by activating the upstream kinase AMPK. Here we report the effects of chronic and systemic administration of the two mTOR inhibitors, rapamycin and metformin, on adult neural stem cells of the subventricular region and the dendate gyrus of the mouse hippocampus. While rapamycin decreased the number of neural progenitors, metformin-mediated inhibition of mTOR had no such effect. Adult-born neurons are considered important for cognitive and behavioral health, and may contribute to improved health span. Our results demonstrate that distinct approaches of inhibiting mTOR signaling can have significantly different effects on organ function. These results underscore the importance of screening individual mTOR inhibitors on different organs and physiological processes for potential adverse effects that may compromise health span.

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Two Weeks of Metformin Treatment Enhances Mitochondrial Respiration in Skeletal Muscle of AMPK Kinase Dead but Not Wild Type Mice

.PLoS One from University of Copenhagen [2013].

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Abstract:

Metformin is used as an anti-diabetic drug. Metformin ameliorates insulin resistance by improving insulin sensitivity in liver and skeletal muscle. Reduced mitochondrial content has been reported in type 2 diabetic muscles and it may contribute to decreased insulin sensitivity characteristic for diabetic muscles. The molecular mechanism behind the effect of metformin is not fully clarified but inhibition of complex I in the mitochondria and also activation of the 5′AMP activated protein kinase (AMPK) has been reported in muscle. Furthermore, both AMPK activation and metformin treatment have been associated with stimulation of mitochondrial function and biogenesis. However, a causal relationship in skeletal muscle has not been investigated. We hypothesized that potential effects of in vivo metformin treatment on mitochondrial function and protein expressions in skeletal muscle are dependent upon AMPK signaling. We investigated this by two weeks of oral metformin treatment of muscle specific kinase dead α2 (KD) AMPK mice and wild type (WT) littermates. We measured mitochondrial respiration and protein activity and expressions of key enzymes involved in mitochondrial carbohydrate and fat metabolism and oxidative phosphorylation. Mitochondrial respiration, HAD and CS activity, PDH and complex I-V and cytochrome c protein expression were all reduced in AMPK KD compared to WT tibialis anterior muscles. Surprisingly, metformin treatment only enhanced respiration in AMPK KD mice and thereby rescued the respiration defect compared to the WT mice. Metformin did not influence protein activities or expressions in either WT or AMPK KD mice.

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We conclude that two weeks of in vivo metformin treatment enhances mitochondrial respiration in the mitochondrial deficient AMPK KD but not WT mice. The improvement seems to be unrelated to AMPK, and does not involve changes in key mitochondrial proteins.

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Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries

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Journal of the American College of Cardiology [2006], from University of Glasgow Cardiovascular Research Centre
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Abstract:

We conducted an 8-week double-blind, randomized, placebo-controlled study of metformin 500 mg twice a day in 33 women with a prior history of normal coronary angiography but 2 consecutive positive (ST-segment depression ≥1 mm) exercise tolerance tests. Women randomized to metformin (n = 16) showed significant improvements in endothelium-dependent microvascular function (p < 0.0001) and maximal ST-segment depression (p = 0.013), and a trend (p = 0.056) toward reductions in chest pain incidence relative to placebo recipients. Hence, metformin may improve vascular function and decrease myocardial ischemia in nondiabetic women with chest pain and angiographically normal coronary arteries. Larger controlled trials of longer duration are warranted.

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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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Metformin Targets Aging – no lactic acidosis, no significant hypoglycemia in 18,000 patients-years of follow-up


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Metformin targets multiple pathways affected by aging (pdf)

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Authors Nir Barzilai, Jill P. Crandall, Stephen B. Kritchevsky, and Mark A. Espeland from aging research centers at Albert Einstein Medical School and Wake Forest Medical School, Cell Metabolism June 2016

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….in 2012, when over 18,000 patients-years of follow-up had accrued, and by which time 20% of the cohort was age 70 or older (mean age 64). There were no cases of lactic acidosis or significant hypoglycemia (Diabetes Prevention Pro- gram Research Group, 2012). Mild anemia occurred in 12% of metformin-treated participants versus 8% in the placebo group (p = 0.04). Vitamin B12 deficiency occurred in 7% of metformin group versus 5% in placebo group after 13 years; risk of B12 deficiency increases with duration of use but was not greater in older compared with younger subjects in DPPOS (Lalau et al., 1990). Further, the risk of lactic acidosis appears to be related to renal function, not age per se, and is currently considered to be very low (Aroda et al., 2016).

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B12 deficiency is related to MTHFR. I prescribe the doses of B vitamins to take daily, as published by University of Oxford for seniors. Their work shows it prevents 90% of brain atrophy in those areas that are known to involve Alzheimers Disease [avoid toxic B6 doses that damage brain].

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When time permits, I will be adding more on metformin.

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If low blood sugar (hypoglycemia) occurs, juice works quickly but rapidly disappears and then blood sugar is low again in minutes. Use good diet practices, and use plenty of small protein snacks if needed. Protein lasts longer and does not trigger sugar spikes like juice.

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Common side effects, if present at all, are mostly GI such as diarrhea, nausea, gas, distension of the belly with discomfort, indigestion, anorexia, headache, asthenia. If present, stop the drug, wait till all resolve, and very slowly, increase only as tolerated. This is not a speed test.

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Lactic Acidosis potential rare side effect

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The potentially serious side effect of concern is lactic acidosis. I advise patients to review its list of potential side effects.

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http://www.medsafe.govt.nz/profs/PUarticles/5.htm

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https://www.healthgrades.com/conditions/lactic-acidosis–symptoms

Introduction

Symptoms

Causes

Treatments

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What are the symptoms of lactic acidosis?

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Symptoms of lactic acidosis may include nausea and vomiting, abdominal pain, weakness, rapid breathing, rapid heart rate or irregular heart rhythm, and mental status changes.

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Common symptoms of lactic acidosis

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If you experience lactic acidosis, it may be accompanied by symptoms that include:

Abdominal pain

Anxiety

Fatigue

Irregular heart rate (arrhythmia)

Lethargy

Nausea with or without vomiting

Rapid breathing (tachypnea)

Rapid heart rate (tachycardia)

Shortness of breath

Weakness

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Serious symptoms that might indicate a life-threatening condition

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In some cases, lactic acidosis can be life threatening.

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Seek immediate medical care (call 911) if you, or someone you are with, have any of these life-threatening symptoms including:

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Bluish coloration of the lips or fingernails

Change in level of consciousness or alertness, such as passing out or unresponsiveness

Chest pain, chest tightness, chest pressure, palpitations

High fever (higher than 101 degrees Fahrenheit)

Not producing any urine, or an infant who does not produce the usual amount of wet diapers

Rapid heart rate (tachycardia)

Respiratory or breathing problems, such as shortness of breath, difficulty breathing, labored breathing, rapid breathing, or not breathing

Severe abdominal 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.

.

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

~~

This site is not for email and not for appointments.

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

~~~~~

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

..

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

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METFORMIN for Nerve Pain


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Is metformin the new wonder pill or snake oil? Based on one man’s response to metformin and recent exciting research on the drug, I am looking forward to finding out how it works clinically for my patients with intractable pain (and possibly treatment resistant depression). Hopefully most will confirm it is well tolerated. I am just beginning to trial it after learning this one man’s amazing story:

 

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50% relief of nerve pain &

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musculoskeletal pain

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after 2nd week on metformin

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One Man’s Story

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A few days ago I spoke with a man, not my patient, who had 50% relief of pain after the second week on metformin. He’s taken it for 3 months now, but the big change came dramatically after the second week when he had been on the 2,000 mg dose a full week. In 2013, he was on the side of the freeway median lane, and had crawled into the engine of his disabled Ford F350 reaching in with his left hand when his vehicle was hit by a Lexus SUV going 70 mph and he was thrown. He doesn’t talk about his pain. Ever. He needs total knee replacement in the next few weeks, and has had four surgeries on his left wrist, mangled in that engine, now with a long steel plate in the wrist. He broke the titanium plate and it wasn’t healing. Since metformin, the skin and surgical scar is healing. He’s one of these quiet guys who don’t ever talk about pain. His wife simply said these days he’s sleeping since on metformin.

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But no one had asked him about pain since on metformin or for years either. It took 30 minutes to get one little bit of information from him on pain, like pulling teeth: Since metformin, he’s had 50% relief including the nerve pain at his wrist.

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She said he used to sit up all night in pain for years and was very irritable. Irritability is what happens with no sleep; pain is worse with no sleep. I could not get him to rate his pain. Stoic. Bright man, stoic. Devilish sense of humor. Severe pain for so many years he would never talk about. His surgeon had him stop the Vicodin 5/325 weeks before his last surgery “to help it heal.”

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Some of his relief may have also been influenced by blood sugar dropping from 170 to 90, no more excessive thirst and urination keeping him awake, but the neuropathic pain at his wrist had been nasty a few years. Pain had kept him up for months. He had no side effects.

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Metformin

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Metformin is a medication approved in Canada in 1972 and in the United States by the FDA in 1994 for type 2 diabetes. It is well tolerated when prescribed for people who do not have diabetes but who have other conditions such as PCOS (polycystic ovary syndrome), infertility; and it is the focus of intense activity being studied for its

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(1) anti-aging (PDF from Wake Forest University or the Albert Einstein Medical School Longevity study clinicaltrials.gov), 

(2) anti-cancer (ithas become the focus of intense research as a potential anticancer agent” per Cancer Treat. Res. publication 2014) and now recently being studied for

(3) anti-inflammatory analgesic effects.

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“Metformin increases the number of oxygen molecules released into a cell, which appears to boost robustness and longevity. It works by suppressing glucose production in the liver and increasing insulin sensitivity, therefore benefiting patients with type 2 diabetes.”

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I am very interested by all the new research being done on an old drug, metformin, that has suddenly turned heads in just the last few months as we learn its mechanisms involving the pain matrix. Is this metformin some miracle drug, another hot trendy bandwagon people jump on in medicine? It’s an old drug already FDA approved, now repurposed, with excellent safety, and four months ago a publication shows it to be a glial modulator and anti-inflammatory, centrally active. Best of all, it was dramatically potent in the setting of this man’s intractable nerve and musculoskeletal pain.

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But how do we get from 1994 to 2017, through the Decade of Pain, seeing patients who have astonishing pain relief without asking a single patient, millions of patients if it helped pain? A recent past president of the American Endocrine Society said: “No good data on metformin to treat pain. Everything else, but not pain.” He also said, “Safe. We do it all the time for people with PCOS, infertility, cancer, etc. The anti-aging people use it all the time. No risk of hypoglycemia. Just be sure their GFR is above 40.” So ask your doctor who may not know it’s hot research right now.

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When was it first mentioned for pain?

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Less than one year ago, a report on metformin’s use for pain was a 2016 poster presentation at the annual meeting of the American Pain Society from Ted Price’s lab at University Texas Dallas. “The AMPK activator metformin has been shown by our lab to reverse the effects of chronic neuropathic pain in various short term studies….The treatment successfully decreased the hypersensitivity and cold allodynia associated with neuropathic pain, and showed persistent relief for several weeks post-injection. Metformin also decreased the activation of microglia in the spinal cord.”

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I have cautiously held back prescribing it for pain until I heard this man’s story a few days ago, and days later I am still astonished at the relief he had. I immediately suspected metformin must be a strong glial modulator and that mechanism was confirmed in a publication four months ago, in animal (discussed at end).

 

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 SIDE EFFECTS

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If some develop side effects, stop the medication until all side effects are zero. Then at your own body’s rate, as slowly as needed, increase if needed to 1000 mg twice daily.

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If you again have side effects, again stop til all are zero. Maybe your top dose with no side effects is less than 2,000 mg/day.

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More information on potential side effects  are on the next metformin post – almost none in 18,000 patient years, and not a single case of lactic acidosis.

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STUDIES NEEDED

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It would be extremely helpful to see a study on metformin’s use for pain in a major cancer center, including the range of all underlying diagnoses of those patients who may not be in best of health.  What are % of side effects?

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INFLAMMATION

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Metformin helps inflammation. Inflammation is the cause of 90% mortality. Almost all disease in the body begins with inflammation including atherosclerosis that leads to plaque, heart attacks, stroke. And the same risk factors for heart disease are same for Alzheimers. Inflammation manifests differently in each of us, but to relieve pain, major depression, bipolar disease, PTSD, it can be very dynamic to see response in a few hours once you have the right dose and combination of glial modulators. If this one can relieve 50% of severe chronic pain in two weeks, with few or no side effects, then millions can benefit now. It is an old generic drug repurposed for pain, that is anti-inflammatory. Best of all anti-inflammatory up there in the brain where the inflammatory cytokines produced by glia make you feel like you have the flu:  difficulty thinking, fatigue, drowsy, achey, irritable, needing sleep. That is inflammation. The innate immune system going into gear to attack a virus or…..damage.

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Studies reported about 2001, NIMH showed brain atrophy and memory loss in chronic depression, and about 2009 others showed the same in chronic low back pain.

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My focus for years has been on inflammation in the CNS (brain, spinal cord) because NSAIDs like ibuprofen, Aleve, do not reach the CNS and do not interact on the cells of interest: glia, the cells of the innate immune system that produce a balance of anti-inflammatory and pro-inflammatory chemicals called cytokines. BALANCE.

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Tolerance is a big issue in treating pain or major depression. I strongly recommend reading yesterday’s post on tolerance, i.e. when the body stops responding to ketamine or morphine or an antidepressant after several days or weeks or years. Inflammation may be one cause.

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A publication four months ago shows metformin has both immune and glial suppressive effects that can relieve tolerance to morphine.  It’s a centrally acting analgesic because that’s where chronic pain or major depression is, in the CNS.

 

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MECHANISM of PAIN RELIEF

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It has both immune and glial suppressive effects: J Neuroinflammation. 2016 Nov 17;13(1):294.

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Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation.

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ABSTRACT

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BACKGROUND:

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Tolerance [see post on this subject yesterday] seriously impedes the application of morphine in clinical medicine. Thus, it is necessary to investigate the exact mechanisms and efficient treatment. Microglial activation and neuroinflammation in the spinal cord are thought to play pivotal roles on the genesis and maintaining of morphine tolerance. Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception. Metformin, a biguanide class of antidiabetic drugs and activator of AMPK, has a potential anti-inflammatory effect. The present study evaluated the effects and potential mechanisms of metformin in inhibiting microglial activation and alleviating the antinociceptive tolerance of morphine.

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RESULTS:

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We found that morphine-activated BV-2 cells, including the upregulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, pro-inflammatory cytokines, and Toll-like receptor-4 (TLR-4) mRNA expression, which was inhibited by metformin.Metformin suppressed morphine-induced BV-2 cells activation through increasing AMPK phosphorylation, which was reversed by the AMPK inhibitor compound C. Additionally, in BV-2 cells, morphine did not affect the cell viability and the mRNA expression of anti-inflammatory cytokines. In bEnd3 cells, morphine did not affect the mRNA expression of interleukin-1β (IL-1β), but increased IL-6 and tumor necrosis factor-α (TNF-α) mRNA expression; the effect was inhibited by metformin. Morphine also did not affect the mRNA expression of TLR-4 and chemokine ligand 2 (CCL2). Furthermore, systemic administration of metformin significantly blocked morphine-induced microglial activation in the spinal cord and then attenuated the development of chronic morphine tolerance in mice.

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CONCLUSIONS:

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Metformin significantly attenuated morphine antinociceptive tolerance by suppressing morphine-induced microglial activation through increasing AMPK phosphorylation.

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The material on this site is for informational purposes only.

.

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

.

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

~~

This site is not for email and not for appointments.

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

~~~~~

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

..

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

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Intranasal Ketamine in Major Depressive Disorder


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

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A Randomized Controlled Trial of

Intranasal Ketamine in Major Depressive Disorder

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Conclusions

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“This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression.”

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

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

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Entire generations of scientists are now lost forever.

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Ketamine Safety

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Ketamine is one of the safest medications I have prescribed in 40 years of medicine. And I meticulously obtain laboratory studies at least twice a year to verify any potential harm as it has been reported in addicts that it may affect bladder, kidney, liver or biliary system. I first prescribed ketamine about 14 years ago for intractable pain rated 10 on a scale of 10 for 30 years; and prescribed ketamine since Spring 2012 for Major Depression. For years I searched to find a spray with a metered dosing system. Thus since late 2011, intranasal has been the delivery I find most useful. When given as nasal spray or under the tongue, not swallowed, it goes straight to the bloodstream, bypassing the liver, and works for depression because the liver does not convert it to a different metabolite.

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Nevertheless, it is important to stress that ketamine must be monitored for any possible adverse effects including toxicity and/or addiction. I require long distance patients to be followed by a psychiatrist or psychologist regularly while on ketamine. So far, my returning patients have been stable for years.

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Further, when given by the nasal or sublingual route, I do not see the side effects that my anesthesiology colleagues see after I.V. infusion. I’ve been in board meetings with some of the finest anesthsiology pain specialists in the country sharing and comparing experience. I don’t see those complications. But that is what is published and I.V. is how it is given in the few centers where ketamine is used for treatment of Major Depression or Bipolar Depression.

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Ketamine is a short acting medication whether it is given I.V. or nasally or under the tongue. But it is quite bitter and most prefer nasal delivery.  Review the case study of the professional who traveled out of state once or twice weekly for one year to receive I.V. ketamine. She had failed ECT 9 or 10 times – memory loss was so bad she got lost in her own neighborhood. She now does very well on a small dose every 48 hours given nasally. In the same post, I reported the patient with Juvenile Bipolar Disorder, Fear of Harm phenotype whose profound thermoregulatory abnormalities respond in seconds to ketamine, with a very small dose of 10 mg nasal spray every 3 days. That’s it! Temperature responds in seconds, and the depression responds in 10 minutes in her case.

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Unfortunately research protocols require the study of fixed dosages in order to be a cost effective study for one sample size at one dose to be even slightly meaningful, even then 18 patients studied at Mt. Sinai is a small study at the one dose they used.

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The principle that I have always used is “start low, go slow.” That allows for the discovery that some large men may require the tiniest dose and some tiny 90 pound seniors may require some of the largest doses I’ve seen. It cannot be predicted by body weight. Anesthesiologists generally think in terms of mg/kg body weight, for example the 0.5 mg/kg I.V. generally used for depression. But ketamine’s dosage variance is unrelated to weight. That likely explains why some develop frightening symptoms when given IV, and others do not respond. One size does not fit all. That method either under-doses or overdoses.

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There are case reports on this website giving examples of some individuals I have seen with Major Depressive Disorder. One man is unusual in needing a small dose only every 6 to 8 weeks, but most use the nasal spray daily or every second or third day. I suspect that after initially starting ketamine on a daily basis for one or two weeks, the frequency of dosing may be lowered to every two or three days. Less is more.

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Professor David Feifel at UCSD guesstimates that ketamine helps 70% of persons with Major Depression. I think that’s a fair statement given that we are unlikely even to see the unknown number who remain at home, forever feeling they are unable to leave their confinement. We know that effects of ketamine are blocked in mice that are deficient in BDNF. We may speculate that when ketamine fails in persons with Major Depression, that may be due to lack of BDNF. We know exercise helps Major Depression and exercise increases BDNF. Much more research is needed.

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The use of ketamine is essentially a first line drug for Complex Regional Pain Syndrome (CRPS). That may never be said in publications, but that has been the case for years in persons with CRPS who have failed all other medications. I specialize in CRPS, a form of neuropathic pain that leads to suicide more often than any other pain syndrome.

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For pain, intranasal ketamine is far shorter lasting, typically three hours, rarely six. And requires doses far higher than for Major Depression or Bipolar Depression. Even then, when used for pain six times daily in very high doses, it has proven to be profoundly safe with few if any side effects that last less than half an hour, if present at all.

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Inflammation

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The role of inflammation and glia in the pathogenesis of depression has been well established since 2000, and discussed here. The study of ketamine has taken on new life with the discovery that it profoundly lowers pro-inflammatory cytokines produced by microglia. Inflammatory cytokines have been shown to be elevated in chronic pain and in Major Depression. That is why I feel it is important to prescribe adjuncts that also lower inflammatory cytokines. And patients with Major Depression and Bipolar Depression have reported the adjuncts make ketamine stronger and last longer. Some don’t even need ketamine after awhile, but remain on the adjuncts.

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Ketamine is not a cure and I find it is best used with adjunct medication. In my experience, ketamine and adjunct medications are likely to help as long as prior to treatment, patients are still able to function, to work at least somewhat. I do have 4 patients in the last four years who have not left their home or their bed for many years, and they failed to respond. Sadly, one older woman had to be institutionalized for life, her melancholic depression was so deep. When ketamine is even partially effective, I have patients who had been too fatigued to work before treatment, yet who are able to return to graduate school for a PhD and do well for years on a stable dose. It is immensely rewarding to be a part of this unique therapy, to see them regain life and function after years of misery and disability.

 

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Studies

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S-Ketamine

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It is my hope to be able to compare S-ketamine, that is not yet FDA approved, with the racemic* ketamine that we now have, that was FDA approved in 1970 in high dose as an anesthetic. Obviously we do not use high anesthetic doses for control of pain or Major Depression. I understand unfortunately that when clinical studies are completed, S-ketamine will be available only in emergency departments.

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*Racemic means the molecule has equal amounts of left and right-handed enantiomers (mirror images) of a chiral molecule (meaning, you cannot superimpose the left hand with the right hand. They mirror but do not superimpose). Thus both left and right racemic ketamine mixture has been FDA approved, but the S-ketamine, the left sided molecule is considered a different drug, and must be FDA approved.

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

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Given the lack of funding for almost any research in this country, I would consider doing a patient-funded study if patients showed interest. It would be modeled on the intranasal study published in the Mt. Sinai study, above, i.e. short term, randomized, double blind, placebo controlled.

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It is reported that S-ketamine may be more effective with fewer side effects. This must be proven and cannot be taken at face value without several studies. Shockingly, some publications in recent years have been fabricated and woven into mythology.

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

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

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“Ketamine administration was associated with a substantial reduction in measures of mania, fear of harm and aggression. Significant improvement was observed in mood, anxiety and behavioral symptoms, attention/executive functions, insomnia, parasomnias and sleep inertia. Treatment was generally well-tolerated.”

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PUBLIC WARNING

reprinted with permission of Demitri Papolos, MD
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Ketamine is a controlled substance.
Administered improperly, or without the guidance of a qualified doctor,
Ketamine may cause injury or death.
No attempt should be made to use Ketamine
in the absence of counsel from a qualified doctor.

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

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

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This site is not for email and not for appointments.

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

 

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

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

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CurcuVIVA reduces joint pain, helps Alzheimers – Oxycodone use much lower


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Rheumatoid arthritis pain is much better in a 54 year old female. She had half the month’s supply of oxycodone left at end of month for breakthrough pain – a big surprise! She had begun CurcuVIVA one daily for that month. It is a dietary supplement available without prescription.

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PJ’s Prescription Shoppe carries it to make it easier for patients though it is available elsewhere.

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CurcuVIVA is a capsule taken once daily. You will see the name Longvida on its label and in the literature. It is the same thing.

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It is curcumin, the active ingredient in turmeric. It differs from turmeric because this form does cross the blood brain barrier to reach brain. Turmeric does not reach the brain, therefore turmeric has no effect on Alzheimers Disease or tauopathies (accumulation of tau proteins). Tau in Alzheimers Disease and frontotemporal dementia and parkinsonism has been linked to chromosome 17.

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UCLA Alzheimers research unit developed this form of curcumin under the direction of Sally A. Frautschy and Greg Cole. On December 2012 they published in the Journal of Biological Chemistry showing Curcumin corrects molecular, synaptic and behavioral deficits in aged human tau transgenic mice.

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For more information on other actions of curcumin such as pain, etc, see a detailed review on the website of Memorial Sloan Kettering Cancer Center Herbs and Botanicals. I link to them on my website (bottom right column) as it is difficult to find. Curcumin has antiplatelet properties that may increase risk of bleeding. I recommend reading the details of mechanism of action and drug interactions.

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Do not combine with other over-the-counter pain medications without checking this link for interactions.

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It “exhibits neuroprotective, choleretic, anti-inflammatory, immunomodulatory, anti-proliferative and chemopreventive effects.” It was “found to be safe and equally effective as a non-steroidal anti-inflammatory drug for the treatment of osteoarthritis of the knee.”

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Caution: “Patients with gastrointestinal disorders or predisposed to kidney stone formation should…use this supplement with caution.”

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Contraindications: “Patients with bile duct obstruction, gallstones, and GI disorders including stomach ulcers and hyperacidity disorders should not take this supplement.”

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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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Palmitoylethanolamide “PEA” – Review of Anti-inflammatory, Analgesic, Neuroprotective Mechanisms


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A review of palmitoylethanolamide, or PEA, has been published this June by Mireille Alhouayek and Guilio G. Muccioli from the Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Bruxelles, Belgium.

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The authors review the impact of PEA on inflammatory and neurodegenerative diseases, and show that inhibiting the breakdown of PEA (the hydrolysis) may increase levels of PEA. This could lead to treatment of inflammatory and neurodegenerative diseases.

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To address the loss of PEA that occurs in various diseases we must either

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1.  replace the decreased levels of endogenous PEA that is made by the brain by taking a capsule such as PeaPure,  a food supplement that contains 100% palmitoylethanolamide, to reconstitute the needed levels

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2.  inhibit the breakdown (hydrolysis) of PEA.

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.I directly quote palmitoylethanolamide4pain that has outlined key quotes from that scientific review:

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They start outlining the focus of the paper:

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Our focus here is on PEA, which is a known anti-inflammatory compound with analgesic, neuroprotective and antiallergic properties.

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Important for understanding the therapeutic relevance of PEA is the next remark:

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Evidence suggests that PEA metabolism is disturbed during inflammation, and that a decrease in PEA levels contributes to the inflammatory response.

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This explains why it is so useful to administer exogenous PEA as a supplement during states of chronic inflammation. Decreased PEA levels induce more inflammation and a vicious circle has started. Administering PEA (for instance as PeaPure capsules of 400 mg, a foodsupplement) can stop this circle and help the organism to restore the PEA levels and decrease inflammation.

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PEA’s mechanism of action

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The next quote is related to PEA’s main mechanism of action:

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Although it is now clear that PEA is a ligand for PPAR-a, some of its effects occur through as yet unidentified receptors.

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Although there are many ways PEA acts in the cell, the PPAR-a receptor indeed seems the most important one; through that receptor PEA can downregulate overactive inflammatory responses.

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PEA levels also decreased following sciatic nerve constriction injury or ligation of the sciatic nerve in spinal cord and brain areas involved in nociception

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PEA levels are not only decreased during chronic inflammation, also during chronic pain states, such as in sciatic pain.

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The fact that an anti-inflammatory treatment restores PEA levels reinforces the role of PEA as an anti-inflammatory mediator.

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PEA levels can be restored also by treatment with classical anti-inflammatory compounds such as NSAIDs, this however triggers many side effects and that can be avoided by treating with PEA itself!

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PEA as a protective molecule

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In the brain, PEA levels seem to be increased following injurious stimuli, and this has been proposed as a homeostatic mechanism aimed at counteracting inflammation and blunting the inflammatory response.

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PEA has self-reparative properties and indeed can be defined as the molecule of self-reparation and self-protection.

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This ‘pro-homeostatic’ increase, although probably slowing disease progression, seems insufficient to exert anti-inflammatory effects in itself, and should be further amplified…

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One of the classical ways to amplify PEA is to administer it as food supplement: start dose is 1200 mg/daily and in cases of insufficient response we suggest to double the dose.

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Although the first identification of PEA as an anti-inflammatory compound occurred more than 50 years ago, general interest in its anti-inflammatory and analgesic properties was not sparked again until the mid-1990s.

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It was due to the work of the Nobel laureate professor Rita Levi-Montalcini that the scientific community understood the importance of PEA in the 90s. However, as patents on this natural compound were not possible, no great interest emerged, as pharmaceutical companies were uninterested. It was due to the work of small companies, such as Epitech Srl and JP Russell Science that PEA was brought to the attention of the general public.

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Mechanism of action in addition to the PPAR receptor

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The authors nicely summarized the effects of PEA:

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PEA inhibits phosphorylation of kinases involved in activation of pro-inflammatory pathways, such as mitogen-activated protein kinase (MAPK), c- Jun N-terminal kinase (JNK) and extracellular signal-regulated kinases (ERK), and the nuclear translocation of the transcription factors nuclear factor (NF)-kB and activator protein 1 (AP-1) and prevents degradation of the inhibitory IkB-a, which when associated to NF-kB prevents its nuclear translocation.

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Besides reducing inflammatory cells activation and recruitment, PEA modulates the expression of enzymes involved in pro-inflammatory processes, such as COX-2 and inducible nitric oxide synthase (iNOS) and reduces nitric oxide and pro-inflammatory cytokines production in vitro and in vivo.

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Relevance for Alzheimer, Parkinson’s and MS

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The neuroprotective effects of PEA are in part the result of its effects on downregulating the inflammatory cascade. Indeed, many neurodegenerative diseases are associated with a strong inflammatory component, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) or MS

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The follow stating:

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This neuroinflammation is no longer simply considered as a consequence of neurodegeneration, but might be a primary factor in some cases; therefore, anti-inflammatory treatments might represent interesting therapeutic strategies in these diseases

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After discussing modern pharmaceutical ways to block the hydrolysis of PEA with pharmaceutical new compounds, they end their overview with an important statement:

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The potential of using PEA as a beneficial endogenous bioactive lipid in the setting of inflammation is well established

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My thanks to palmitoylethanolamide4pain for the outline of key points in this review of PEA.

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The material on this site is for informational purposes only.

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

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

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Palmitoylethanolamide (PEA) – Boosting Its Anti-inflammatory Immune Response


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Discovery could lead to new immune-response drugs for allergies, illnesses and injuries

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Improved spinal cord injury & inflammation in mice

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Medical news November 17, 2009, announced that “UC Irvine pharmacology researchers have discovered a way to boost levels of a natural body fat that helps decrease inflammation, pointing to possible new treatments for allergies, illnesses and injuries related to the immune system.”

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“For decades, it has been known that this fat, called palmitoylethanolamide (PEA), is a potent anti-inflammatory substance that reduces both allergic symptoms and occurrences of rheumatic fever, but researchers understood little about how PEA works.”

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I”n a study appearing online in the Proceedings of the National Academy of Sciences, Daniele Piomelli, the Louise Turner Arnold Chair in Neurosciences at UCI, and colleagues found that levels of PEA are tightly regulated by immune system cells. In turn, PEA helps control the activity of these cells, which are called into action to fight infection, disease and injury in the body.”

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They found a protein, an enzyme that breaks down molecules that control cell inflammation and deactivates PEA. They then created a novel compound that prevents the breakdown.

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“When given to rodents, the compound increased the levels of PEA in their immune cells and reduced the amount of inflammation elicited by an inflammatory substance. Furthermore, when administered to the spinal cords of mice after spinal cord injury, the compound decreased inflammation associated with the trauma and improved the recovery of motor function.”

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UCI is collaborating with the Italian Institute of Technology in Genoa to develop a range of immune-response drugs. 

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Source: University of California – Irvine

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Refer an earlier post on PEA here.

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Palmitoylethanolamide is sold as PeaPure, a food supplement, available from the Netherlands and imported by a local pharmacy here. I have submitted a paper for publication on the treatment of vulvodynia and proctodynia with PeaPure and a topical cream. That source will be posted once it is accepted.

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I have been seeing some exciting responses to treatment of intractable pain with PeaPure. I invite others who use it to add comments below so that we may all learn from your experience.

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The material on this site is for informational purposes only.

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

~~~~~

Please understand that it is not legal for me

to give medical advice without a consultation.

If you wish an appointment, please telephone my office.

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

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