Statin Drugs Can Cause Neuropathy

Many HIV patients have cholesterol problems, either as a result of medication or lifestyle issues. However, if you have HIV plus neuropathy plus high cholesterol problems, you may want to talk to your doctor about the drugs being used to lower your cholesterol. These Statin drugs can reduce your cholesterol but make your neuropathy far worse and this needs to be borne in mind both by yourself and your doctor. There is another post about the dangers of Statins elsewhere on the blog (look in the alphabetical list on the right) but this video from one of the best medical communicators around; Dr. John D. Erickson from Denver, helps explain the issue.

Can Opioids Actually Cause More Pain

Today's post from sciencedaily.com (see link below) looks at a very important possibility to do with opioid use in controlling (neuropathic) pain. Most people who have reached the stage when opioids are necessary to keep their symptoms under control are told and believe that eventually they will need more of the same to achieve the same pain control. This article shows that it has been found that opioids can actually increase pain during a series of events at a cellular level. This is not good news for the patient but if you feel that your pain has got worse since beginning opioids (it may be better to give it some time before you jump to that conclusion), it would be advisable to discuss it with your doctor or specialist. Alternative medications may be possible to achieve the same effect.

The Pain Puzzle: Uncovering How Morphine Increases Pain in Some People

Jan. 6, 2013 The above story is reprinted from materials provided by Université Laval

For individuals with agonizing pain, it is a cruel blow when the gold-standard medication actually causes more pain. Adults and children whose pain gets worse when treated with morphine may be closer to a solution, based on research published in the January 6 on-line edition of Nature Neuroscience."Our research identifies a molecular pathway by which morphine can increase pain, and suggests potential new ways to make morphine effective for more patients," says senior author Dr. Yves De Koninck, Professor at Université Laval in Quebec City. The team included researchers from The Hospital for Sick Children (SickKids) in Toronto, the Institut universitaire en santé mentale de Québec, the US and Italy.

New pathway in pain management

The research not only identifies a target pathway to suppress morphine-induced pain but teases apart the pain hypersensitivity caused by morphine from tolerance to morphine, two phenomena previously considered to be caused by the same mechanisms.

"When morphine doesn't reduce pain adequately the tendency is to increase the dosage. If a higher dosage produces pain relief, this is the classic picture of morphine tolerance, which is very well known. But sometimes increasing the morphine can, paradoxically, makes the pain worse," explains co-author Dr. Michael Salter. Dr. Salter is Senior Scientist and Head of Neurosciences & Mental Health at SickKids, Professor of Physiology at University of Toronto, and Canada Research Chair in Neuroplasticity and Pain.

"Pain experts have thought tolerance and hypersensitivity (or hyperalgesia) are simply different reflections of the same response," says Dr. De Koninck, "but we discovered that cellular and signalling processes for morphine tolerance are very different from those of morphine-induced pain."

Dr. Salter adds, "We identified specialized cells -- known as microglia -- in the spinal cord as the culprit behind morphine-induced pain hypersensitivity. When morphine acts on certain receptors in microglia, it triggers the cascade of events that ultimately increase, rather than decrease, activity of the pain-transmitting nerve cells."

The researchers also identified the molecule responsible for this side effect of morphine. "It's a protein called KCC2, which regulates the transport of chloride ions and the proper control of sensory signals to the brain," explains Dr. De Koninck. "Morphine inhibits the activity of this protein, causing abnormal pain perception. By restoring normal KCC2 activity we could potentially prevent pain hypersensitivity." Dr. De Koninck and researchers at Université Laval are testing new molecules capable of preserving KCC2 functions and thus preventing hyperalgesia.

The KCC2 pathway appears to apply to short-term as well as to long-term morphine administration, says Dr. De Koninck. "Thus, we have the foundation for new strategies to improve the treatment of post-operative as well as chronic pain."

Dr. Salter adds, "Our discovery could have a major impact on individuals with various types of intractable pain, such as that associated with cancer or nerve damage, who have stopped morphine or other opiate medications because of pain hypersensitivity."

Cost of pain

Pain has been labelled the silent health crisis, afflicting tens of millions of people worldwide. Pain has a profound negative effect on the quality of human life. Pain affects nearly all aspects of human existence, with untreated or under-treated pain being the most common cause of disability. The Canadian Pain Society estimates that chronic pain affects at least one in five Canadians and costs Canada $55-60 billion per year, including health care expenses and lost productivity.

"People with incapacitating pain may be left with no alternatives when our most powerful medications intensify their suffering," says Dr. De Koninck, who is also Director of Cellular and Molecular Neuroscience at Institut universitaire en santé mentale de Québec.

Dr. Salter adds, "Pain interferes with many aspects of an individual's life. Too often, patients with chronic pain feel abandoned and stigmatized. Among the many burdens on individuals and their families, chronic pain is linked to increased risk of suicide. The burden of chronic pain affects children and teens as well as adults." These risks affect individuals with many types of pain, ranging from migraine and carpel-tunnel syndrome to cancer, AIDS, diabetes, traumatic injuries, Parkinson's disease and dozens of other conditions.

http://www.sciencedaily.com/releases/2013/01/130106145747.htm

Can Skin Signals Cause Neuropathic Pain

Not the easiest article to understand but one that gives a fascinating alternative to the idea that neuropathic pain is caused by damaged nerves. It comes from esciencenews.com (see link below) and suggests that the pain signals are produced by the skin itself. The science is fairly complex but further Googling will provide further information. This one may surprise your neurologist when you next visit him or her.

Researchers discover potential cause of chronic painful skin
Published: Wednesday, June 8, 2011

A new study may explain why only 50% of patients experiencing chronic nerve pain achieve even partial relief from existing therapeutics. The study, published in the June 6 online version of the international research journal PAIN, reveals that certain types of chronic pain may be caused by signals from the skin itself, rather than damage to nerves within the skin, as previously thought.

A Medical Mystery
For years, researchers have known that increased amounts of a molecule called Calcitonin Gene-Related Peptide (CGRP) is found in the skin of chronic pain patients. The source of the increased CGRP was thought to be certain types of sensory nerve fibers in the skin that normally make and release a type or "isoform" called CGRP-alpha. Curiously, however, the authors of the current study found that nerve fibers containing CGRP-alpha are actually reduced under painful conditions – leading them to investigate where the increased CGRP in the skin came from.

The answer, surprisingly, was that the skin cells themselves generate increased amounts of a lesser-known "beta" isoform of CGRP. This skin cell-derived CGRP-beta is increased in painful conditions and may be sending pain signals to remaining sensory nerve fibers in the skin. The discovery of CGRP-beta as a therapeutic target presents a potentially important new treatment approach.

"Since CGRP-alpha normally plays an important role in both the regulation of blood flow and normal inflammatory responses, targeting this molecule as a treatment for chronic pain could cause undesired side-effects on circulation," said the paper's corresponding author, Phillip J. Albrecht, Ph.D., Assistant Professor of Neuroscience at Albany Medical College and Vice President at Integrated Tissue Dynamics, LLC, whose team conducted the research. "However, since we know that these two forms of CGRP are derived from separate genes, we may be able to selectively manipulate the beta isoform without affecting the alpha, and dramatically reduce unwanted toxicities -- a common problem limiting the successful development of novel pain therapeutics. This is really a two-for-one discovery: a novel mechanism we can specifically target in a novel skin location."

The discovery that CGRP-beta from keratinocyte cells of skin may be causing pain has profound implications for the treatment and study of a host of chronic neuropathic pain conditions such as shingles, diabetic neuropathy, and physical injury, which altogether affect approximately 30 million people in the U.S. who collectively spend more than $4.5 billion each year to treat chronic nerve pain.

A New Translational Research Platform

The present study was a comprehensive translational research project that integrated results from cell culture, animal models of chronic pain and human pain condition tissues to confirm that CRGP is generated in keratinocytes in each of those systems. The study also demonstrates how a translational research platform can be utilized to discover novel targets and provide drug companies with better predictive data that can be used to make time- and cost-reducing decisions early in the drug discovery process.

To observe differences between CGRP in healthy and inflamed or painful skin, the researchers used an imaging methodology called chemomorphometric analysis (CMA), a technique they use to observe, quantify, and characterize molecules like CGRP in the microscopic structure of skin samples half the size of a pencil eraser. A commercially expanded version of the technique, pioneered by Integrated Tissue Dynamics, LLC, interpreted those results and integrated them with assessments of the genetic activity for each CGRP isoform, which led to the discovery that the beta molecule, not the alpha, predominated in keratinocytes.

"We are especially excited by our translational research results because the identification of beta CGRP in keratinocytes will have immediate value in the clinical setting, and also demonstrates how our CMA technology can deliver on the promise of translational medicine," said Frank L. Rice, Ph.D., Professor of Neuroscience at Albany Medical College and CEO at Integrated Tissue Dynamics, LLC. "Furthermore, the identification of beta CGRP in skin keratinocytes may become a useful independent biomarker for the therapeutic effectiveness of chronic neuropathic pain treatments."

The initial discovery stems from the Ph.D. dissertation research of Albany Medical College graduate student Quanzhi Hou, M.D., who is being co-mentored by Drs. Albrecht and Rice, in conjunction with research by Travis Barr, Ph.D., a former graduate student in the lab. Dr. Hou's research was made possible with the support of an international network of researchers and clinicians from Albany Medical College, the Feinberg School of Medicine of Northwestern University, Boston College, the University at Albany, the University of Brescia (Italy), the Israel Institute of Technology, and companies Vertex Pharmaceuticals and Integrated Tissue Dynamics. Dr. Rice noted that "As a co-discovery in the labs of Albany Medical College and Integrated Tissue Dynamics, we are filing a patent to develop our research and commercialization options."

About the Study

The present study found CGRP levels increased in keratinocytes of painful skin from humans with postherpetic neuralgia (PHN) and complex regional pain syndrome type 1 (CRPS). Elevated CGRP levels were also found in skin keratinocytes from monkeys infected with the equivalent of HIV, and in rats with nerve injury and inflammatory pain conditions similar to those caused by accidents and shingles. CGRP was also found in human keratinocyte cell cultures, and the beta isoform predominated.

Previous research has documented abnormally increased levels of CGRP in the skin, blood, and cerebral spinal fluid under a variety of human and animal chronic pain conditions, and CGRP has consequently become a leading target for chronic pain therapeutics. However, prior research has largely not distinguished between the two isoforms and it has been assumed that the increased CGRP seen in previous studies was the alpha isoform generated by nerves that supply sensory innervation to the skin.

Recently, members of the Intidyn and the Medical College group also published a pioneering study demonstrating that CGRP (likely alpha) innervation to the blood vessels plays a previously unknown role in normal skin sensation. The current findings now add to that story, the role of a second (beta) isoform produced in a unique location (keratinocytes) - which likely also plays a critical role in both normal sensation and chronic painful conditions.

http://esciencenews.com/articles/2011/06/08/researchers.discover.potential.cause.chronic.painful.skin

How Important Is It To Know The Cause Of Your Neuropathy

Today's post from neuropathyjournal.org (see link below) is written by LtCol Eugene B Richardson who has quite rightly been a long-term critic of general diagnoses such as 'idiopathic neuropathy' (where they can't find the cause) and 'peripheral neuropathy' which can refer to any number of branches of nerve damage. In this article, he encourages patients to push for more accurate diagnoses and for better testing to pinpoint the probable reasons for a patient's symptoms. That said, there are often cases where no matter how stringent the testing; isolating the cause can be pretty much like thrusting the needle in the proverbial haystack and a diagnosis of idiopathic neuropathy is unavoidable. It's also true that addressing the symptoms (which are pretty much common to most neuropathy forms) is the main aim and depending on a patient's history, the cause may stem from several other conditions and treatments from the past. Nevertheless this is an excellent article and well worth a read.

Neuropathy Types: How Important?
By LtCol Eugene B Richardson, USA (Retired) BA, MDiv, EdM, MS Aug 2015

Patients must work with their doctor to obtain a diagnosis of their type of neuropathy and never settle for a diagnosis that is limited to Idiopathic and/or just Peripheral Neuropathy.

Why?

By identifying the type of neuropathy, there is a very high probability that the type of neuropathy will point to a possible cause, especially the immune mediated neuropathies and even a possible treatment.

A diagnosis of Idiopathic Neuropathy is not helpful to the patient or to the clinical practitioner and is overused for a number of reasons. Too many doctors are not trained or skilled in neuromuscular neurology and worse do not taking neuropathy seriously. (Note: From patient experience Idiopathic means of unknown cause to doctors and no objective proof to lawyers).

With the testing available in 2015 the type of neuropathy, outside the single focus on a cause, will often point to a possible cause. This would include understanding of the EMG, Nerve Conduct Test, Skin Biopsy, Spinal Tap for immune mediated, Radiological examinations, (limited use of the Nerve/Muscle Biopsy), Evoked Potentials, Blood Tests, and Genetic Testing in addition to the careful reading of the patients health history/symptoms and a skilled neurological examination in the hands of a trained Neuromuscular Neurologist.

The type neuropathy will help the patient grasp a concept of what is wrong and provide some hope for finding a cause by the doctor, while helping the patient with coping and seeking support for their condition. (See reference 2 in the Textbook by Dr. Donofrio showing differential diagnosis between types).

Affirmation is no small matter as to what the doctor calls a disease. Without a name for a disease or condition, the diagnosis feels to the patient like they are swinging fists against an unknown wind. Without a name hope wilts and spirits sag. Support systems disappear or grow tired of the endless symptoms in chronic illness that has no meaningful name. The patient may even feel like they are losing their mind and others will imply they are ‘crazy’. Without a name a neuropathy patient is left out on the limb with no place to go except treating symptoms, grasping at ‘snake oil’, endless searching for answers while hoping that it will just go away.

In too many cases, an inappropriate diagnosis of idiopathic neuropathy has delayed treatments which were available or at a minimum the consideration of a possible treatment, while a progressive neuropathy eats away at the nerves increasing the possibility of more serious disabilities. This is exactly what happen to Col Richardson a 27 year military veteran who served in Vietnam and who came to Jacksonville in 2009 to give his lecture on “Coping with Chronic Neuropathy“. This well known DVD on the subject has reached thousands around the world and is endorsed by several nationally known Neurologists. (See his story of struggle and courage with undiagnosed or treated symptoms of neuropathy for over four decades in the article One Man’s Journey).

What are the types of neuropathy to name just a few?

Patients who have read the book by Norman Latov MD PhD, (Reference 1) one of the things that they note stands out is the manifestations within the different types of neuropathy. It became obvious to patients in looking at this information with deductive reasoning in the diagnostic process, is to provide a clue as to what may be happening to the patient! The facts of what is affecting some part of the peripheral nervous system, often points to a type and thus to a cause or even a clue for treatment!

In the book by Drs. Herskovitz, Scelsa, and Schaumburg, (Reference 3) the use of the word idiopathic is used only in reference to the recent research focus on axonal polyneuropathy and small fiber neuropathy and its use is limited and the focus is clearly on the “careful, intensive evaluation of undiagnosed neuropathies” as “this will uncover an etiology in many cases”.

The authors go on to note that about one-third to one-half of these neuropathies will remain ‘idiopathic or cryptogenic”, but these are almost exclusively axonal, either sensory or sensory motor or small fiber types. So why not call them axonal sensory/motor or small fiber neuropathy? The doctors go on to discuss the components of both the known and unknown, while seeking to provide some direction in the diagnosis and treatment for these patients.

The point here is that current books have no chapter dedicated to Idiopathic Neuropathies as in the past. Yet significant coverage is given to the different types of neuropathy and the keys to diagnosis or clues for the clinician to consider for each type.

Dr. Donofrio (Reference 2) who wrote with contributions from other experts does an outstanding job in noting the differences between types, the symptoms, the nerves involved, patients’ symptoms and complaints, the neurological examination, and so on.

Types of Neuropathy: While not exhaustive, this list will provide you with the point being made:
Axonal Neuropathy / Polyneuropathy
Sensory Neuropathy / Polyneuropathy
Multifocal Motor Neuropathy (MMN)
Multifocal Demyelinating Sensorimotor Neuropathy (Lewis Summer Syndromes)
Neuropathy with IgM Monoclonal Gammopathy
Anti-Mag or Gangliosides Antibodies
Sensory/Motor Neuropathy / Polyneuropathy
Immune Mediated Neuropathy / Polyneuropathy
Large Fiber Neuropathy / Polyneuropathy
Small Fiber Neuropathy (SFN)
Autonomic Neuropathy
Autoimmune Sensory Neuronitis
Guillian Barré Syndrome (GBS)
Distal Symmetric Polyneuropathy
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
Sjogren’s Syndrome


Types when there is a suspected cause:
Diabetic Neuropathy or Glucose Intolerance
Diabetic Amyotrophy
Vitamin E, B1, B6, B12 Deficiency
Vitamin B6 toxicity
Bariatric Surgery and Malabsorbtion with nutritional deficiency
Celiac Neuropathy
Chemotherapy/Radiation induced neuropathy
Neuropathy in alcoholic abuse
Neuropathy in Nutritional Deficiencies
Hereditary or genetic neuropathy
Neuropathy in Agent Orange/Blue/White with Arsenic exposure***
Entrapment Neuropathy (Carpel Tunnel Syndrome)
Toxic neuropathy
Drug induced neuropathy
Neuropathy with IgA, IgM Monoclonal Gammopathy
Hepatitis C Infection
Vasculitic neuropathy
Neuropathy in AIDS
Neuropathy in Lyme disease
Diphtheric (bacterial infections) neuropathy
Sarcoid or Parasitic Infection (Chagas’ Disease) neuropathy
Leprosy
Neuropathy in cancer or Lymphoproliferative disorders
Paraneoplastic neuropathy
Neuropathy in myeloma or POEMS
Neuropathy in amyloidosis
Ulcerative Colitis
Crohn’s Disease
Shingles or Cytomegalovirus infections

(***Supported by the findings of the Institute of Medicine in 2010 and confirmed by the Veterans Affairs Administration law in 2012 as presumptive to Agent Orange/Blue/White (arsenic and other toxins) exposure. For guidance in submitting a claim to the VA go to this link on Guidelines for Veterans or send an E Mail to gene@neuropathysupportnetwork.org for more guidance.)

References:
Peripheral Neuropathy: When the Numbness, Weakness and Pain Won’t Stop by Norman Latov, MD PhD Demos Medical Press, New York 2007
Textbook of Peripheral Neuropathy by Peter D Donofrio Professor of Neurology, Chief of the Neuromuscular Section, Vanderbilt University Medical Center, Nashville, TN, Demos Medical Press, New York, 2012 with contributions by other experts.
Peripheral Neuropathies in Clinical Practice by Drs. Steven Herskovitz, Stephen Scelsa and Herbert Schaumberg, Contemporary Neurology Series, Oxford University Press, 2010.
“The Problem with a Diagnosis of Idiopathic Neuropathy” on the Neuropathy Journal website. https://neuropathyjournal.org/the-problem-with-a-diagnosis-of-idiopathic-neuropathy/

https://neuropathyjournal.org/neuropathy-types-how-important/