A New Class of Pain Medicine from Cancer Cells – PD-L1 inhibits acute & chronic pain


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For the nonscientist, this report may explain better:

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Cancer actually yields a painkiller

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Scientists have discovered a potent painkiller in an unlikely place — cancer cells.

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This painkiller strongly inhibits acute and chronic pain in mouse models of melanoma, according to a study published Monday in Nature Neuroscience.

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Called PD-L1, the molecule is known to inhibit immune function, which helps cancers evade immune surveillance. It’s also produced in neurons. If it can be used to make an analgesic drug, it would represent a new class of painkillers, something badly needed.

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The molecule acts by targeting a cellular receptor called PD-1 and has been a longstanding target of cancer therapies called checkpoint inhibitors seeking to activate the immune system. But its painkilling effect is news.

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Ru Rong Ji of Duke University was senior author. Gang Chen and Yoang Ho Kim, also of Duke University, were first authors. The study can be found online at j.mp/cancerspain.

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…..Dr. Patel, oncologist from UCSD says: “This could result in a therapy that helps patients in a year or two years, just because so much has been done in the field.”

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The relationship between cancer and pain is complex, Patel said. PD-L1 suppresses inflammation, which activates the immune system, and also causes pain, Patel said. But there are other ways of activating the immune system, such as with the new cancer immunotherapy treatments, which don’t increase pain, he said.

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….The increased pain response is also caused by the cancer drug nivolumab. The drug, sold under the name Opdivo, targets PD-1 and shows success in treating melanomalymphoma and lung cancer. It produced strong allodynia for five hours in the mice, according to the study.

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Nivolumab is one of the new checkpoint inhibitor cancer drugs that targets PD-L1 receptors with immunomodulatory antibodies that are used to enhance the immune system. They can produce a wide spectrum of side effects termed immune-related adverse events (irAEs) with inflammation due to immune enhancement involving several organ systems.

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This is not my field and perhaps I am wrong. But if treating those cancers with immunotherapy causes the worst known neuropathic pain by blocking checkpoint inhibitors, is it possible that a new pain drug having the opposite mechanism could relieve pain but cause cancer?

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This Nature publication references the growing body of work from the lab of Linda Watkins, PhD, et al, published in 2014:

.Pathological pain and the neuroimmune interface

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Reciprocal signalling between immunocompetent cells in the central nervous system (CNS) has emerged as a key phenomenon underpinning pathological and chronic pain mechanisms. Neuronal excitability can be powerfully enhanced both by classical neurotransmitters derived from neurons, and by immune mediators released from CNS-resident microglia and astrocytes, and from infiltrating cells such as T cells.

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

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


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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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The material on this site is for informational purposes only.

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

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

~~

This site is not for email and not for appointments.

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

~~~~~

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

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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.

~~

This site is not for email and not for appointments.

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

~~~~~

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

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Naltrexone in Low Dose Reduces Pain & Depression


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

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

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

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

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

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

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

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

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

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Funding received from NIH and the Redlich Pain Endowment

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

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  • does it help millions with chronic intractable pain?

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

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

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

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Stanford’s CHOIR Information System

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

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

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

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

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

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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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Avoid opioid use in surgery to reduce postop pain


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Science for years has confirmed that opioids trigger inflammation and that creates pain. Trauma and surgery also create inflammation that leads to pain. How logical is it then to continue use of sufentanil for anesthesia when it is the most highly potent opioid 500 to 1,000 times stronger than morphine. Where is the logic in creating pain by using sufentanil as the anesthetic? A new one on the market will be 10,000 times stronger than morphine. Inflammation is not always easy to reset after you strafe the innate immune system with an opioid.

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Why is ketamine not used more often for surgical anesthesia when we know ketamine profoundly lowers the inflammatory response thus reducing pain more than ever. Studies for years have shown that even a small dose of ketamine reduces postop pain. This is not new.

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A study needs to be done comparing patients who receive no opioids. At least this study showed that when fewer opioids are used, pain scores are 37% lower than if more had been given. Patients given higher doses of opioid, had higher analgesic requirements postop. That increases the risk of persistent chronic pain and the tragic risk of addiction.

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Opioids inflict known lasting harm, pain and suffering, perhaps disability and addiction.

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Reduced opioid use in surgery linked to improved pain scores
Written by Brian Zimmerman

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After anesthesiologists at the University of Virginia Health System in Charlottesville began administering fewer opioids to patients during surgeries, patients’ self-reported pain levels dropped, according to a study led by three UVA anesthesiologists.
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For the study, the team examined 101,484 surgeries that took place in the UVA Health System from March 2011 to November 2015. During this time period, the amount of opioids administered via general anesthesia at the system was reduced by 37 percent.
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For the same time period, self-assessed patient pain scores recorded in post-op recovery units dropped from an average of 5.5 on a 10-point scale to an average of 3.8, marking a 31 percent improvement.

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One of the study’s leaders, UVA anesthesiologist Marcel Durieux, MD, PhD, said the impetus behind the pain score improvements is likely attributable to several factors. One, previous research has indicated opioids can ultimately make people more sensitive to pain. And two, the increased use of non-opioid painkillers like lidocaine and acetaminophen during surgeries at UVA was likely effective.

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….”There is very clear evidence that people can become opioid-dependent because of the drugs they get during and after surgery,” said Dr. Durieux. “I think that by substantially limiting opioids during surgery, we’ve made an important step in addressing that problem.”

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

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

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

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

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

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Medical Marijuana – Cannabis for Pain


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These references include links to peer reviewed journal articles on cannabinoids. They are taken from the Reference Library of the outstanding RSD Association in Connecticut, whose mission is to help relieve pain. They have grouped the articles in helpful folders by subject, and this is one of many folders on the immense subject of pain. Please donate to them as their research helps everyone with pain, not just nerve pain or CRPS. May the references help enrich your lives and help support congress and regulators in legalizing cannabis across the country — the attorney general just now voted in by congress opposes medical marijuana.

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Be aware that states should monitor the plant for bacteria, fungus, pesticides, and heavy metals as discussed in this Smithsonian article:

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“Washington, the second state to legalize recreational marijuana, does require such testing for microbial agents like E. coli, salmonella and yeast mold, and officials there rejected about 13 percent of the marijuana products offered for sale in 2014.”

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Concentrates may be made with toxic butane or heptane. If you have cancer or are immunosuppressed – cancer and autoimmune diseases fall into that category – it is safer not to inhale. Cannabis can be used on the skin or swallowed but be aware when swallowed, it takes 60 to 90 minutes before you feel the effect. It is easy to overdose when swallowed. Check your blood pressure and pulse before use and again while you feel its effect.

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The article also points out that on testing, many of the plants have high THC but no longer have CBD, one of the 86 known cannabinoids, the one that blocks the psychoactive side effects of THC. On its own, CBD has many medical benefits.

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For those who have allodynia, the most intense form of nerve pain, pain that is triggered by a light touch or breath of air:

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Keep in mind that chronic pain is much harder to treat than cancer pain and acute pain. Chronic nerve pain is the hardest of all to treat. We need to be able to prescribe anything that helps. Pain can lead to suicide in these extreme pain conditions.

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Watch out for the munchies – do not get fat.

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O’Shaunessy’s today published articles that may be useful for your Senators, healthcare insurers and states:

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“some additional articles published by cannabis clinicians in O’Shaughnessy’s showing the strength of aggregated case reports. We hope the MBC Marijuana Task Force will give them serious consideration.”

 

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Cannabinoids

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Spinal Cord Stimulators – comment on RSD


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Spinal Cord Stimulators 

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 Craig’s comment

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By no means do I mean to say that I or anyone else has better insight into how to treat pain, but I am against spinal cord stimulators [SCS’s] for treatment of pain due to CRPS, and possibly against use in other situations. I demand that the billions in profit they made be put into a retrospective and prospective study of damage caused by them in order for them to give full informed consent.

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I have 3 goals writing this.

  1. SCS’s

  2. Craig’s experience

  3. The Only Real Answer for severe pain, not damaging the system with opioids

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Informed consent is never given for spinal cord stimulators because it requires truth telling, something our corporations have been reluctant to do. Business ethics are not medical ethics, as we keep being reminded daily in the headlines.

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I enclose, below, a generously expressed and detailed comment by a man who had the patience to sit down and  write the painfully gory details so you can weigh-in on your decision whether to follow your pain specialist’s opinion to give you one. I don’t want anyone to feel suckered into choosing them and if I had pain I’ll admit I’d crave relief too. Anything. I’d be in line before the doors open.

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But if you have CRPS, spinal cord stimulators will create more pain. CRPS evolves unpredictably, by a will of its own. I know some very desperate patients with CRPS everywhere including face, mouth, gums, tongue, organs, trunk, limbs. Spinal cord stimulators will create more pain. Keep in mind, I don’t see the 5 year success stories even for lumbar disc pain. They don’t need me if they are pain free.

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But if you have CRPS and desperate need for pain relief because all else has failed — every known drug in highest possible doses of ketamine, propofol, opioids for weeks in ICU fail to even touch pain— there is one thing, and only one thing to do and I will set it out below. I just sent my recommendation to a patient with CRPS in extreme pain.

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My recommendation, below, is for patients who have nowhere else to turn.

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First I’ll mention the problems Craig encountered with SCS’s. He sent his comment to the opening page of this blog, so I will reproduce below. 

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I am currently undergoing a trial Medtronic SCS. I have had to have it reprogrammed 3 times since it was installed 5 days ago. I have had sensations and issues that I have addressed with my rep and my neurosurgeon. I get a severe headache when the unit is turned on. I get the constant feeling of having to urinate. I have current running through my testicles which they can not seem to program out and I am getting little pain relief. I have had to failed back surgeries, many failed injections and I have CRPS. The leads that were inserted when I was in the table covered my mid back and both legs. After I got to my feet and waited while they programmed the unit in another room. They came in and plugged it in and I no longer had coverage on the right side. My crps is in both legs, my hands, arms and face. The lyrica helped to tamp down some of the burning but I am in pain 24/7 and this was my last resort. I have scar tissue completely surrounding my S1 nerve. By the grace of God, I am on my feet, on crutches. I seem to get a look of disbelief when I tell them the unit is causing these issues or it’s not giving me the relief I was counting on. Relief, only to cause greater issues and pain. Is not relief to me. I can not wait to get this trial out of my back. I believe the leads slipped and that is why I am not getting the full coverage I had on the table. The issues I have had are as follows: severe headache, constant feeling of having to urinate, extreme joint pain, abdominal pain, sleeplessness, involuntary jerking, surges in current even when sitting still. Intense pain around the lead insertion site. Current uncomfortably running through my testicles, regardless of setting. It is my opinion there is still not a lot known about crps and I have read evidence of people have great success with these units. Everyone reacts differently. My body obviously creates a lot of scar tissue and my orthopedic surgeon created a fair amount herself. I can’t imagine even more or being forced into a chair for yet another unlucky decision. The medication helps and I have lived this far without the optimism that it would end soon. I had high hoed for this device but I don’t think it is right for me.

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One of my patients with CRPS was hospitalized for weeks with recurring unusual abscesses and required repeated surgery of hand and forearm. Even before surgery, she had failed opioids, failed ketamine, and was in ICU for weeks and weeks while the same medications were still given along with Propofol and IV Tylenol. Nothing helps her extreme pain.

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Anesthesiologists on staff in ICU threw everything they had at the pain for weeks. Most anesthesia pain doctors would have probably done what they did because that is the limit of tools we have.

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When you have hit the limit of benefit from opioids, ketamine, propofol, we have nothing else that treats pain with one exception: drug holiday.

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Stop all analgesics including Tylenol that destroys the liver as severely as cancer, the severity of which was newly discovered and published yesterday.

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The receptors for these analgesic drugs have up-regulated to such an extent they have caused the situation. Again, I stress, everything that was done during the ICU admissions would be done by any anesthesiology pain specialist. Those are the only tools. They cause the problem. The same for opioid induced hyperalgesia. We used to do it with Parkinson’s drugs in the 80’s.

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The only way to rehabilitate the up-regulation of all those receptors that have now exploded in numbers, immune to anything you throw at them, is stop the drugs.  Stop all of them for weeks, maybe months, years, no one knows, you are all the human guinea pig waiting to happen. But if we restart them, how long do we wait, how quickly will it again lead to this massive hyper-excitable state of pro-inflammatory cytokines that we know have gone wild, flooding the CNS. A flooded engine will not restart.

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Ketamine at least is known to reduce pro-inflammatory cytokines, but the system is too busy exploding, birthing new receptors that take over, and you’ve got a 55 car pile up. Well, more like millions I’d guess. No scientist here. Clnically, when can we resume something after a drug holiday, how soon and which drug? I’d avoid opioids because they create more pro-inflammatory cytokines. Choose ketamine, because they reduce pro-inflammatory cytokines, but if it works at all, stop it at first sign of tolerance, which is the need for increased dose. It becomes less effective. Walk a fine line, endure more pain because unless you do, it will no longer help. Opioids, analgesics of many kinds. 

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How do we get you through a drug holiday because we know withdrawing these drugs will trigger even more pain for possibly weeks until the system settles down?

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Pain storms, hurricanes

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This is complex regional pain syndrome where we see this insanity of pain storms. There is no other condition, unless several neuropathic pains in people with cancer, nowhere I have seen this type of pain in decades except CRPS – comparable to pain of subarrachnoid hemorrhage, blinding pain.

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No one has answers. None. One university does outpatient infusions of ketamine six hours daily for 8 to 12 weeks. Does it help? A small percentage. Outpatient, 6 hours daily, 5 days a week, staying at a hotel, 8 weeks.

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This is CRPS/RSD. No one has answers. It is futile to throw more of the drug in the system. That is my opinion. You have a choice and may choose otherwise. It is your body. You may stay on monthly opioids for decades, until you finally admit how poorly they work. A drug holiday is what we did in the 70s during my ancient training with Parkinson’s patients. They needed full 24-hour support. The American medical system has changed since then and those are not options currently available—cost.

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You need full psychological and psychiatric support.

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The Only Real Answer

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The country needs to invest $10 million to complete the clinical trials needed for an injectable, long-lasting interleukin 10 [IL-10], the anti-inflammatory cytokine. It already has full scientific and animal studies performed by and with the world’s foremost glial scientist at University of Colorado Boulder. Professor Linda Watkins has won awards from many countries. She has been the keynote speaker at the annual academy pain meetings for years. IL-10 can relieve pain for three months in animals that have intractable chronic neuropathic pain. This is not new —–NIH I’m looking at you to fund clinical trials. And those of you who care, do a Kickstarter to fund the clinical trials.

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This is the power of the innate immune system. NIH would rather fund research on the unknowns like stem cells rather than the known. It’s known for decades, NIH does not like to fund pain research. Glia are not all about pain. They are the innate immune system, the key to Alzheimer’s, neurodegenerative diseases, almost all known disease including atherosclerosis. It’s all about inflammation. We need the trials to stop giving drugs that cause inflammation, opioids —–CDC fiats are not as good as a drug that relieves pain, a drug that really works on mechanism. Where will the addicts go if the ER only has IL-10 for pain? That is one way to overspend on ER visits.  And NIH, please get us some real clinical research funding on how to use glia for our benefit. Get us some research on the entourage effect, combining medications to achieve relief especially for neuropathic pain.

Then bring on some crack negotiating teams from insurers to do some negotiation about pharmaceutical prices. Our new president has mentioned that.

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Please bring this to everyone’s attention. One way to get a grip on pain and/or depression is to build hope, help others, and energize behind a goal.

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Kickstarters work to raise tens of millions overnight. 

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IL-10 – animals have been shown to be pain free for three months, already proven in animal studies, by one of the world’s most widely acknowledged pain specialists Professor Linda Watkins, PhD. We need the final steps to fund the clinical trials in humans.

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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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