Metformin – Nerve Pain & Microvascular Pain (angina)


.

.

.

Metformin & Pain

.

.

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

.

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

.

.

References:

.

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

International Journal of Clinical Pharmacology and Therapeutics

.

.

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.

.

.

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

.

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.

.

.

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

PLoS One [2014] from MD Anderson Cancer Center

 .

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.

.

.

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

.

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.

.

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.

.

.

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

.

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.

.

.

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

.

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.

.

.

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

Age [20124, from University of Arizona

.

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.

..

.

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].

.

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.

.

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.

.

.

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

.

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

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.

.

.

.
.
.
.
.
.
.

.

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.

.

.

.

.

.

 

Selenium Supplement


.

.

.

Selenium Toxicity

.

Almost every American is taking supplements without knowing the reactions they are causing. Most do not know the ingredients they take daily for years, then they see neurologists for muscle weakness and neuropathy. 90% of the causes of neuropathy are unknown – selenium is one.  Muscle weakness, another. Doctors don’t ask to review labels on supplements.

.

The biggest issue (no pun) is insulin resistance that leads to diabetes and obesity.

.

.

 

From Memorial Sloan Kettering Cancer Center Herbs & Botanicals

.

“Excessive intake of selenium induces hepatic insulin resistance through opposite regulation of ROS [Reactive oxygen species].”

.

Adverse reactions:

.

“Oral consumption of 10 g of sodium selenate supplements for treatment of prostate cancer resulted in the death of a 75-year-old man.”

.

Chronic selenosis (doses greater than 1000 µg/day): muscle weakness, fatigue, peripheral neuropathy, dermatitis, nail and hair changes/loss, garlic breath/body odor, irritability, growth retardation, hepatic necrosis” (death).

.

Toxicity: “Consumption of gram quantities of selenium can cause severe gastrointestinal and neurological disturbances, acute respiratory distress syndrome, myocardial infarction and renal failure.”

.

.
.
.
.
.
.

.

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.

.

.

.

.

.

Neuropathic Pain Medications – review & metanalysis of 229 studies


.

.

.

.

.

This review was done by many of the best pain specialists from all over the world. You will not find answers in that large review if neuropathic pain has already failed tricyclic antidepressants (Elavil, amitriptyline, Norpramin desipramine, others), gabapentin (Neurontin), pregabalin (Lyrica), lidocaine, capsaicin, or opioids. That is the current paradigm. A new paradigm – glial modulators  – that I discuss on this site, may or may not give relief.

.

A member of the International Association for Study of Pain, IASP, published a brief critique of that comprehensive review of 229 trials of medications for neuropathic pain published in Lancet Neurology February 2015. The critique is posted below, done by a member of the Neuropathic Pain Special Interest Group, NeuPSIG.

 

.

To understand the metanalysis of these 229 trials, you need to understand the simple concept of number needed to treat, NNT.

.

NNT is an estimate of “the number of patients that need to be treated in order to have an impact on one person.”

.

The smaller the number, the more effective the drug. Example, NNT of 7.2 for gabapentin means you need to treat  7.2 people before a response. If 3, need to treat 3 before a response.

.

Barsook (Harvard, ref. below) reviewed ketamine studies in 2009:  “they did show a level of efficacy (of ketamine) based on NNT that equals or betters most drug trials for this condition.”

.

.

“NeuPSIG has just published an up to date systematic review on the effectiveness of pharmacotherapy in Lancet Neurology. They have negotiated with the journal to make it available beautifully open access. You can download it for free here.”

.
Neil O’Connell, Brunel University London

.

“This is a comprehensive review, containing 229 trials of the full range of pharmacological agents using robust methods, to synthesize, summarise and make value judgements about the quality of the available evidence. So what are the take home messages?”

.

“Using a primary outcome of achieving at least 50% pain relief trial outcomes were described as “generally modest”. The number of patients needed to treat with the drug compared to a placebo for one more person to achieve this outcome ranged from a relatively rosy 3.6 (95% confidence interval 3 to 4.4) for tricyclic antidepressants such as amitryptiline, 4.3 (95%CI 3.4 to 5.80 for strong opioids to a less impressive 7.2 (95%CI 5.9 to 9.21) for gabapentin, and 7.7 (6.5 to 9.4) for pregabalin (often sold under the brand-name Lyrica). It’s interesting, at least to me, how much better the older more traditional agents seem to have fared compared on effectiveness to the more modern (and commonly more expensive) agents although the safety and tolerability of gabapentin seems superior.”

.

“The spectre of publication bias also raises its head. The reviewers carefully took a number of routes to try to unpick this notoriously difficult issue and estimate that there has been overall a 10% overstatement of treatment effects. Published studies reported larger effect sizes than did unpublished studies. This is not a problem restricted to the field of pain trials. It is a burning issue across the world of clinical trials. It is very important because if we fail to base our clinical recommendations on the totality of relevant evidence (because some data are hidden from us) we are in danger of mis-estimating the benefits and the harms and as a result patients are put at risk. If you think that is pretty important then there are ways that you can help. Check out the All-Trials campaign.”

.

“Overall what does this mean? Many drugs are effective but not as effective as we would wish them to be. No pharmacological agent really impresses and for any drug the most probable outcome is failure to produce 50% pain relief. There are various potential reasons for this. The first is that the drugs may only be moderately or marginally effective, another is that neuropathic pain includes quite a mixed bag and our ability to accurately diagnose and to target drugs to specific mechanisms in the clinic is currently fairly poor.”

.

“The NeuPSIG review team formulate a number of recommendations for revision of their clinical guideline for managing NP pain, balancing the benefits, harms, costs and strength of the evidence.”

  • a strong recommendation for use and proposal as a first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin;

    .

    • a weak recommendation for use and proposal as a second line treatment for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only.

      .

“This email [from IASP’s NeuPSIG] is also published as a blogpost at www.bodyinmind.org”

.

References

.

Finnerup NB, Attal N, Haroutounian S et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73.

.

.

.

.

Glial modulators – another paradigm

.

From my January 2012 brief review of publications on ketamine, only one of a handful of glial modulators, this author says reviews “show a level of efficacy based on NNT that equals or betters most drug trials for this condition.

.

 .

Ketamine and chronic pain – Going the distance, David Barsook, Director, P.A.I.N. Group, Massachusetts General, McLean and Children’s Hospitals, Harvard Medical School, Boston, MA;

~

This paper covers essential points not mentioned by many, thus quoted at length below:

.

Our current therapeutic armamentarium is quite limited in terms of analgesic efficacy in controlled trials. Some would argue that the small efficacy (both at a population level and the magnitude of change in VAS score) this is related to the fact that we need to consider mechanistic approaches to chronic pain subgroups. However, patients and clinicians find themselves in a position of “what to do now”.

.

Ketamine, brain function and therapeutic effect – neuroprotective or neurotoxic

.

With the onset of chronic pain (including CRPS) a number of changes in brain function occur in the human brain including but not limited to: (1) central sensitization ; (2) functional plasticity in chronic pain and in CRPS; (3) gray matter volume loss in CRPS ; (4) chemical alterations ; and (5) altered modulatory controls. Such changes are thought to be in part a result of excitatory amino acid release in chronic pain. Excitatory amino acids are present throughout the brain and are normally involved in neural transmission but may contribute to altered function with excessive release producing increased influx of calcium and potentially neural death. Here lies the conundrum the use of an agent that potentially deleteriously affect neurons that may already be compromised but may also have neuroprotective properties by mechanisms that include reducing phosphorylation of glutamate receptors resulting in decreased glutamatergic synaptic transmission and reduced potential excitotoxicity . Alternatively, ketamine may affect glia regulation of glutamate and inhibit glutamate release within glia. However, by whatever mechanism ketamine acts on CRPS pain, there does seem to be a dose/duration effect in that longer doses at levels tolerated by patients seem to prove more effective in terms of the duration of effects.

.

So what could be happening in the brain and what is required to alter brain systems and reverse the symptomatic state? Ketamine may diminish glutamate transmission and “resets” brain circuits, but it seems that a minimal dose and/or duration of treatment is required. Alternatively, ketamine may produce neurotoxicity and damage or produce a chemical lesion of affected neurons. These two issues are important to be understood in future trials. Reports from patients who have had anesthetic doses have included prolonged pain relief for many months. While the authors did not address issues such as the effect of dosing duration or repetitive dosing at say 6weeks, they did show a level of efficacy based on NNT that equals or betters most drug trials for this condition.”

….

Conclusions

.

As a community we have a major opportunity to define the efficacy and use of a drug that may offer more to CRPS (and perhaps other) patients than is currently available. This is clearly an opportunity that needs urgent attention and a number of questions remain to be answered. For example, is ketamine more effective in early stage disease? How does ketamine provide long-term effects? Further controlled trials evaluating dose, duration, anesthetic vs. non-anesthetic dosing are needed. Few of us really understand what it is like to suffer from a chronic pain condition such as CRPS. Ketamine therapy may be a way forward that can be brought into our clinical practice through further controlled studies that will allow for appropriate standards for use in patients.

.

.

.

~
~
~


The material on this site is for informational purposes only, and is not a substitute for medical advice,

diagnosis or treatment provided by a qualified health care provider.

.

~

Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, please telephone my office.

~

~

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

~
~
~
~
~

Be the change you wish to see – or walk away. Money at NIH


 

 

A Turning Point

 

$$$$$ MONEY $$$$$

 

at NIH

 

May not come this way again

 

NIH developing

5-year NIH-wide Strategic Plan

 

 

 

Donate to organizations, below

They can provide feedback to NIH via the

RFI Submission site


 

 

 

John C. Liebeskind, 1935 – 1997, distinguished scholar and researcher, past president of the American Pain Society, had the radical idea that pain can affect your health.

 

Research decades ago by an Israeli team at UCLA and others had shown “that pain can accelerate the growth of tumors and increase mortality after tumor challenge.” Decades ago Professor Liebeskind lectured all over the country: Pain kills.

 

He wrote an editorial in 1991, summarizing a life’s work:

 

“Pain and stress can inhibit immune function.”

 

 

Quoting John Bonica, the father of modern pain management, he wrote:

 

“Bonica has long argued that the term ‘chronic benign pain’ (used in distinction to pain associated with cancer) is seriously misleading.  Chronic pain is never benign, he contends; “it is a ‘malefic force’ that can devastate its victims’ lives and even lead to suicide.”

 

 

Liebeskind continues, “It appears that the dictum ‘pain does not kill,’ sometimes invoked to justify ignoring pain complaints, may be dangerously wrong.”

 

Pain mediates immune function

 

Importantly

 

  Opioids mediate the suppressive effect of stress on natural killer cells,

 

 published in 1984, immune system.

 

Alcohol increases tumor progression, 1992, immune system.

 

It used to be news.

He did not live to see change.

 

People just want to go on doing what they’re doing.

They want business as usual.

 

 

After 1991, we saw the great discoveries of neuroinflammation, pioneered by Linda Watkins, PhD, the early understanding of the innate immune system, its involvement in chronic pain and depression, and a few weeks ago, a British team showed neuroinflammation in teens with early signs of schizophrenia and DNA markers.

 

 

Major Depression has the same neuro-inflammation found in chronic pain, often responding to same medications, in particular glial modulators – immune modulators. Now, perhaps early schizophrenia will respond to glial modulators, reducing inflammation seen on scan in teens, before they become homeless and burned out by antipsychotic drugs

 

Inflammation out of control destroys neurons

 

Fire on the brain

 

 

We must be the change we wish to see

 

It’s not just the Bern. It’s been starting. Forces are finally coming together. We want change. It’s been too much. Too long.

 

We won’t take it anymore.

 

I figure if I tell you about it, you might just mention it to someone to pass it on. That is all. One small action may lead to change. Activate inputs to the NIH strategic plan.

 

 

~ Action needed ~

 

Prices of drugs becoming unaffordable

No new drugs for pain or major depression

Research to repurpose existing drugs

Expose the politics destroying our compounding pharmacies

 

Above all

The #1

Major Priority:

Request NIH to solicit priority call for research on

Glial modulators of the

Innate immune system

 

 

Why?

 

Glia modulate

chronic pain, major depression

and almost every known disease

 

Glia are your innate immune system

 

Inflammation kills

 

 

 

 Stress kills. Inflammation kills.

 

 

Pain kills

 

In the 1970’s, Professor Liebeskind and an Israeli team at UCLA injected cancer cells to two groups of rats that had sham surgery. Cancer spread much faster and killed far sooner in the group with poor treatment of surgical pain.

 

 

~ Pain kills ~

 

He lectured all over the country

 

Forty five years ago

 

 

I’m gonna be dead before I see this country do anything but unaffordable opioids and the magical ineffective trio of gabapentin, Lyrica, Cymbalta to treat chronic pain. The devastating, blind, nationwide emphasis does nothing to address the cause: inflammation, the innate immune system gone wild.


 

 

Innate immune system in action

 

Untreated pain suppresses the hormone systems too.

 

Untreated depression – same inflammation kills lives.

 

Where’s the money?

 

We are the change we wish to see. It’s pitiful I am so lazy. Suddenly, too late, we may need something, but, aha, no new drugs in the pipeline.

 

 

 

~ Make a joyful cry to NIH ~

 

They are soliciting input from professional societies

 

If your condition has failed all known drugs for pain or major depression, then make a joyful cry to NIH, now, before they give away all that nice new $$$$$money$$$$$.

 

 

Follow and join

 

American Pain Society

 

 

International Association for Pain

celebrating 40 years of pain research

 

 

Reflex Sympathetic Dystrophy Syndrome Association

help for CRPS/RSD  

 

 

 

The key to CRPS/RSD pain will apply to all forms of chronic pain, in particular the most difficult form, neuropathic pain. RSDSA funds research into all forms of chronic pain, not only Complex Regional Pain Syndrome (CRPS/RSD). Their scientific board members are not funded by opioid money.

 

 

 

Exactly

what is the annual cost of care

as fraction of GDP

for the growing population of Americans on opioids

for one year, for lifetime?

 

 

People are dying from prescription opioids and those who need them find they don’t work well enough. Prescriptions opioid costs must be a huge fraction of the medical costs in the United States GDP. You are required  to see a doctor every single month each year, often lifelong, just for one opioid, 12 months a year x 30 years x tens of millions of people and increasing – a growth industry. Not even counting $600 a day for the opioid, what the cost of monthly visits for 30 years? Not counting the army of DEA, FDA, CDC agents watching the opioids like a hawk. We all have to be sharp, addiction is growing. Addiction aside, deaths from prescription opioids are shaking up the CDC forcing urgent change this coming month.

 

 

 

Opioids do not work well for chronic pain

We need better

It’s not just the $600/day price

They just don’t work

 

 

donate

 

 

Raise a joyful noise at NIH now or write back at us readers with comments and better suggestions. Tell others what you’d like to see. Which politicians do you know would be most interested in this at national levels and organizations?

 

You may never see this change unless you do it now. Other forces will get this new money.

 

 

Turning point now

May not return

 

 

We are at a turning point and we will fail to catch the sail that’s coming fast to carry all research money in their shiny big stem cell direction. They never look back.

 

 

There is so many medications we can use today, FDA approved drugs that can be re-purposed and applied to recent cutting edge science. Someone must pay to do the work to study this.

 

 

Re-purpose old drugs

 

 

Stanford just showed a popular generic drug improved recovery of stroke paralysis in mice to begin at 3 days rather than 30. Old drug, new purpose, of course more years of testing to confirm in humans. Brilliant team applying new science.

 

 

Request
NIH to solicit a

Special Invitation

for 30 good protocols to

repurpose old drugs

 

 

Hundreds of old drugs, already approved, could be involved in mechanisms we have recently learned about. Speak up or money will go to shiny new stem cells. None for chronic pain or major depression. No company will find this profitable – it must be funded by NIH. A popular generic sleeping pill can bring astonishing return from stroke paralysis.

 

 

Congress has not opened this new money to NIH in many long years. How often will there be extra money?

 

 

donate

 

 

Lawrence A. Tabak, D.D.S., Ph.D.
Principal Deputy Director, NIH, solicits you to

Review the NIH Strategic Initiative Plan and their

Request for Information (RFI) and the NIH website

and provide your feedback via the RFI Submission site

 

 

This is for “stakeholder organizations (e.g., patient advocacy groups, professional societies) to submit a single response reflective of the views of the organization/membership as a whole. We also will be hosting webinars to gather additional input. These webinars will be held in early to mid-August.

 

 

 

Be the change you wish to see

Donate to those organizations

to solicit the change you wish to be

 

 

 

Happy New Year

Rejoice!

There’s money at NIH

 

 

 

 

 

 

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.

Relevant comments are welcome.

If any questions, please schedule an appointment with my office.

This site is not for email.

~~~~~

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

 

 

 

 

Proposal: A 5-Year Study of Best Methods to Treat Intractable Pain


.

.

.

PROPOSAL

.

A controlled trial to improve care for chronic pain:

The study to understand prognoses and preferences for

outcomes and risks of treatments

.

..

 

..

Model after Joanne Lynn’s 1995 SUPPORT Study

.

A controlled trial to improve care for seriously ill hospitalized patients:

The study to understand prognoses and preferences for

outcomes and risks of treatments (SUPPORT)

.

.

Proposal

 .

A controlled five-year trial to improve care for outpatients with chronic pain. The study will be designed to understand prognoses and preferences related to the outcomes and risks of various treatments.

.

The focus:

.

Intractable pain, those who have failed pain medications and procedures or those with moderate to severe pain who only partially respond.

.

Study polypharmacy, compare medications that may show synergy or that additively improve relief.

.

Study and search for glial modulators – medications that reduce proinflammatory cytokines.

.

.

Problem

.

Research is needed to give persons with intractable pain the data and the confidence that they can affordably use to choose the best treatment needed to get their lives back again. They have already spent tens of thousands. They may be unable to work. We all need these options.

.

There are a few small islands in this country doing a radical experiment in managing pain without opioids [narcotics, the police term] as discussed in the New York Times in May 2014, and the 2008 Mayo Clinic study. Efforts such as these need to be supported with data as soon as possible in order to reduce the burden of disability and pain in our society, especially our youth, our children, our veterans, our aging seniors, well everyone. We can be productive and we want to be.

.

I have seen remarkable outcomes, pain that failed to respond to all known pain medications, going into partial and even total remission, lives restored after weaning off opioids and appropriate treatment given.

.

We cannot expect any medication to work every time. How often can we achieve better results after opioids are tapered off? Opioids may prolong pain in Complex Regional Pain Syndrome where remission seems possible only after they are stopped, yet opioids may be essential in many forms of chronic pain. We need data on the radical experiment to manage pain without opioids, and determine how best to manage chronic pain with them.

.

Opioids have a long history of being the drug of choice to treat chronic intractable pain by doctors who lack information and training about other exciting options now coming to the fore. Compounding the problem is the fact that physicians do not know how to diagnose musculoskeletal pain and do not know how that good physical therapy is actually effective.

.

Healthcare providers need data about all the options to begin to address the toll that chronic intractable pain exacts and government worldwide need to know what is cost effective and possible. Many countries cannot obtain opioids.

.

We must not be insensitive to the financial burden that frustrates patients when they spend tens of thousands of dollars for drugs that provide little if any benefit.

.

Investment in developing nonopioid treatments for pain does not even begin to compare to the investment in opioids for pain. The few medication choices we have are not enough. Often they fail to help. Expensive drugs are not the best choice if they are not affordable or they are limited to diabetic neuropathy when more than 100 types of peripheral neuropathy have been identified, plus many more types of even more severe neuropathic pain not classified as neuropathy. Shall we continue to ignore all those because FDA has classed these few new drugs for diabetic neuropathy exclusively?

.

Let me be clear, prescription of opioids is justified and they are valuable. Opioids are on the World Health Organization list of ten essential drugs. BUT there is little or no research on treatment of intractable pain without opioids.

.

Neuropathic pain, nerve pain, is the most difficult to treat. Neuropathy, radiculopathy, transverse myelitis, adhesive arachnoiditis, central pain, RSD, Guillain-Barre, trigeminal neuralgia, Tic Douloureaux, post herpetic neuralgia, to name a few. It is not enough to limit research of neuropathic pain to diabetic neuropathy when it fails to address all other causes. When FDA approves a drug only for diabetic neuropathy, insurers deny the drug for the other 95% of you without diabetes. Insurers may choose to read guidelines as mandates, fiats,  marching orders.

.

Neuropathic pain is not the only concern. Physicians do not know how to diagnose musculoskeletal pain. How can they if only 3% of medical schools teach pain management and when doctors do not know how to assess ineffective physical therapy when they have never seen better.

A patient dislocated her hip 7 times, manually repositioned each time in ER. The 6th surgeon impinged a wide band of muscle in the joint causing muscle all down the thigh to bulge 5 to 7 mm high, of rock hard spasm with intense relentless pain. The 7th surgeon had the gentle ability to restore position and release the entrapment. A light touch across the thigh even through clothing can detect the cause. Would a surgeon have discovered to release the entrapment unless she had dislocated a 7th time? Simple muscle strain, undiagnosed by a surgeon who deals with muscle all the time, was not even noticed and he ignored the acute pain it caused. She has now learned how to avoid dislocating that new hip. Had the muscle not been appropriately identified as cause, she would not be able to move by now. But the surgeon should have had the skills to notice instantly before those muscles became chronically strangled. She was referred for manual physical therapy and thankfully, before all else could occur, she dislocated and was repositioned by the 7th surgeon. A wonderful teaching case for a teaching hospital that should be every hospital. Grand Rounds for pain cases.

.

.

MAJOR FUNDING DECLINE IN PAIN RESEARCH

.

 BEFORE 2008

.

 BEFORE CONGRESS CUT NIH BUDGET BY UNTHINKABLE 30% IN 2010

.

Perhaps the biggest impediment to gathering data about pain management is the lack of government funding for pain research and lack of a Pain Institute at NIH. If not, funding will continue to be fragmented and split elsewhere, not to learn about one of the most costly problems in every society.

.

In 2008, before the worldwide depression, pain research was in major decline. The AAAS, the American Association for Advancement of Science told us then:

.

“Federal funding for pain research is declining sharply, more than 9 percent a year since 2003, according to a new study published in The Journal of Pain. Pain research, as a result, now accounts for only 0.6 percent of all grants awarded by the National Institutes of Health (NIH), despite the high prevalence of chronic pain in the U.S.

.

“This startling finding shows the government’s meager investment in pain research is seriously out of proportion with the widespread chronic pain incidence in our society, which is estimated at one in four Americans and accounts for more than 20 percent of all physician office visits,” said Charles E. Inturrisi, president of the American Pain Society and professor of pharmacology at Weill Cornell Medical College, New York. “And this disparity is not attributable to years of budget cuts at NIH because the Journal of Pain study clearly shows pain research has a higher percentage decline than the overall NIH budget. So the drop in agency funding has not affected all research areas equally.”

.

[emphasis mine.]

.

Research in pain was sharply declining prior to 2008. Then a 30% cut across the board in 2010. Thank the American Pain Society for those ancient 2008 figures. No one had ever asked – which is why we need a Pain Institute at NIH.

.

Frustration is compounded the last few years by insurers no longer willing to authorize many opioids and non-opioid medications, even generics.

.

As for the cost of opioids,  a single opioid for one patient may exceed $80,000 per month when the patient is required to use with another long acting opioid, and often several nonopioid adjuncts just to bring pain down from 9 on scale of 10, to a slightly more bearable 7 or 8 which is severe, relentless and prevents sleep and ability to concentrate. One drug that costs pennies to make, sells for $80,000 a month to allow 4 a day when at least 6 a day are needed and it is only one of many for pain every day.

.

Prescription of opioids is justified and may be invaluable.

but there is little or no research on

 treatment of intractable pain without opioids.

.

 

.

We need national consensus guidelines based on data

.

We must do a better job treating intractable pain. We need guidelines that have more to offer than the few opioids and few adjuvants we now have, so few in number, so great the need. Can we know when is it true that opioids are indicated? Our use is many times more than all the other First World countries?

 

.

Treatment must be individualized

.

Data is needed to guide choice

.

.

Compounded Medications are among the

most useful drugs we have for treatment of intractable pain

.

Compounded medications may be the only ones that help, and can reduce pain to zero. We can re-purpose the delivery of any medication, as long as it has been FDA approved. But the last few years insurers have been discontinuing coverage for compounded medications and Medicare has never covered them.

.

This must change. Who is funding that political blockade that denies coverage for compounded medicine? The cost may be $120 for one compounded medication vs $80,000 for one opioid. Either way, the person with intractable pain likely needs 3 or 4 or 5 or 6 medications, compounded or not. Who can afford $400 per month out of pocket for compounded medications that work, when insurance will not cover the affordable drugs. Who can afford that out-of-pocket expense if insurers cover nothing for your pain, neither the bright shiny opioid or the compounded sprays, capsules, suspensions, creams, troches, as well as the essential solutions instilled into the bladder for interstitial cystitis?

.

This must change. Lawmakers must be called to account for allowing and perpetuating the inhumane taking advantage of those who suffer intractable pain.

.

A first step in getting lawmakers to pay attention is to amass a body of compelling data.

.
.
BALANCE IS NEEDED

..

The United States as a society cannot afford for pain research to die and go bankrupt and leave only opioids as the standard treatment for hundreds of types of pain. Someone has to begin the needed studies. It does not just bankrupt the patient, it leaves us all bankrupt, the country most importantly. It ends marriages, tears apart families. To be struck down as a child with intractable nerve pain the rest of your life, or be struck in your prime, is devastating. And disability gets routinely denied for pain. Why? Perhaps because pain is taught in only 3% of university medical schools. How are doctors to imagine that pain can end lives when they have no experience seeing how disabling it can be?

.

.

 If doctors cannot see the devastating toll that pain takes,

how can we expect accountants to see it?

.

.

.

The Study We Need

.

Solution

.

 To gain a comprehensive and compelling picture of how pain impacts the population and how to effectively treat it we need a large-scale study:

 .

  • Five years in duration

  • 10,000 outpatients – statistically this must be adjusted to obtain multiple outcomes

  • At five major university teaching hospitals for regional differences

.

 Outcomes

.

The study will yield important information about the following:

..

  • Efficacy

  • Pain Numeric Rating Scores, Percent Improvement

  • Functional Improvement, etc

  • Compounded medications

  • Racial and Gender Disparities

  • Addicts who have chronic pain

  • Top notch manual physical therapy* [see below], not for what passes in most places. This must change ASAP. United States is far behind other countries. Even if the condition is neuropathic, it often becomes musculoskeletal after splinting for months, years

  • Interventional procedures

  • Meditation

    How you brain can heal your body and your body heal your brain.

  • Pain changes DNA, neurotransmitters. Have we permanently changed them with opioids?

  • Polypharmacy. When employing one drug alone is unlikely to lead to a successful outcome.

  • Stem cells for joint pain – autologous lipid derived mesenchymal stem cells

  • rTMS, experimental after 20 years, is it still better for acute than for chronic pain?
    Who will benefit, for how long? How many weeks of relief for that $15,000 investment?

  • Glia, the Innate Immune System

Opioids create pro-inflammatory cytokines that create pain and opioid tolerance.

Restore cytokine balance, reduce inflammation and pain.

Which of our existing medications either trigger or reduce inflammatory cytokines in the CNS?

  • Pain in the person with Alzheimers dementia

  • Danger of combining opioids with benzodiazepines

  • Danger of long term use of opioids (regardless if short or long acting)

  • Appropriateness of using opioids as a first choice in acute pain (loss of a milk tooth, sore throat in a teenager, acute back pain, ankle strain, etc.)

  • Appropriateness of opioid holidays.

  • Post op pain can be avoided completely with combined use of oral low dose naltrexone and ketamine IV anesthesia. Patients discharged directly from recovery room with no need for pain medication for months or years

  • Cost Benefit Analysis

 

.

Five Conditions Will Be Studied

.

Strong emphasis must be placed on neuropathic pain that so often fails to respond to any intervention

.

1. Complex Regional Pain Syndrome

The Netherlands invested €25 million over 5 years to study this one devastating pain condition, far out of proportion to the incidence in that small country. There are pain specialists who cannot recognize it and/or doctors who routinely deny disability for this devastating pain, like death in life.

.

2. Low Back Pain

Define criteria for surgery.

If we wait too long before surgery is done, will we ever reverse the chronic pain that has set in?

Have we condemned that patient to monthly visits for opioid the remaining 50 years of their life?

.

3. Other neuropathic pain conditions such as adhesive arachnoiditis, trigeminal neuralgia, transverse myelitis, Tic Douloureaux, Post Herpetic Neuralgia, Interstitial Cystitis, Vulvodynia, Proctalgia, Pudendal Neuropathy


4. Painful peripheral neuropathy nondiabetic and Painful Small Fiber Neuropathy  all forms of painful neuropathy

.
5. You choose – central pain?

.

.

.

What We Must Do Now

 

.

  • Find a pain advocate like the cancer advocate of the 1950’s that changed attitudes for research

  • Fund the pain SUPPORT study

  • This will spin off enormous research ideas that we must begin separately to implement with research as each develops, the need is beyond urgent. How many more years can we make everyone wait?

  • Write letters, to congress, the White House. Real letters, not email, not signature lists. Congress will not hear us unless we speak in very, very large numbers.

  • Help the topic of intractable pain become a part of the 2016 presidential conversation.

  • Incentivize teaching hospitals to teach pain management and to develop options for nonopioid treatment of chronic intractable pain. Pain is a multidisciplinary field, not limited to Anesthesiology procedures.

  • Create an Institute for Pain Management in addition to the 28 institutes at NIH, three of which are for addiction, none for pain. Pain is the number one reason people seek medical help.

  • Require that pain specialists sit on the FDA advisory committees for pain medication – none recently.

  • Require insurance coverage for compounded medications.

  • Prevent FDA from limiting medication to cancer pain.
    Cancer pain does not exist.

    There are basic types of pain that occur in persons who have cancer, neuropathic pain being worse than other forms of “cancer pain.” It has the same medication response or failure to respond as persons whose pain is not due to cancer.

  • How do we restrict the use of opioids to severe pain when there is nothing else to offer and after everyone is started on opioids by their family doctor years before they see a pain specialist?

  • Novel and ancient methods for treatment of pain should be explored including cannabis and possibly hallucinogens

  • Isolation of pharmacologically important medicine from rainforest and deep seas must be done before they disappear.

.

.

Physical Therapy is the #1 Key to Chronic Pain

.

Manual Physical Therapy was introduced to the United States in the late 1970’s but is rarely practiced or not done well. It does not mean “hands on.” It derives from techniques brought to us by British Commonwealth and Scandinavian countries. Our healthcare providers do not know how to differentiate between good and useless practices. Fortunes and lives are wasted hinging on that distinction. Pills never can undo the harm brought about by common musculoskeletal issues – and our providers have no training in recognizing simple muscle trigger points, let alone intractable connective tissue contractures. My patients have been misdiagnosed as histrionic, drug seeking, personality disorders, and worse. It boils down to ignorance and lack of basic training, let alone believing what the patient says and not having the tools to help.

.

The trend is for year long residency programs following the 3 year Doctorate of Physical Therapy (DPT).  The year long residency program is a very positive step.  The limitations are that it is a year with a clinical staff that may have a specific perspective.  The push towards evidence based practice is a reasonable step but should not exclude considerations of outside the box treatment options.

.

The osteopathic manipulative technique has been a cornerstone of best education for physical therapists.  The craniosacral approach is an offshoot from that tradition.  When we get to visceral mobilization, the evidence is much harder to produce but that does not have me shy away from its application.

.

Movement is critical for the hormonal regulation of the body.  Chronic stasis leads to numerous changes that compound an underlying medical diagnosis.  We see that with a 16 y/o female, Lyme’s disease, CRPS diagnosis, bedridden for years.  She is significantly benefiting from stretching dysfunction and improving axial extension.  Another who quit walking had global lower limb connective tissue contracture.  Walking is currently limited by soft tissue contracture through the tarsal tunnel, affecting the plantar nerves and the burning and tingling with walking greater than 5 minutes at a time.  Mobilizing the soft tissues will ultimately restore function. This 20 year old quit college due to pain and one first visit requested motorized wheelchair and Social Security Disability. This young person will walk again.

.

There is no end point to this educational process except when we think we know it all.  No certification, no degree, no one course signifies competency.  Ongoing intellectual curiosity is the most important element in preparation.

.

Prescription painkiller overdose epidemic in the U.S.

Not in other countries

.

Pain Management centers at major universities closed in 1991. They lose money, are time consuming, require team conferences that are not reimbursable. Thus began the era when prescription opioids took off for noncancer pain, and no one was generating nonopioid approaches to chronic pain. Anesthesiologists shifted to procedures – that is their focus after all. Procedures are not applicable to many types of pain.

.

“Since 1999, the amount of prescription painkillers prescribed and sold in the U.S. has nearly quadrupled, yet there has not been an overall change in the amount of pain that Americans report.”

from the CDC report of prescription painkiller overdose epidemic

.

 

I feel I have failed when I have to point out to my own patient whose pain is severe, that the high dose opioid I have prescribed is not helping, or is creating pain; when I know there are other options which are not available because the FDA has not approved them or because they are prohibitively expensive. I have failed when so many medications I prescribe are not on the formulary.

 

We need a mandatory formulary available for those with intractable pain.

.

There were 16,651 deaths from prescription opioids in the U.S.in 2010, “Starting with 4,030 deaths in 1999….” “…nearly 60 percent of the drug overdose deaths (22,134) involved pharmaceutical drugs. Opioid analgesics, such as oxycodone, hydrocodone, and methadone, were involved in about 3 of every 4 pharmaceutical overdose deaths (16,651).” It’s far higher now. A CDC report stated that one in every 20 U.S. adults has a history of [opioid] use – not abuse, but use.

.

Monitor risk, yes, but that should not get all the investment. Many addicts would not be there if there were better treatments for pain, if they had not been given opioids after a minor procedure or injury that is better treated with real therapy, not drugs.

.

People with pain do not mention the pain has taken their lives. We may see them as weak. That young child with fractures on the ball field is going to need the best care so pain does not become chronic. Give him or her opioids and opioids cause pain, pain becomes worse, intractable before the 6th grade. That is not an addict, but that child and his or her parents are often treated like addicts, at least with suspicion, drug seeking. What is best for that child with chronic pain when she becomes pregnant? When nursing? Think of our young veterans, some with 3 or 4 different pains, and each type addressed differently. What if either of them was an addict before the pain? If we don’t treat them, they will turn to drugs. What are the best, most efficient, options for treatment of intractable pain? When will we learn? We need to identify and treat before it becomes chronic.

.

Chronic pain can be reduced or eliminated in many situations now even possibly without drugs, provided the issue is properly identified – and that will never happen until providers are educated in how to identify first class physical therapy. Further research will help to release persons with intractable pain from the prison that too often makes them feel that life is unbearable and that they can more easily face death. We all need to wake up to this situation.

.

If we continue to passively allow nothing to be done, then there may be nothing to help us when we fall into the sudden bind of intractable pain when we wake up one day with shingles or a pinched nerve or when pain of the face prevents us from eating or sleeping or speaking or even wanting to live. It will be too late.

.

Sharp like a razor’s edge is the path,
The sages say, difficult to traverse.

.

Shall we let those we love hang on the edge while we fail to move this multi-tentacled monster forward? How do we light the fire that enables us to solve this fearful fragmentation of choices?

.

 

 

See how beautifully it works when the right combinations are brought together?

.

Yellow rose blue hibiscus

 

 

.

.

.

.

.

.

.

.

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.

.

.

.

.

.

.

.

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


.

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.

.

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.

.

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

.

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

.OR

2.  inhibit the breakdown (hydrolysis) of PEA.

.

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

.

They start outlining the focus of the paper:

.

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

.

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

.

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

.

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.

.

PEA’s mechanism of action

.

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

.

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

.

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.

.

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

.

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

.

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

.

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!

.

PEA as a protective molecule

.

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.

.

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

.

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

.

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.

.

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.

.

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.

.

Mechanism of action in addition to the PPAR receptor

.

The authors nicely summarized the effects of PEA:

.

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.

.
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.

.

Relevance for Alzheimer, Parkinson’s and MS

.

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

.

The follow stating:

.

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

.

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

.

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

.

.

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

.

.

.

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.

~~~~~

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

.

.

.

 

.

Oxytocin, Astrocytes, Modification of Amygdala Circuits and Pain – IASP Early Research Career Grant Report


.

.

As a physician who prescribes Oxytocin [OT] and sees profound relief of many forms of intractable pain and/or relief of treatment refractory Major Depressive Disorder or Anxiety and Panic Disorder, this research on mechanisms is deeply meaningful and long awaited. Oxytocin is a hormone made in the brain, but also in the heart and other organs in women and men. It is rare to find work on glia and oxytocin.

.

Today the International Association for Study of Pain announced the final report from their 2012 Early Research Career Grant:

.

“Dr. Alexander Charlet of the Centre National de la Recherche Scientifique (CNRS) in Strasbourg, France, has submitted his final report for his project “Involvement of astrocytes in the endogenous oxytocin modification of amygdala microcircuits….”

.

“Dr. Charlet’s project focuses on the functional consequences of endogenous OT release in amygdala microcircuits on nociception and pain. In addition, he aims to decipher the precise mechanism, cellular and molecular, by which OT exerts its action. Thus, the purposes of his project are to characterize in vivo and in vitro the effects of endogenous OT in the amygdala on pain-related symptoms….

.

.….”In addition, he was surprised to discover that perceptions of his project’s importance grew once it was awarded and triggered future collaborations: a Marie Curie European Action Career Integration Grant and the French Initiative d’Excellence Attractivity.”

.

“As a result, Dr. Charlet also received two major personal prizes: an award from Swiss Society for Biological Psychiatry in 2012 and award from the French Académie nationale de medicine with the prestigious Albert Sézary price in 2013. Finally, he has been recruited as a neurosciences permanent researcher by the CNRS and recently opened his independent lab.”

.

.

.

~~~~~

The material on this site is for informational purposes only.

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

~~~~~

Please understand that it is not legal for me

to give medical advice without a consultation.

If you wish an appointment, please telephone my office.

.

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

.

.

.

PeaPure – Palmitoylethanolamide for Nerve Pain or Migraine


..

PeaPure is a glial modulator. It is available in Italy and the Netherlands as a food supplement and has been studied in multicenter clinical trials in Europe for several years. It is well tolerated with no side effects and is very helpful for neuropathic pain, headache, and osteoarthritis. It is anti-inflammatory and neuroprotective.

.

Because it inhibits astrocyte activation and the over-expression of pro-inflammatory molecules and signals, it is being investigated in Alzheimer’s Disease.

.

The mechanism of action of PEA was discovered in 1993 by Nobel laureate Rita Levi-Montalcini in her work on nerve growth factors. She found it is involved in metabolism of mast cells and published a series of papers on its self-healing effect of the body in response to inflammation and pain. Two recent publications from Jan M Keppel Hesselink, MD, PhD, and his colleagues at the Institute for Neuropathic Pain, Amsterdam, The Netherlands, describe case reports, one of which is the case of a woman with CRPS.

.

The purpose of this post is to clarify dosing of PeaPure and how to take it for a sudden flare of pain. My apologies for failing to recall the source of these instructions which I believe was from the manufacturer and from here and here. The latter includes an excellent review of its mechanism.

.

Description of PeaPure® 400 mg capsules
PeaPure® is a food supplement based on a natural and fatty-acid like compound.
The substance palmitoylethanolamide (PEA) is a physiologically active molecule that the body produces naturally.
.
What the user should know prior to ingestion:
•    There are no known significant side effects.
•    PeaPure® can be taken simultaneously with other medicine. In case of doubt, it is recommended to first consult your doctor or a pharmacist.
•    Use during pregnancy is NOT recommended.
•    PeaPure® does not contain sugar, yeast, allergens, sorbitol, magnesium stearate, povidone or other ingredients.

.

Dosage and administration – please refer to the manufacturer.

.

UPDATE SEPTEMBER 2014

.

It is with a heavy heart that I report this news:

.

Palmitoylethanolamide is

now available only from the Netherlands,

sold as PeaPure, a food supplement.

  It is no longer able to be imported by a pharmacy, but we are hoping

that may change if we can interest a supplement manufacturer to make it available for the US.

Patent rights, attorneys are far beyond the resources of my local pharmacy.

 

.

I have published this year, 2014, on the treatment of

vulvodynia and proctodynia with PeaPure and a topical cream.

.

There are no studies to show us how often it may relieve nerve pain, but it is astonishing when it works. No toxicity, no side effects. Your brain makes it, plants make it. There is a growing literature on it and I have posted on some of its mechanisms. And in particular, its Anti-inflammatory, Analgesic, Neuroprotective Mechanisms.

.

.


The material on this site is for informational purposes only, and is not a substitute for

medical advice, diagnosis or treatment provided by a qualified health care provider.

.

~

Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, please telephone my office or contact your local psychiatrist.

~

~

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

~
.
.

RSD, Complex Regional Pain Syndrome – a case report


.

Severe Pain for Three Years,

 80% better in 10 days

.

“This has been life altering.”

.

This is a very bright young woman who was an all state volleyball player until onset of Complex Regional Pain Syndrome three years ago in the right hand and wrist. It began after blood was drawn from the hand for a chemistry study and, one week later, the fingers turned black, lost blood flow, followed by emergency surgery for removal of a blood clot from the back of her hand. She woke after surgery, tearing the sheet off due to intense pain on light touch — that is called allodynia — and then developed severe edema from the hand to the shoulder.

.

It was four excruciating weeks before the diagnosis of complex regional pain syndrome was made.

~

CRPS or RSD is a diagnosis that every MD,

every surgeon, every ER doctor,

every psychiatrist and psychologist, every nurse and therapist should know how to diagnose.

.

Because she was a minor, they would not do nerve blocks.

.

She developed contractures of the fingers and hand,

was unable to move the fingers.

  A major university hospital diagnosed Munchausen Syndrome;

mom was diagnosed with Munchausen’s by proxy.

.

This happens so often. This is 2012.

If it’s not the doctors,

it’s the insurance companies

creating roadblocks to diagnosis or treatment or both.

.

Why is pain management not taught at medical schools?

Only 3% of schools today give 30 hours instruction in four years, Yale most recently.

.

.

At a major university hospital two hours away, she failed to respond to 14 stellate and brachial plexus blocks. But the wound reopened by itself, the stitch fell out. The psychiatry department evaluated her after she was so drugged with methadone, she does not even recall the interview. They diagnosed Munchausen Syndrome. That changed everything. Relationship went sour. Distrust of MD’s began and was confirmed many times in many places along the northeastern corridor and Texas.

.

That fall, she became a student at the university of her dreams. The diagnosis of CRPS was confirmed at their university medical center hospital where they wanted to continue the same blocks that had failed. Elsewhere, the chief of a renowned ivy league university pain service wanted to talk to her only about spinal cord stimulators, declined by the family.

.

In May 2010, she qualified for an NIH study of neurotropin double blind 6 weeks on, 6 weeks placebo. Failed.

.

She was seen by Dr. Schwartzman in Philadelphia October 2011, and sent from there to NYC to rule out neuroma dorsum right hand, negative.

.

On Lyrica, she gained 20 lbs, then back to 130 lbs baseline when off of Lyrica. Intolerance to Morphine – hives, Duragesic – total body itching. Ambien – hallucinations, Lunesta – hyper. Benadryl helped somewhat. Detoxing from Nucynta – lips were bright red.

.

Her weight dropped from 130 to 115. Many medications were trialed and failed. Marinol helps pain slightly and gives the best sleep in years, better appetite. It does cause anxiety, but she had not slept in three years, and it gives 4 to 6 hours of good sleep. She developed sharp bitemporal headaches. I advised headache is a side effect of Pristiq —- now thankfully discontinued and better.

.

Since August 2011, she has had CRPS pain in the right leg, worse walking, weight bearing.  There is discoloration of the dorsum hand usually, at times along proximal forearm, recently at right foot and leg. She had edema up to the shoulder measuring 30 cm. Nails growth faster at the right hand, possibly less hair growth right hand. Temperature usually cooler on the right hand, at times at night the hand and foot become hotter. No change in sweating noted.

The first year, she had almost total loss of function in the hand with pain and contractures —and forced herself to move the fingers with OT and PT, then home exercise. She still has days when the fingers remain flexed, but 98% of the time there is full movement as she continually tries to use the hand/fingers to write and type. Nose may become ice cold and tingly since CRPS spread to right side of face and right lower limb. At times tingling fingers. She struggles with memory when pain is severe and with lack of sleep.

 .

Pain ranges 7 to 10, average 8. Edema was significant for one year, now comes and goes. Allodynia is present hands and feet, now a different scale than before when she could not even be in the car.

However, with weight bearing and walking, pain of the right lower limb became most intense.  She will be 21 in July, but on a bad day was unable to leave her bedroom to walk downstairs as pain was too severe. She would communicate with family by loudly calling or texting. It was unthinkable to make plans for the next week due to severe pain. She has osteoporosis with atrophy of the right upper limb, and has had color changes and edema of the hand.

.

She lives in an eastern state inland, two hours away from the mid Atlantic seaboard and major medical center. She failed ketamine infusion at a major university medical center on the east coast. The cost and inconvenience was significant and the family did not know that ketamine may fail to have any effect if taking opioid analgesics. Once mom discovered that, she was able to wean off the opioid medication. Ultimately, after many more interventions, much later, in crisis, she did benefit from IV ketamine infusion, and was able to regain some movement of her fingers on the right hand, but there was no lasting relief. It was a struggle to obtain approval through her insurance.

.

She has been spending a great deal of time in bed for months. Morning stiffness is widespread for one to two hours. Bending is difficult, feels as if “hit by a bus,” but she does stretching, moving, distraction and Yoga when able.

.

Much better in 10 days

.

Day one: pain of the entire right side, face, trunk, limbs, rated 7 to 10 on a scale of 10, average 8. She guards the dominant right hand and the signature is difficult. Atrophy of the right upper limb is present, nails longer on the right hand, dusky dark erythema and long jagged scar over the dorsum right hand, mild erythema of the right upper and right lower limbs.

.

On the first day, in the office, she tried the first dose of ketamine nasal spray and after a repeat dose, she was puzzled, thinking to herself, then let us know she realized she was able to concentrate. A small dose is not enough to relieve severe pain, but even major depression can vanish at that dose. Two sprays relieved the brain fog of depression; pain was still 8 on a scale of 10. Blood pressure and pulse did not change before and after doses. She felt hopeful.

.

In the next few days she was able to do the unthinkable: make plans with friends, walk 45 minutes, become active, and remain active in a way that had not been possible. She was far more active with much less pain.  Over the weekend, six days after she arrived, after we had sequentially added several new medications, she found the dosage of nasal and sublingual ketamine that worked for her. She has actually had times when she was pain free. As noted during prior ketamine infusions, she requires a far higher dose than most patients to achieve effect. The plan now is to use higher doses at home when time permits for best effect, and booster sprays of nasal ketamine as needed when away from home. She can carry it in her pocket. There is no need for ICU infusions and the fight to get insurance coverage for those stays.

.

Of great significance, she has even made plans for the entire summer.

.

More details of her case will be added, as time permits. For now, this page is here to allow the patient and family and others to send comments. She will continue slow titration of other medications that will take three months before reaching the target dose, before we can assess efficacy. Based on my experience treating chronic intractable neuropathic pain including CRPS, it is possible these medications will be able to stabilize and relieve pain without ketamine.

.

See other case reports of treatment of CRPS here, here, and here.

.

You can read some of the science of pain, glia and inflammation. Ketamine is significantly anti-inflammatory. Three of her new medications are glial modulators. Treatment of severe chronic pain usually involves rational polypharmacy, not one medication and not medication alone. It requires a holistic approach to heal: P.T., O.T., massage, cognitive behavioral therapy, guided imagery, visualization, positive thinking, remaining active, and other modalities that depend upon the underlying cause: physical, emotional, spiritual, and financial. The treatment for CRPS is not specific for that condition alone, but the gains can be possible with tremendous discipline, effort, single minded determination and the loving support of friends and family.

.

Be cautious of spinal cord stimulators. Try everything else first.

They can create pain and scarring or tether the spinal cord.

Be proactive.

Remember that guidelines and strategies for diagnosis and treatment are outdated.

Support RSDSA.org if you can.

They support high quality pain research.

You can go directly to their site or donate to them (not me)

using the link at the top of my site here.

.

.

Patients and doctors do not understand that opioids create pain.

A 2006 publication from Vanderbilt shows how much better pain can be to taper off.

The abstract:

Significant pain reduction in chronic pain patients after detoxification from high-dose opioids.

The article:

Significant pain reduction in chronic pain patients after detoxification from high-dose opioids.

.

.

More on this young woman’s journey coming.

It’s been busy!

.

.

~~~~~

The material on this site is for informational purposes only,

and is not a substitute for medical advice,

diagnosis or treatment provided by a qualified health care provider.

~

Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, you will need to telephone my office.

~

~

For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

.

.

Glia a Promising Target for Neuropathic Pain – Ketamine Acting on Glia More Than on Neuronal NMDA Receptors?


.
.

 Three important new articles from March, August and November 2011, show ketamine acts on glia.

Emphasis within articles is mine.

.

.

Microglia: a promising target for treating neuropathic and postoperative pain, and morphine tolerance.

Abstract

Management of chronic pain, such as nerve-injury-induced neuropathic pain associated with diabetic neuropathy, viral infection, and cancer, is a real clinical challenge. Major surgeries, such as breast and thoracic surgery, leg amputation, and coronary artery bypass surgery, also lead to chronic pain in 10-50% of individuals after acute postoperative pain, partly due to surgery-induced nerve injury. Current treatments mainly focus on blocking neurotransmission in the pain pathway and have only resulted in limited success. Ironically, chronic opioid exposure might lead to paradoxical pain. Development of effective therapeutic strategies requires a better understanding of cellular mechanisms underlying the pathogenesis of neuropathic pain. Progress in pain research points to an important role of microglial cells in the development of chronic pain. Spinal cord microglia are strongly activated after nerve injury, surgical incision, and chronic opioid exposure. Increasing evidence suggests that, under all these conditions, the activated microglia not only exhibit increased expression of microglial markers CD 11 b and Iba 1, but also display elevated phosphorylation of p38 mitogen-activated protein kinase. Inhibition of spinal cord p38 has been shown to attenuate neuropathic and postoperative pain, as well as morphine-induced antinociceptive tolerance. Activation of p38 in spinal microglia results in increased synthesis and release of the neurotrophin brain-derived neurotrophic factor and the proinflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor-α. These microglia-released mediators can powerfully modulate spinal cord synaptic transmission, leading to increased excitability of dorsal horn neurons, that is, central sensitization, partly via suppressing inhibitory synaptic transmission. Here, we review studies that support the pronociceptive role of microglia in conditions of neuropathic and postoperative pain and opioid tolerance. We conclude that targeting microglial signaling might lead to more effective treatments for devastating chronic pain after diabetic neuropathy, viral infection, cancer, and major surgeries, partly via improving the analgesic efficacy of opioids.

.

 

Ketamine depresses toll-like receptor 3 signaling in spinal microglia in a rat model of neuropathic pain.

Abstract

Reports suggest that microglia play a key role in spinal nerve ligation (SNL)-induced neuropathic pain, and toll-like receptor 3 (TLR3) has a substantial role in the activation of spinal microglia and the development of tactile allodynia after nerve injury. In addition, ketamine application could suppress microglial activation in vitro, and ketamine could inhibit proinflammatory gene expression possibly by suppressing TLR-mediated signal transduction. Therefore, the present study was designed to disclose whether intrathecal ketamine could suppress SNL-induced spinal microglial activation and exert some antiallodynic effects on neuropathic pain by suppressing TLR3 activation. Behavioral results showed that intrathecal ketamine attenuated SNL-induced mechanical allodynia, as well as spinal microglial activation, in a dose-dependent manner. Furthermore, Western blot analysis displayed that ketamine application downregulated SNL-induced phosphorylated-p38 (p-p38) expression, which was specifically expressed in spinal microglia but not in astrocytes or neurons. Besides, ketamine could reverse TLR3 agonist (polyinosine-polycytidylic acid)-induced mechanical allodynia and spinal microglia activation. It was concluded that intrathecal ketamine depresses TLR3-induced spinal microglial p-p38 mitogen-activated protein kinase pathway activation after SNL, probably contributing to the antiallodynic effect of ketamine on SNL-induced neuropathic pain.

~

Microglial Ca(2+)-activated K(+) channels are possible molecular targets for the analgesic effects of S-ketamine on neuropathic pain.

Abstract

Ketamine is an important analgesia clinically used for both acute and chronic pain. The acute analgesic effects of ketamine are generally believed to be mediated by the inhibition of NMDA receptors in nociceptive neurons. However, the inhibition of neuronal NMDA receptors cannot fully account for its potent analgesic effects on chronic pain because there is a significant discrepancy between their potencies. The possible effect of ketamine on spinal microglia was first examined because hyperactivation of spinal microglia after nerve injury contributes to neuropathic pain. Optically pure S-ketamine preferentially suppressed the nerve injury-induced development of tactile allodynia and hyperactivation of spinal microglia. S-Ketamine also preferentially inhibited hyperactivation of cultured microglia after treatment with lipopolysaccharide, ATP, or lysophosphatidic acid. We next focused our attention on the Ca(2+)-activated K(+) (K(Ca)) currents in microglia, which are known to induce their hyperactivation and migration. S-Ketamine suppressed both nerve injury-induced large-conductance K(Ca) (BK) currents and 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS1619)-induced BK currents in spinal microglia. Furthermore, the intrathecal administration of charybdotoxin, a K(Ca) channel blocker, significantly inhibited the nerve injury-induced tactile allodynia, the expression of P2X(4) receptors, and the synthesis of brain-derived neurotrophic factor in spinal microglia. In contrast, NS1619-induced tactile allodynia was completely inhibited by S-ketamine. These observations strongly suggest that S-ketamine preferentially suppresses the nerve injury-induced hyperactivation and migration of spinal microglia through the blockade of BK channels. Therefore, the preferential inhibition of microglial BK channels in addition to neuronal NMDA receptors may account for the preferential and potent analgesic effects of S-ketamine on neuropathic pain.

~


The material on this site is for informational purposes only,

The material on this site is for informational purposes only,

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


For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

.

.

.

.

.

Gliopathic Pain — when Neuropathic Pain Treatment Fails


`

`

`

Coming soon, though these stand on their own:

`

`

Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness.

Abstract

Microglia play a crucial role in the maintenance of neuronal homeostasis in the central nervous system, and microglia production of immune factors is believed to play an important role in nociceptive transmission. There is increasing evidence that uncontrolled activation of microglial cells under neuropathic pain conditions induces the release of proinflammatory cytokines (interleukin – IL-1beta, IL-6, tumor necrosis factor – TNF-alpha), complement components (C1q, C3, C4, C5, C5a) and other substances that facilitate pain transmission. Additionally, microglia activation can lead to altered activity of opioid systems and neuropathic pain is characterized by resistance to morphine. Pharmacological attenuation of glial activation represents a novel approach for controlling neuropathic pain. It has been found that propentofylline, pentoxifylline, fluorocitrate and minocycline decrease microglial activation and inhibit proinflammatory cytokines, thereby suppressing the development of neuropathic pain. The results of many studies support the idea that modulation of glial and neuroimmune activation may be a potential therapeutic mechanism for enhancement of morphine analgesia. Researchers and pharmacological companies have embarked on a new approach to the control of microglial activity, which is to search for substances that activate anti-inflammatory cytokines like IL-10. IL-10 is very interesting since it reduces allodynia and hyperalgesia by suppressing the production and activity of TNF-alpha, IL-1beta and IL-6. Some glial inhibitors, which are safe and clinically well tolerated, are potential useful agents for treatment of neuropathic pain and for the prevention of tolerance to morphine analgesia. Targeting glial activation is a clinically promising method for treatment of neuropathic pain.

~

Microglia: a promising target for treating neuropathic and postoperative pain, and morphine tolerance.

Source

Department of Anesthesiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA.

Abstract

Management of chronic pain, such as nerve-injury-induced neuropathic pain associated with diabetic neuropathy, viral infection, and cancer, is a real clinical challenge. Major surgeries, such as breast and thoracic surgery, leg amputation, and coronary artery bypass surgery, also lead to chronic pain in 10-50% of individuals after acute postoperative pain, partly due to surgery-induced nerve injury. Current treatments mainly focus on blocking neurotransmission in the pain pathway and have only resulted in limited success. Ironically, chronic opioid exposure might lead to paradoxical pain. Development of effective therapeutic strategies requires a better understanding of cellular mechanisms underlying the pathogenesis of neuropathic pain. Progress in pain research points to an important role of microglial cells in the development of chronic pain. Spinal cord microglia are strongly activated after nerve injury, surgical incision, and chronic opioid exposure. Increasing evidence suggests that, under all these conditions, the activated microglia not only exhibit increased expression of microglial markers CD 11 b and Iba 1, but also display elevated phosphorylation of p38 mitogen-activated protein kinase. Inhibition of spinal cord p38 has been shown to attenuate neuropathic and postoperative pain, as well as morphine-induced antinociceptive tolerance. Activation of p38 in spinal microglia results in increased synthesis and release of the neurotrophin brain-derived neurotrophic factor and the proinflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor-α. These microglia-released mediators can powerfully modulate spinal cord synaptic transmission, leading to increased excitability of dorsal horn neurons, that is, central sensitization, partly via suppressing inhibitory synaptic transmission. Here, we review studies that support the pronociceptive role of microglia in conditions of neuropathic and postoperative pain and opioid tolerance. We conclude that targeting microglial signaling might lead to more effective treatments for devastating chronic pain after diabetic neuropathy, viral infection, cancer, and major surgeries, partly via improving the analgesic efficacy of opioids.

 

~
~
~

The material on this site is for informational purposes only, and is not a substitute for medical advice,
diagnosis or treatment provided by a qualified health care provider.
~
~
For My Home Page, click here:  
~
~
~
~

`

`

Painkiller Efficacy in 2010 Less Than in 2000


~

This research shows efficacy of analgesics decreasing since 2000.

~

“The evidence for pharmacological treatment of neuropathic pain” publication is a good meta-analysis of the current state of evidence-based treatment of neuropathic pain.

~

I have quoted extensively from the article as it is important.

~

“Abstract: One hundred and seventy-four studies were included, representing a 66% increase in published randomized, placebo-controlled trials in the last 5 years. Painful poly-neuropathy (most often due to diabetes) was examined in 69 studies, postherpetic neuralgia in 23, while peripheral nerve injury, central pain, HIV neuropathy, and trigeminal neuralgia were less often studied. Tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, the anticonvulsants gabapentin and pregabalin, and opioids are the drug classes for which there is the best evidence for a clinical relevant effect. Despite a 66% increase in published trials only a limited improvement of neuropathic pain treatment has been obtained. A large proportion of neuropathic pain patients are left with insufficient pain relief. This fact calls for other treatment options to target chronic neuropathic pain. Large-scale drug trials that aim to identify possible subgroups of patients who are likely to respond to specific drugs are needed to test the hypothesis that a mechanism-based classification may help improve treatment of the individual patients.”

~

 

~The bla

The black circles are recent circles, the light circles are from the past. Shift to the right means less effect.

~

“Fig. 1. It shows the combined numbers needed to treat (NNT) values for various drug classes in all central and peripheral neuropathic pain conditions (not including trigeminal neuralgia). The figure illustrates the change from 2005 values in light grey to 2010 values in dark grey.  [emphasis mine]The circle sizes indicate the relative number of patients who received active treatment drugs in trials for which dichotomous data were available. Please note that the differences in study design and the patient populations preclude a direct comparison of NNT values across drug classes (see text). BTX-A: botulinum toxin type A; TCAs: tricyclic antidepressants; SNRIs: serotonin noradrenaline reuptake inhibitors; SSRIs: selective serotonin reuptake inhibitor.”

~

“Fig. 2. It shows the combined numbers needed to treat (NNT) values for different drug classes against specific disease etiologies. The symbol sizes indicate the relative number of patients who received active treatment drugs in the trials for which dichotomous data were available.”

~~

 A disease-based classification: fact or fiction?

“Since (1) there are no clear indications that specific diseases should be treated with specific treatments, (2) symptoms and signs overlap in various neuropathic pain conditions [6], and (3) currently available drugs act with unspecific neurodepressant actions rather on pivotal pathophysiological mechanisms, at present there is no good rationale for a treatment algorithm that discriminates between underlying etiologies [45]. Nevertheless, the vast majority of trials have been done in painful diabetic neuropathy and PHN and few, if any, in certain other conditions (e.g. Guillain–Barré syndrome and small-fiber neuropathy), and recommending a treatment for other conditions may seem to be an unjustified jump.”

~

“Supplementary Figure 1L’Abbé plot showing pain relief for all drugs for different neuropathic pain conditions. Each point illustrates one comparison against placebo (for trials listed in Supplementary Table 1). The axes indicate the percentage of patients with at least 50% pain relief with active and placebo treatment.© 2010 International Association for the Study of Pain”

 ~

Conclusion

~

“Pharmacological treatment still represents the main option for treating chronic neuropathic pain. Our understanding of neuropathic pain-generating mechanisms has grown considerably within the last few decades, but unfortunately this research has not been matched by a similar improvement in treatment efficacy. We are still limited in our efforts in managing neuropathic pain by relying on treating the symptoms of pain rather than identifying the underlying disease mechanisms causing the pain. Although 69 new randomized controlled trials have been published in the past 5years compared with 105 published trials published in the preceding 39years, only a marginal improvement in the treatment of the patients with neuropathic pain has been achieved.”

© 2010 International Association for the Study of Pain

The study is part of the European project, funded by the Innovative Medicines Initiative Joint Undertaking

~

~


The material on this site is for informational purposes only,

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

~
~

For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

~~

~
~
~

RSD – Complex Regional Pain Syndrome – A Case Report


~~


Rational Polypharmacy

Naltrexone is a remarkable drug for intractable pain

~

I first saw this RN in June 2006.

~~

She is now 60 years old.  She was an OR scrub nurse for almost 30 years, but was disabled for the last 5 years before seeing me. She had Reflex Sympathetic Dystrophy [RSD] of both legs with “arthritis” of the feet/ankle that felt like she was “90 years old” with cold allodynia. Allodynia is pain from a stimulus such as light touch or a breath or air that is not normally painful. Imagine a light touch that feels like severe nerve pain, one of the most disturbing pains a person could have. The temperature of her feet was 81 degrees, hands 92 degrees.

~

Pain of both feet felt like a vise grip, gnawing, penetrating, “like broken bones in the feet,” variable at different times but always worse as the day progressed, with a crushing sensation that penetrated through foot and ankle. She was unable to tolerate socks or anything on her feet after 5 pm, unable even to tolerate air on the area, unable to tolerate coolness below waist, but felt hot above waist. She wore a blanket and covers on the hottest 120 degree days, and forced herself to tolerate touch at the legs in order to desensitize them, as we instruct patients to do. She felt constant tingling numbness of the soles of feet for 3 years, with weakness, stiffness “almost solid” like a block. Spasm in soles of feet had resolved the last 6 months before seeing me.

Pain ranged from 2 to 9 on a scale of 10, where 10 is the worst pain imaginable, worst after 5 pm. Average pain was 3. It interfered with sleep at times, and she used a tented frame to keep blankets off her feet, preheated the bed to avoid any coolness, and avoided cold under all circumstances. In the morning, the joints felt like she had a broken ankle. She would massage the feet with lotion, put on alpaca socks, and slowly begin to walk. Then tried to mobilize the joints. Walking made pain worse though walking had always been a favorite activity.~

Before seeing me she had had more than 10 sympathetic blocks, was hospitalized 11 days due to headache from prednisone 60 mg that had been trialed to relieve her pain. She had been prescribed Procardia to relieve the “vascular” disease that she did not have but the drug led to gangrene of the gall bladder; she had been prescribed almost every “adjuvant” used to relieve pain and as much as 9 grams of Neurontin daily, all of this to attempt to relieve the severe pain in her legs and feet.

~

This is how she got better

~

When I first saw her in 2006, I prescribed low dose oral ketamine that gave relief lasting up to 3 hours from each dose. She then requested referral to Dr. Schwartzman, chief of neurology at Drexel University in Philadelphia, for continuous 5 day ketamine infusion that was done May 2007. She was pain free but it completely lost effect after 8 months, despite booster infusions every 4 to 6 weeks for 4 hours daily over 2 days during those 8 months. After insurance the cost out of pocket was $45,000 in 2007 alone. Dr. Schwartzman had nothing more to offer after it failed and said most patients have relief for less than 6 months if at all.

~

In March 2007, I started her on a combination of Namenda 55 mg daily with lamotrigine 350 mg daily that relieved 90% of the pain, but once every 6 to 8 weeks she needed 12.5 to 25 mg low dose oral ketamine for breakthrough pain. Even more rarely, she used oxycodone 10 to 20 mg.

~

In October 2008, adding naltrexone 1 mg by mouth, she became pain free. Since then she has not needed anything for breakthrough pain and on 3/5/09, she reported that her last use of ketamine and oxycodone occurred with the addition of low dose naltrexone.

 

~

In 2009, she hiked 30 miles down the Grand Canyon and back up in 3 days.

~

Naltrexone was later increased to 4.5 mg as she completely tapered off lamotrigine.

~

By December 2009, the RSD was 98% better and she reported that it was not pain anymore. Medications then were naltrexone 12.5 mg at bedtime and Namenda 55 mg daily in divided doses. She had just a “remnant” of a little buzz, but no crushing except when active, late in the day.

~

A few months later she slowly tapered off Namenda with no increase in pain; and in October 2010, on my advice she tapered naltrexone 12.5 mg from daily to every third day. There has been no increase in pain but she is reluctant to discontinue naltrexone for fear that RSD may recur.

.

She hikes 2 miles 3 to 4 times a week, does Iron Mountain once a week, does “Silver Sneekers” exercise 1 hour 3 times a week and sleeps well 8 to 10 hours a night without a sleeping pill.

~~

She remains on low dose naltrexone as her sole medication for this

previously disabling neuropathic pain syndrome~

~

She has returned to part time work and spends a few weeks a month traveling the world, hiking, volunteering, sightseeing.

.

Research funding is needed to view whether we can detect

activated glia in the spinal cord, as discussed here.

If there are no signs of activated glia, she may feel reassured that the condition has resolved.

Naltrexone is an immune modulator.

The site of action of naltrexone is at the Toll-like receptor (TLR4) attached to the cell surface membrane of glia.

The ability to view activated glia would help greatly in treatment of so many conditions including neuropathic pain.

~

Naltrexone

~

I have found that naltrexone is a remarkable medication for various pain conditions, and going through the steps of rational polypharmacy may be very rewarding for some patients though at times it may work all on its own. It has caused me to completely reassess how I approach the treatment of intractable pain – not just RSD or CRPS but arthritis, sciatica and various forms of mechanical pain. And it has led to further changes in the timing and dosing of naltrexone based upon the experiences patients have reported back to me over the years. It is hoped that further research will lead to better understanding of how naltrexone acts upon pain pathways. Surprisingly we already know quite a fair amount.

~

My deepest gratitude to Dr. Jau-Shyong Hong, Chief of Neuropharmacology at NIH, whose many generous discussions, emails and research publications have helped me to understand it’s profound anti-inflammatory effect in the central nervous system through its actions on microglia. I previously posted a discussion of mechanisms of naltrexone and dextromethorphan in greater detail here. Naltrexone and dextromethorphan are classified as morphinans, morphine-like. They suppress Superoxide, a free radical that destroys neurons which may cause or contribute to Alzheimers and Parkinsons Disease. That research goes back to the late 1980’s and continues to grow. Phase II studies with morphinans are now being done on those conditions. Studies are also going on now with naltrexone/Wellbutrin combination for weight loss. The drug is called Contrave, from Orexigen Therapeutics Inc. and the dose I believe is 32 mg naltrexone – I do not know how they decided upon that dosage.

~

In my experience, naltrexone is a very benign drug at these low doses, though colleagues who prescribe 400 mg for the FDA approved use at that high dose may see some liver toxicity. I always begin at 1 mg or 4.5 mg, depending upon whether or not the patient is a slow drug metabolizer, i.e. may lack one of the CYP P450 chromosomes for metabolizing drugs. I have long suspected it also has an effect on the hypothalamus because a few patients with profound postmenopausal hot flashes have reported that is no longer a problem and that their husbands simply cannot believe the bonus, and this may explain the effect upon appetite that Orexigen has found. At higher doses than I generally use there may be some constipation which is treatable. It may cause vivid dreaming in some, and a small percentage may have insomnia for a few days. Pharmacology and safety is discussed here.

~

Stay tuned. I’ll be adding more case reports of different pain conditions in the near future. They are truly fascinating. It has changed my entire approach to treating pain.

~

Cost

~

Wouldn’t it be nice if NIH funded more for pain research? Imagine how much money that would save the country and save the lives of each person with disability who could recover? As I posted here, the American Pain Society has shown that NIH spends 0.67% of its budget on pain research – less than 1% – though 10 to 20% of the population in the US suffers from chronic pain, an estimated 60 million Americans, and pain conditions are more prevalent among the elderly.

~

I am told by my pharmacist that perhaps 70% of the time insurance will approve coverage for compounded low dose naltrexone. It is very affordable but some insurance carriers deny payment for naltrexone. Medicare will not pay for compounded medication either. Compare this low cost compound to the wholesale price for 100 tablets of Oxycontin, $1300, which may not be relieving pain – then multiple that by 2 or 3 each month for one patient. Imagine if the $22 billion of federal money for health insurance technology, for software which is untested and will expire in a few years, instead went into NIH funding for pain research. What a lovely thought.

~

The material on this site is for informational purposes only, and

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

~

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

~

~

Ketamine


Ketamine for persons with severe pain

cancerIn special circumstances, I may suggest a trial of low dose oral ketamine. It is formulated by a compounding pharmacist as an oral suspension. It is safe to use without significant adverse effects, though you may experience transient symptoms lasting 20 to 40 minutes after the first few doses. For most people, it may relieve pain when all other methods have failed, possibly including total pain relief with no side effects in patients who have then been able to discontinue all opioids.

Keep all your medicine, opioids and ketamine, in a lock box to prevent abuse by others. This is a Schedule III drug like Vicodin.

Achieving control of chronic pain requires a partnership

based upon trust and effort

Requirements: I will work closely with you on ketamine and ask you to keep a log of pain before each dose and 30 minutes after. In addition, for the first week I ask that you log blood pressure and heart rate before each dose and 30 minutes after. This requires that you see me in the office one week later. If you have any questions or problems, I ask that you call me the same day, whether it be weekend or holiday. If you are unable to keep these logs before and after the dose, and the appointment one week later, the trial will be discontinued. You have no authority to continue without my consent.

Blood Pressure: Usually no change occurs in blood pressure. Some have reported that ketamine lowers their blood pressure and they are lightheaded when they stand up. If your blood pressure drops or if you are lightheaded, be very cautious as that may lead to fainting and brief loss of consciousness. Anytime a person faints, that could result in potentially serious injury such as hip fracture, other fractures, bleeding or brain injury if you strike your head. Your blood pressure should be above 100 when standing.  Ketamine has been reported to increase blood pressure and pulse, but I have not found that to occur with these doses.

Side Effects: Ketamine has a very narrow therapeutic window for pain control. This means that once you find the dose that relieves pain, a very slight increase in dose may produce intolerable side effects. Unfortunately some patients reach a dose that produces side effects before they experience any pain relief.

Most patients have no side effects with the low doses used by this protocol, though some may have mild symptoms lasting up to 40 minutes. If you do, then try decreasing the dose a small amount.

It is possible but rare that you may experience severe, frightening hallucinations or may feel you are outside the body observing it do things, called a dissociative reaction.

These side effects are dose related and have been short lasting, usually no longer than 40 minutes.  The antidote is Ativan.

Steps to follow: Read all steps carefully before you begin

  • Take ketamine 30 minutes prior to your other pain medication
  • For the first dose, remain seated or lie down for 20 minutes after you take the dose to avoid risk of falling. Do not take the dose and walk around.
  • A few persons have had severe imbalance lasting 10 or 20 minutes. This has resolved after the first few doses in those persons. It may not happen to you, so test with caution. If it has not occurred at the first dose, it is unlikely to occur at all.
  • Follow the dosing guidelines in the log I give you and which I repeat in this next step:
    Begin with 0.25 mL and increase by increments of 0.25 mL every 6 hours or longer than 6 hours, until you have some pain relief. Do not increase that dose or dosing interval.

Example: begin 0.25 mL, then 0.5, next 0.75, 1.0, 1.25, 1.5, 1.75, 2.0

If you have had no effect on pain by 2.0 mL, schedule an appointment for further instructions.
If your pain decreases only 1 or 2 points, that is your dose.  It will NOT get better by increasing the dose.  Stop increasing.

  • If you have intolerable side effects, you may use 1 or 2 Ativan tablets immediately as an antidote, and every 30 minutes, up to 5 of them.
  • CAUTION: Be alert to the opioid-sparing effects of ketamine!

This means that if ketamine relieves your pain, you do not need to take the opioid as that would be an opioid overdose and may cause serious side effects.

Reduce or temporarily stop your opioid medication if pain is gone after using ketamine.

This is why you take ketamine 30 minutes before the opioid. Some people have been able to completely stop all opioid medication due to pain relief from ketamine alone.

  • CAUTION: Do not drive for 6 hours after a dose.

This is for the protection of you and others. You may not be aware of very subtle side effects.

  • You may take a dose every 6 hours, or longer than 6 hours. Less is more.

If ketamine loses its effect, stop use for 2 or 3 days, then resume. It can be a fickle drug.  That is why increasing the dose causes loss of effect.

Some take ketamine only before sleep. If you do that, use it 30 minutes before sleep in order to log its effect and take blood pressure/pulse before and after. Continue this initially until further changes are approved.

Ketamine was approved for use as an anesthetic by the FDA in 1970

It’s use for pain is “off label” as it was approved only in high doses for anesthesia. It has been used safely in babies. Unlike opioids, it does not depress breathing or bowel function, and usually does not depress cardiovascular function. Since the late 1980’s, numerous scientific articles have been published on its use as a third line choice for some pain conditions; there are few double blind control studies, one is listed below. If you search ketamine on various internet search engines you find it is abused by addicts just as other drugs are. You find medical articles when you search the literature using Google Scholar or PubMed in the National Library of Medicine. If you find a medical article with adverse effects, let me know. I have spoken to leading brain and psychiatric researchers who have verified there are no lasting side effects from its use.

Many publications on ketamine use multi-day infusions at much higher dosages than the oral dosages in my protocol. Drexel University has treated over 3,000 patients with infusions of 40 mg/hour for 5 days with no lasting adverse effects. Even higher doses than that are used for surgical anesthesia. Ketamine is a powerful tool for treating pain.

Medical Publications


You can click and download each reference in blue below

High dose ketamine improves neurological outcome after stroke in rats, Reeker et al, Canadian J Anesth 47:572-578, 2000

Ketamine, Pasero C, McCaffery M, Amer J Nursing, 105:60-64, 2005
An excellent review, more clinical, easier to read than some more technical papers

Ketamine in Chronic Pain Management: An Evidence Based Review, Hocking & Cousins, Anesth Analg, 97(6):1730-1739, 2003This nine page article is the best comprehensive review of ketamine’s use in almost every known pain condition including post stroke pain.  Easier to read; a catalogue of pain syndromes and references.

Ketamine Stops Aura in Familial Hemiplegic Migraine, Neurology, 55:139-141, 2000 Two mechanisms may account for this. First, ketamine can increase cerebral blood flow, which may counteract the marked hypoperfusion induced by cortical spreading depression, as observed in migraine with aura. Second, in experimental animals, ketamine accelerates the  restitution of neuronal function after hypoxia.

Ketamine oral use in 8 chronic pain patients, Canadian J. of Anesthesia, 2004


§


The Reflex Sympathetic Dystrophy Association library has many articles on RSD, CRPS and ketamine. Remember most of the articles are written for scientists and physicians.

From their library I particularly recommend the first article, below.  The last two are very technical but important new research.


Expectations of Pain: I Think, Therefore I Am, Jones-London M, National Institute of Neurological Disorders and Stroke

For pain mechanisms, read
Beyond Neurons: Evidence that Immune and Glial Cells Contribute to Pathological Pain States, Watkins L and Maier SF, Physiology Review. 2003;82:981-1011.

For pain mechanisms, read
Complex Regional Pain Syndrome (CRPS): Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy),  Oaklander AL et al., Pain. 2006;120:235-243.

There is no link to the following double blind controlled research publication:

Mercadante S, Arcuri E, Tirelli W, Casuccio A. Analgesic effect of intravenous Ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study. J Pain Symptom Manage 2000;20:246-252. Mercadante et al compared intravenous infusions of Ketamine (0.25 and 0.5 mg/kg) with placebo in a double-blind, crossover study of 10 cancer patients with neuropathic pain.

Please note that the free Adobe Acrobat Reader is needed to read some references.

You can download the free reader now.

~~~~~The material on this site is for informational purposes only, and is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider. ~~~~~

%d bloggers like this: