Can We Learn About Medication Via Internet Chatrooms

Today's video from www.live.wsj.com (see link below) is an interesting one for people with neuropathy and other illnesses (including HIV) because it highlights something many people already know. There is much more information available on the internet about drug interactions and reactions than your doctors may themselves be aware of. Visiting a trustworthy forum and seeing how other people have reacted to certain drugs, can help build up your knowledge base before discussing it with your doctor. That's not to say that you should believe everything you read on internet forums; far from it but if you notice that a significant number of people have had the same experience, it may be worth taking that information with you to your appointment. For people with neuropathy and HIV for instance, the number of different drugs being taken can be alarmingly high. Knowing what they can potentially do to you may be very useful - knowledge is always power in this respect.





Can Web Chatter Make Medication Safer?
From live.wsj.com - October 10, 2012

Is it possible to make medication safer by analyzing information publicly available on the internet, such as patient complaints on web chats? The medical community is starting to think so, reports Shirley Wang on Lunch Break.

http://live.wsj.com/video/can-web-chatter-make-medication-safer/46F629BD-8D3A-4BF2-8917-F6201DB60C9E.html#!46F629BD-8D3A-4BF2-8917-F6201DB60C9E

New Book About Neuropathy Jan 2014

Today's post from novapublishers.com (see link below) is another advertisement for a new book about Neuropathy. We normally don't advertise for publishers, in the same way that we don't advertise for clinics or private companies but if the book seems to be a taking a slightly different approach, it may offer more information to its readers than the standard texts. There are many books about neuropathy available and this one does state that they aim to 'challenge' their readers, which may mean that it's difficult to read, however, ordering it via a library, or glancing through in a bookshop may help with your decision as to whether it's going to help you or not. It does discuss neuropathies associated with HIV infection, where many others avoid the subject completely.

Contemporary Issues in Peripheral Neuropathy

Editors: Daniel L. Menkes (UCHC Neurology Department, Farmington, Connecticut, USA)

Book Description: There are many books on polyneuropathy available that are comprehensive in nature. Many of these are encyclopedic in their scope. However, there are very few books that review the basics of clinical neurophysiological testing, genetics and the commonly encountered neuropathies. There are even fewer that are willing to address less commonly encountered neuropathies such as amyloidosis and neuropathies associated with HIV infection. Many such textbooks also avoid interdisciplinary topics such as the management of pelvic floor dysfunction and the surgical treatment of compression and traumatic neuropathies. This book addresses this void by dividing this book into three distinct sections. The first three chapter section addresses basic clinical neurophysiological techniques, genetic testing and the inherited neuropathies. The larger middle section addresses acquired demyelinating neuropathies, monoclonal gammopathies, HIV neuropathy and familial amyloidosis. The final section concludes with a summary of neuropathies affecting pelvic function and a plastic surgeon’s approach to the treatment of compression and traumatic neuropathies. The authors who wrote these chapters have extensive expertise in these topics such that the literature review was comprehensive. The final chapter on the surgical treatment of compression neuropathies may be viewed as controversial by some and even heretical by others but it provides a unique perspective on the management of patients who are symptomatic and yet have relatively unremarkable clinical and electrodiagnostic investigations. The reader will find up to date information on a variety of topics; common and uncommon. This book attempts to educate as well as challenge the reader. (Imprint: Nova Biomedical)

Table of Contents: Preface Chapter 1. The Role of Clinical Neurophysiology in the Diagnosis of Peripheral Neuropathies (Elisabeth Chroni, Department of Neurology, University of Patras, Greece) Chapter 2. Role of Genetic Testing in Peripheral Neuropathy (Charles H. Whitaker, University of Connecticut Health Center Farmington, Connecticut, USA and others) Chapter 3. Hereditary Peripheral Neuropathies (Meriem Tazir, Mounia Bellatache and Sonia Nouioua, Service de Neurologie, CHU Mustapha Bacha, Algiers, Algeria, and others) Chapter 4. Guillain–Barré Syndrome (Akiyuki Hiraga, Masahiro Mori and Satoshi Kuwabara, Department of Neurology, Graduate School of Medicine, Chiba University, Japan) Chapter 5. Evolving Concepts in the Pathogenesis of Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) (Paolo Ripellino, Thomas Fleetwood, Roberto Cantello and Cristoforo Comi, Department of Translational Medicine, Section of Neurology and Interdisciplinary Research Centre of Autoimmune Diseases (IRCAD), Amedeo Avogadro University, Novara, Italy) Chapter 6. Chronic Inflammatory Demyelinating Polyneuropathy in Children: A Pediatric Neurologist's Perspective (Christian Ionita, Connecticut Children's Medical Center/University of Connecticut Health Center, Connecticut, USA) Chapter 7. Monoclonal Gammopathy of Undetermined Significance and Polyneuropathy (Kam Newman, Ihab El-Hemaidi, Jagar A. Jasem and Mojtaba Akhtari, Section of Transfusion Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA and others) Chapter 8. Peripheral Neuropathies in HIV Infection (Maurizio Osio, Caterina Nascimbene, Alessandra Vanotti and Cristoforo Comi, Neurology Department. University of Milan, "L. Sacco" Hospital, Milan, Italy and others) Chapter 9. Familial Amyloid Polyneuropathy (FAP): Clinical Features, Pathophysiology, and Treatment (Mª Teresa Tomás, Helena Santa-Clara, Élia Mateus and Estela Monteiro, Exercise and Health Laboratory, Interdisciplinary Center for the Study of Human Performance, Lisbon, Portugal and others) Chapter 10. Peripheral Neuropathy in Pelvic Floor Dysfunction (Consuelo Valles-Antuna and Jesus M. Fernandez-Gomez, Hospital Universitario Central de Asturias, Universidad de Oviedo, Spain) Chapter 11. The Surgical Treatment of Peripheral Neuropathies: A Plastic Surgeon’s Perspective (Sean Wolfort, Surgery Department, Florida State University, and University of Central Florida, Florida, USA) Index

		https://www.novapublishers.com/catalog/product_info.php?products_id=46986&osCsid=1e608f8a26aa73770b1f10f4ab284d91

VM202 Yet More Information About The Promising Gene Therapy For Neuropathy

Today's post from the always excellent sciencedaily.com (see link below) is another article about VM202 - (that unattractively-named, new non-viral gene therapy we've mentioned a couple of times in the last 2 weeks). The difference here is that it is relatively easy for the casual reader to understand and certainly seems to be something to start becoming cautiously excited about. Remember too, that just because the title includes the word 'diabetics' doesn't mean that it doesn't apply to most other forms of neuropathy too.

Neuropathy: Relief for diabetics with painful condition
Date:March 5, 2015 Source: Northwestern University 

Summary:

Those with painful diabetic neuropathy who received two low dose rounds of a non-viral gene therapy called VM202 had significant improvement of their pain that lasted for months, researchers report. "Right now there is no medication that can reverse neuropathy," the study's first author said. "Our goal is to develop a treatment. If we can show with more patients that this is a very real phenomenon, then we can show we have not only improved the symptoms of the disease, namely the pain, but we have actually improved function."

Walking barefoot on sand "felt like walking on glass" for Keith Wenckowski, who has lived with type-one diabetes for more than two decades.

One of the participants in a new Northwestern Medicine study who suffered from painful diabetic neuropathy (PDN), Wenckowski finally found relief from the constant foot pain that required him to wear shoes at all times, even to the beach.

The study found that those with PDN who received two low dose rounds of a non-viral gene therapy called VM202 had significant improvement of their pain that lasted for months.

"I can now go to a beach and walk on the sand without feeling like I am walking on glass," Wenckowski said.

The results of this phase two, double-blind, placebo-controlled study will be published March 5 in the journal Annals of Clinical and Translation Neurology.

Right now there is no treatment for this disease of the peripheral nerves that affects 20 to 25 percent of diabetics. Patients with the most extreme form of the disease feel intense pain with a slight graze or touch. The pain can interfere with daily activities, sleep, mood and can diminish quality of life.

"Those who received the therapy reported more than a 50 percent reduction in their symptoms and virtually no side effects," said Dr. Jack Kessler, lead author of the study. "Not only did it improve their pain, it also improved their ability to perceive a very, very light touch."

Kessler is the Ken and Ruth Davee Professor of Stem Cell Biology in the department of neurology and a professor in the department of pharmacology at Northwestern University Feinberg School of Medicine. He also is an attending physician at Northwestern Memorial Hospital.

VM202 contains human hepatocyte growth factor (HGF) gene. Growth factor is a naturally occurring protein in the body that acts on cells -- in this case nerve cells -- to keep them alive, healthy and functioning. Future study is needed to investigate if the therapy can actually regenerate damaged nerves, reversing the neuropathy.

Wenckowski had continuous numbness, but now, more than a year since he received the therapy, his symptoms have not returned. "I am hoping the effects I am feeling do not cease," he said.

Patients with painful diabetic neuropathy have abnormally high levels of glucose in their blood. These high levels of glucose can be toxic.

Damaged nerve cells send out abnormal signals, causing the patients to feel pain, usually in their lower limbs and fingertips. The condition can lead to injuries, chronic foot ulcers and even amputations.

Painkillers and other medications can alleviate symptoms, but those drugs often come with undesirable side effects.

"We are hoping that the treatment will increase the local production of hepatocyte growth factor to help regenerate nerves and grow new blood vessels and therefore reduce the pain," said Dr. Senda Ajroud-Driss, associate professor in neurology at Feinberg, an attending physician at Northwestern Memorial Hospital and an author of the study.

Eighty-four subjects with PDN completed this study. They went to a clinic twice in a two-week timespan for a series of injections into the back of their calf muscles and lower legs. Some received injections of a saline placebo, others a low dose of the therapy and others a higher dose.

"We found that the patients who received the low dose had a better reduction in pain than the people who received the high dose or the placebo," Ajroud-Driss said. "Side effects were limited to injection site reaction."

The subjects reported their pain symptoms to the researchers over the next nine months. At three months, patients in the low-dose group experienced a significant reduction in pain compared to the placebo group. The effect persisted at six and nine months in the low-dose group, the scientists said.

A future, much larger phase three study will soon be underway.

"Right now there is no medication that can reverse neuropathy," Kessler said. "Our goal is to develop a treatment. If we can show with more patients that this is a very real phenomenon, then we can show we have not only improved the symptoms of the disease, namely the pain, but we have actually improved function."

Story Source:

The above story is based on materials provided by Northwestern University. Note: Materials may be edited for content and length.

Journal Reference:
John A. Kessler, A. Gordon Smith, Bong-Soo Cha, Sung Hee Choi, James Wymer, Aziz Shaibani, Senda Ajroud-Driss. Double-blind, placebo-controlled study of HGF gene therapy in diabetic neuropathy. Annals of Clinical and Translational Neurology, 2015; DOI: 10.1002/acn3.186

http://www.sciencedaily.com/releases/2015/03/150305110534.htm

Everything You Want Or Need To Know About Small Fibre Neuropathy

Today's long post from ccjm.org (see link below) addresses small fibre neuropathy in some detail. Small fibre neuropathy is a diagnosis that many neuropathy patients receive but rarely understand and it's also a term that many other neuropathy patients hear, or read about and wonder if it applies to them too. Many parts of this article apply to all patients living with nerve damage (especially the parts about treatment) so it's worth reading even if you haven't been labelled with small fibre neuropathy. You'll learn so much more than you ever imagined by reading it but it may well raise many questions which apply to your own case - next step, a talk with the doctor or neurologist treating you, or doing more research yourself to explain some of the complexities you may encounter here, Don't be put off by the length - it'll fill in many of the gaps in your knowledge (and we all have them!)

Small fiber neuropathy: A burning problem 
CCJM 2009 May;76(5):297-305.
10.3949/ccjm.76a.08070
JINNY TAVEE, MD
Neuromuscular Disease Center, Neurological Institute, Cleveland Clinic

LAN ZHOU, MD, PhD
Director, Cleveland Clinic Cutaneous Nerve Laboratory, Neuromuscular Disease Center, Neurological Institute, Cleveland Clinic

ADDRESS: Lan Zhou, MD, PhD, Neuromuscular Disease Center, Neurological Institute, S90, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail zhoul2@ccf.org.

 In many cases of peripheral neuropathy, the impairment is mostly in small nerve fibers, and the clinic presentation consists of pain, burning, tingling, and numbness in a stocking-glove distribution.

ABSTRACT
 Small fiber neuropathy is increasingly being recognized as a major cause of painful burning sensations in the feet, especially in the elderly. Although strength remains preserved throughout the course of the disease, the pain and paresthesias are often disabling. Diabetes mellitus is the most common identifiable cause of small fiber neuropathy, and impaired oral glucose tolerance and individual components of the metabolic syndrome are often associated with it. Some cases, however, are idiopathic. Skin biopsy (with an evaluation of the density of intraepidermal nerve fibers) and tests of autonomic nerve function are useful for the diagnosis. Management involves controlling pain and identifying and aggressively treating the underlying cause.

KEY POINTS
Symptoms of small fiber neuropathy typically start with burning feet and numb toes.
Causes and associated conditions can be found in over 50% of cases. These include glucose dysmetabolism, connective tissue diseases, sarcoidosis, dysthyroidism, vitamin B12 deficiency, paraproteinemia, human immunodeficiency virus infection, celiac disease, neurotoxic drug exposure, and paraneoplastic syndrome.
Findings on routine nerve conduction studies and electromyography are typically normal in this disease.
Management includes aggressively identifying and treating the underlying cause, advising lifestyle modifications, and alleviating pain.

Medication Adherence and Long-Term CV Outcomes

An estimated 15 to 20 million people in the United States over age 40 have some type of peripheral neuropathy.1 In many, the impairment is purely or predominantly in small nerve fibers, and the clinical presentation consists of pain, burning, tingling, and numbness in a length-dependent or stocking-glove distribution. (“Length” refers to distance from the trunk; distal fibers are affected first.) Symptoms typically begin in the feet and slowly ascend to the distal legs, at which point the hands may also be affected (FIGURE 1).

In many of these patients, the findings on neurologic examination, nerve conduction studies, and electromyography are normal, although some may show signs of mild distal sensory loss on physical examination. The lack of objective findings on routine nerve conduction studies and electromyography may lead many physicians to attribute the symptoms to other disorders such as plantar fasciitis, vascular insufficiency, or degenerative lumbosacral spine disease.

The past 2 decades have seen the development of specialized tests that have greatly facilitated the diagnosis of small fiber neuropathy; these include skin biopsy to evaluate the density of nerve fibers in the epidermis and studies of autonomic nerve function. Common etiologies have been identified for small fiber neuropathy and can be specifically treated, which is critical for controlling progression of the disease. Pain management is becoming easier with more available options but is still quite challenging.





FIGURE 1. Symptoms are pain, burning, numbness,
and autonomic dysfunction (lack of sweating) in the
hands and feet in a stocking-glove distribution.
Strength is not affected. Tendon reflexes are normal,
as are nerve conduction studies.

WHAT IS SMALL FIBER NEUROPATHY?

Small fiber neuropathy is a disorder of the peripheral nerves that primarily or exclusively affects small somatic fibers, autonomic fibers, or both, resulting in sensory changes and autonomic dysfunction when both types are involved (FIGURE 2).2

Peripheral nerve fibers can be classified according to size, which correlates with the degree of myelination.
Large nerve fibers are heavily myelinated and include A-alpha fibers, which mediate motor strength, and A-beta fibers, which mediate vibratory and touch sensation.
Medium-sized fibers, known as A-gamma fibers, are also myelinated and carry information to muscle spindles.
Small fibers include myelinated A-delta fibers and unmyelinated C fibers, which innervate skin (somatic fibers) and involuntary muscles, including cardiac and smooth muscles (autonomic fibers). Together, they mediate pain, thermal sensation, and autonomic function.

Small fiber neuropathy results from selective impairment of small myelinated A-delta and unmyelinated C fibers.

Sensory symptoms: Pain, burning, tingling, numbness

Damage to or loss of small somatic nerve fibers results in pain, burning, tingling, or numbness that typically affects the limbs in a distal-toproximal gradient. In rare cases, small fiber neuropathy follows a non-length-dependent distribution in which symptoms may be manifested predominantly in the arms, face, or trunk.

Symptoms may be mild initially, with some patients complaining of vague discomfort in one or both feet similar to the sensation of a sock gathering at the end of a shoe. Others report a wooden quality in their feet, numbness in their toes, or a feeling as if they are walking on pebbles, sand, or golf balls. The most bothersome and fairly typical symptom is burning pain in the feet that extends proximally in a stocking-glove distribution and is often accompanied by stabbing or aching pains, electric shock-like or pins-and-needles sensations, or cramping of the feet and calves.

Symptoms are usually worse at night and often affect sleep. Some patients say that their feet have become so exquisitely tender that they cannot bear having the bed sheets touch them, and so they sleep with their feet uncovered. A small number of patients do not have pain but report a feeling of tightness and swelling in their feet (even though the feet appear normal).

Examination often reveals allodynia (perception of nonpainful stimuli as being painful), hyperalgesia (perception of painful stimuli as being more painful than expected), or reduced pinprick and thermal sensation in the affected area. Vibratory sensation can be mildly reduced at the toes. Motor strength, tendon reflexes, and proprioception, however, are preserved because they are functions of large nerve fibers.


FIGURE 2.

Autonomic symptoms

When autonomic fibers are affected, patients may experience dry eyes, dry mouth, orthostatic dizziness, constipation, bladder incontinence, sexual dysfunction, trouble sweating, or red or white skin discoloration.2 Examination may show orthostatic hypotension and skin changes. The skin over the affected area may appear atrophic, dry, shiny, discolored, or mildly edematous as the result of sudomotor and vasomotor abnormalities.

WHAT CAUSES SMALL FIBER NEUROPATHY?

Small fiber neuropathy has been associated with many medical conditions, including glucose dysmetabolism,3 connective tissue disease,4,5 dysthyroidism,6 vitamin B12 deficiency, paraproteinemia, human immunodeficiency virus (HIV) infection,7 hepatitis C virus infection, celiac disease,8 restless legs syndrome,9 neurotoxic drug exposure, hereditary diseases, and paraneoplastic syndrome. While most of these conditions cause a length-dependent small fiber neuropathy, others (Sjögren disease, celiac disease, and paraneoplastic syndrome) can cause a form of small fiber neuropathy that is not length-dependent.4,8,10

Diabetes and prediabetes

Glucose dysmetabolism, including diabetes and prediabetes with impaired oral glucose tolerance (a glucose level 140–199 mg/dL 2 hours after a 75-g oral dextrose load), is the most common identifiable associated condition, present in about one-third of patients with painful sensory neuropathy11 and in nearly half of those with otherwise idiopathic small fiber neuropathy.12–14

Research findings strongly suggest that even prediabetes is a risk factor for small fiber neuropathy, and that so-called “impaired glucose tolerance neuropathy” may represent the earliest stage of diabetic neuropathy. Several recent studies have found a high prevalence of impaired glucose tolerance in patients with sensory peripheral neuropathy,12–14 with a rate of up to 42% in cases initially thought to be idiopathic14 compared with 14% in the general population.15 Also, a dose-response relationship between the severity of hyperglycemia and the degree of neuropathy was demonstrated in one study, in which patients with impaired glucose tolerance more often had small fiber neuropathy, whereas those with diabetes more often had polyneuropathy involving both small and large fibers.14 And studies in animals and cell cultures have shown that intermittent hyperglycemia, which can be seen in patients with impaired glucose tolerance, caused sensory neuron and nerve fiber damage and increased spontaneous C-fiber firing, resulting in neuropathic pain.8,16,17

Metabolic syndrome

Insulin resistance with prediabetes and diabetes is a part of the metabolic syndrome, which also consists of hypertension, hyperlipidemia, and obesity. The individual components of the metabolic syndrome have been implicated as risk factors not only for cardiovascular and cerebrovascular disease but also for small fiber neuropathy.

One study in 548 patients with type 2 diabetes showed that those with the metabolic syndrome were twice as likely to have neuropathy as those without.18 Another study showed that in 1,200 patients with type 1 diabetes without neuropathy at baseline, hypertension, hyperlipidemia, and increased body mass index were each independently associated with a higher risk of developing neuropathy.19

A recent study of 219 patients with idiopathic distal symmetrical peripheral neuropathy and 175 diabetic patients without neuropathy found a higher prevalence of metabolic syndrome in patients with neuropathy than in normal populations. The prevalence of dyslipidemia (high levels of total and low-density lipoprotein cholesterol and triglycerides and low levels of high-density lipoprotein cholesterol), but not hypertension or obesity, was higher in patients with neuropathy than in patients with diabetes but no neuropathy.20 The findings linked dyslipidemia to neuropathy and showed the need for further studies of the potential pathogenic role of dyslipidemia in neuropathy.

Hereditary causes

Hereditary causes of small fiber neuropathy are rare and include Fabry disease, Tangier disease, hereditary sensory autonomic neuropathy, and hereditary amyloidosis.

HOW DO YOU EVALUATE PATIENTS WITH SUSPECTED SMALL FIBER NEUROPATHY?

A thorough history should be taken to obtain details regarding onset and features of neuropathy symptoms, exacerbating factors, and progression. It is also important to ascertain whether the patient has any associated conditions as mentioned above, a family history of neuropathy, risk factors for HIV or hepatitis C virus infection, or a history of neurotoxic drug exposure.

Clinical suspicion of small fiber neuropathy should be high if a patient presents with predominant small fiber symptoms and signs with preserved large fiber functions.

Nerve conduction studies and electromyography

For diagnostic testing, routine nerve conduction studies and electromyography assess the function of large nerve fibers only and are thus normal in small fiber neuropathy. These tests should still be ordered to rule out subclinical involvement of large fibers, which may affect the diagnostic evaluation, prognosis, and treatment plan. However, if the results of these tests are normal, specialized studies are needed to evaluate small fibers.

Although several tests are available to evaluate somatic and autonomic small fibers, the two that have the highest diagnostic efficiency for small fiber neuropathy and that are used most often are skin biopsy, to evaluate intraepidermal nerve fiber density, and quantitative sudomotor axon reflex testing (QSART), to assess sudomotor autonomic function.21–23

Skin biopsy

Skin biopsy is a minimally invasive procedure in which 3-mm-diameter punch biopsy specimens are taken from the distal leg, distal thigh, and proximal thigh of one lower limb. The procedure takes only 10 to 15 minutes.

Biopsy specimens are immunostained using an antibody against protein gene product 9.5, which is a panaxonal marker. Small nerve fibers in the epidermis are counted under a microscope, and intraepithelial nerve fiber densities are calculated and compared with established normative values. The diagnosis of small fiber neuropathy can be established if the intraepidermal nerve fiber density is lower than normal (FIGURE 1). Nerve fiber density may be normal in the early stage of small fiber neuropathy, but in this setting skin biopsy often shows abnormal morphologic changes in the small fibers, especially large swellings,24 and repeat biopsy in 6 to 12 months may be considered.

The diagnostic efficiency of skin biopsy is about 88%.21,23 For diagnosing small fiber neuropathy, it is more sensitive than quantitative sensory testing21,25 and more sensitive and less invasive than sural nerve biopsy.26 Intraepidermal nerve fiber density also correlates well with a variety of measures of severity of HIV distal sensory neuropathy and thus may be used to measure the severity and treatment response of small fiber neuropathy.27

Quantitative sudomotor axon reflex testing

QSART is an autonomic study that measures sweat output in response to acetylcholine, which reflects the function of postganglionic sympathetic unmyelinated sudomotor nerve fibers. Electrodes are placed on the arms and legs to record the volume of sweat produced by acetylcholine iontophoresis, in which a mild electrical stimulation on the skin allows acetylcholine to stimulate the sweat glands. The output is compared with normative values.

One prospective study showed that 67 (72.8%) of 92 patients with painful feet had abnormal results on QSART, ie, low sweat output.28 A retrospective study found that 77 (62%) of 125 patients with clinical features of distal small fiber neuropathy had a length-dependent pattern of QSART abnormalities.22 QSART abnormalities were detected in some patients without autonomic symptoms.

If these tests are not available

Skin biopsy and QSART are objective, reproducible, sensitive, and complementary in diagnosing small fiber neuropathy. One or both can be ordered, depending on whether the patient has somatic symptoms, autonomic symptoms, or both. However, these two tests are not widely available. Only a few laboratories in the country can process skin biopsy specimens to evaluate intraepidermal nerve fiber density. Nevertheless, it is easy to learn the skin punch biopsy procedure, and primary care physicians and neurologists can perform it after appropriate training. (A concern is avoiding damage to the epidermis.) They can then send specimens to one of the cutaneous nerve laboratories (but not to a routine reference laboratory).

A special technique, including unique fixative and cryoprotectant, is used to fix and process the biopsy specimens, because routine techniques for processing dermatologic punch biopsy specimens often result in lower intraepidermal nerve fiber densities. Therefore, it is very important to contact the laboratory regarding fixative and processing before performing a biopsy.

QSART requires specialized equipment and must be performed on site. In addition, the test is very sensitive to drugs that can affect sweating, such as antihistamines and antidepressants, and such drugs must be discontinued 48 hours before the study.

KEY POINTS
Symptoms of small fiber neuropathy typically start with burning feet and numb toes.
Causes and associated conditions can be found in over 50% of cases. These include glucose dysmetabolism, connective tissue diseases, sarcoidosis, dysthyroidism, vitamin B12 deficiency, paraproteinemia, human immunodeficiency virus infection, celiac disease, neurotoxic drug exposure, and paraneoplastic syndrome.
Findings on routine nerve conduction studies and electromyography are typically normal in this disease.
Management includes aggressively identifying and treating the underlying cause, advising lifestyle modifications, and alleviating pain.

Basic laboratory tests to find the cause

Once the diagnosis of small fiber neuropathy is established, the next important step is to order a battery of laboratory tests to search for an underlying cause. The tests should include the following:
Complete blood cell count
Comprehensive metabolic panel
Lipid panel
Erythrocyte sedimentation rate
Thyroid-stimulating hormone level
Free thyroxine (T4) level
Antinuclear antibody
Extractable nuclear antigens
Angiotensin-converting enzyme (ACE) level
Serum and urine immunofixation tests
Vitamin B12 level
2-hour oral glucose tolerance test.

Oral glucose tolerance testing is much more sensitive than measuring the hemoglobin A1c and fasting glucose levels in detecting diabetes and prediabetes. These two conditions were detected by oral glucose tolerance testing in more than 50% of patients with otherwise idiopathic sensory-predominant peripheral neuropathy and normal hemoglobin A1c and fasting glucose levels.13,14 Therefore, every patient with small fiber neuropathy without a known history of diabetes or prediabetes should have an oral glucose tolerance test.

Special laboratory tests in special cases
If there is a history of gastrointestinal symptoms or herpetiform-like rash, then testing for gliadin antibody and tissue transglutaminase antibodies as well as small-bowel biopsy may be pursued to evaluate for celiac sprue.
Serologic tests for HIV or hepatitis C should be ordered if the patient has risk factors.
If there is a significant family history, further genetic testing should be considered.
Lip biopsy or bone marrow biopsy should be considered if clinical suspicion is high for Sjögren disease, seronegative sicca syndrome, or amyloidosis.
The serum ACE level has a low sensitivity and specificity; therefore, if sarcoid is suspected clinically, additional confirmatory testing, such as computed tomography of the chest, should be ordered despite a normal ACE value.

HOW DO YOU TREAT SMALL FIBER NEUROPATHY?

Treatment of small fiber neuropathy should target the underlying cause and neuropathic pain. Cause-specific treatment is a key in preventing small fiber neuropathy or slowing its progression.

Glucose control, weight control, and regular exercise

As glucose dysmetabolism is the condition most often associated with small fiber neuropathy (and since individual components of the metabolic syndrome are potential risk factors for it), tight glycemic control and lifestyle modification with diet control, weight control, and regular exercise are of paramount importance in patients with these conditions.

The Diabetic Prevention Program,29 a study in 3,234 people with prediabetes, found that diet and exercise were more effective than metformin (Glucophage) in preventing full-blown diabetes. At an average of 2.8 years of follow-up, the incidence of diabetes was 11.0 cases per 100 patient-years in a group assigned to receive placebo, compared with 7.8 in those assigned to receive metformin (31% lower), and 4.8 (58% lower) in those who were assigned to undergo a lifestyle intervention that included at least 150 minutes of physical activity per week with a weight-loss goal of 7%. Put another way, to prevent one case of diabetes over 3 years, 6.9 patients would have to undergo the lifestyle intervention program, or 13.9 would have to receive metformin. Since impaired glucose tolerance neuropathy may represent the earliest stage of diabetic neuropathy, the neuropathy at this stage may be reversible with lifestyle intervention and improvement of impaired glucose tolerance.

This concept is supported by a 3-year study in 31 people, which showed that lifestyle intervention significantly improved impaired glucose tolerance, reduced the body mass index, and lowered total serum cholesterol levels.30 Changes in these metabolic variables were accompanied by significant improvement of neuropathy as evidenced by significantly increased intraepidermal nerve fiber density, increased foot sweat volume, and decreased neuropathic pain.30

Treatment of other diseases

It has also been reported that treatment of sarcoidosis, autoimmune diseases, and celiac disease improved the symptoms of small fiber neuropathy resulting from these conditions.8,31 Therefore, it is important to identify the cause and treat it to prevent and slow the progression of small fiber neuropathy, and doing so may improve the disease in some mild cases.

Pain management

Pain management is crucial in the treatment of small fiber neuropathy, as neuropathic pain can be debilitating and can cause depression. Pain management often requires a multidisciplinary team, including a primary care physician, a neurologist, a pain specialist, and a psychiatrist. Medications include antidepressants, anticonvulsants, and topical anesthetics (TABLE 1) as well as narcotic and non-narcotic analgesics and antiarrhythmics. Nonpharmacologic management includes transcutaneous electrical nerve stimulation (TENS), heat, ice, and massage of painful areas (reviewed by Chen et al32 and Galluzzi33).

First-line choices of pain medications are the anticonvulsants gabapentin (Neurontin) and pregabalin (Lyrica), the tricyclic antidepressants amitriptyline (Elavil) and nortriptyline (Aventyl), a 5% lidocaine patch (Lidoderm), and the semisynthetic opioid analgesic tramadol (Ultram). These can be used alone or in combination.

Gabapentin is relatively well tolerated, but drowsiness can occur, especially with high starting doses. We usually start with 300 mg daily and increase it by 300 mg every week up to 1,200 mg three times a day as tolerated. Most patients need 600 to 900 mg three times a day.

Pregabalin is a newer antiepileptic drug, similar to gabapentin but less sedating. It can be started at 75 mg twice a day and gradually increased to 300 mg twice a day as needed. Weight gain and, rarely, swelling of the lower extremities may limit the use of both of these drugs.

Tricyclic antidepressants, such as amitriptyline, nortriptyline, and desipramine (Norpramin), are proven effective in controlling neuropathic pain, although no response with amitriptyline was seen in patients with painful HIV distal sensory neuropathy.34

Lidocaine patch is preferred if the painful area is small. Patients should be instructed to use the patch to cover the painful area 12 hours on and 12 hours off. If it does not provide relief within 1 week, it should be discontinued.

Tramadol is also helpful in treating neuropathic pain. It can be started at 50 mg two to four times a day as needed.

Nonsteroidal anti-inflammatory drugs and selective serotonin reuptake inhibitors are typically less effective than the other drugs mentioned.

Opioids should be reserved for refractory cases, given the potential for addiction, but they are sometimes necessary in patients with disabling pain that does not respond to other drugs.

TENS may be of benefit. The patient controls a pocket-size device that sends electrical signals to leads placed on affected areas.

Alternative therapies for small fiber neuropathy, such as meditation, yoga, and acupuncture, have yet to be studied.

It is also important to explain to patients that the typical course of small fiber neuropathy is relatively benign, as many patients worry about developing weakness and eventually not being able to walk. These concerns and fears can aggravate pain and depression, which can make treatment difficult.




WHAT IS THE PROGNOSIS OF SMALL FIBER NEUROPATHY?

Most patients with small fiber neuropathy experience a slowly progressive course, with symptoms and signs spreading proximally over time.

In one study, only 13% of 124 patients with small fiber neuropathy showed evidence of large-fiber involvement over a 2-year period. 21 None went on to develop Charcot joints, foot ulcers, weakness, or sensory ataxia, as is often seen in patients with long-standing or severe large fiber neuropathy. Neuropathic pain worsened in 30% and resolved spontaneously in 11%.21

Most patients with small fiber neuropathy require chronic pain management. Again, treatment of the underlying cause is important and can improve the prognosis.

We believe that the overall progression of small fiber neuropathy is slow. A longitudinal study with a follow-up longer than 2 years would be useful to confirm this.

TAKE-HOME POINTS

As the population continues to age and as more patients develop diabetes and the metabolic syndrome, the prevalence of small fiber neuropathy will rise. Patients who present to their primary care physicians with painful, burning feet require a thorough diagnostic evaluation, which may include referral for specialized neurodiagnostic testing. Aggressive cause-specific treatment, lifestyle modification, and pain control are key elements of a team approach to managing small fiber neuropathy.

http://www.ccjm.org/past-issues/past-issue-single-view/small-fiber-neuropathy-a-burning-problem/2e6a5924d840eef79f213dd53bb68ccf.html

Arm Yourself With Facts About Neuropathy

Today's post from dressamed.com (see link below) is another why, what and how, article about neuropathy. You know there are now dozens of these articles here on this blog but every one is slightly different and every one has the potential to teach you something new about the nerve damage you're dealing with. I strongly advise looking through a few of these general articles about neuropathy (use the search button on the right of this blog) and by doing this you'll build up a much more reliable picture of what you're going through and learn so much more about neuropathy than a doctor can tell you in the time you have with them. This particular article is plainly written, easy to absorb and importantly factually correct, without bias. Not everything will apply to your particular case but that in itself is something you need to know about this complex and confusing condition. Take what you need to know and go to your next appointment armed with enough knowledge to save time in your discussions. Doctors love patients who have done their homework but hate those who have not done it properly and have found one piece of information that doesn't apply to them, while insisting it must be true. Dealing with neuropathy has to be a partnership to get the best results.

The 5 Whats and Hows of Peripheral Neuropathy 
Posted on May 11, 2016 Posted in Staff Pick by Staff Pick

What is peripheral neuropathy?

Peripheral neuropathy is a term which describes the damage done to peripheral nerves. This damage can be caused by more than 100 different known diseases. If only one nerve is involved it is called a mononeuropathy an example of which is carpal tunnel syndrome. If 2 or more nerves are involved in separate areas it is called a multiple mononeuropathy. This is usually the type of neuropathy meant when people say they have a peripheral neuropathy. If a spinal nerve root is involved it is called a radiculopathy such as sciatica from a herniated disc. If there is diffused involvement of the peripheral nerves it is called a polyneuropathy.

What is damaged in peripheral neuropathies?

The symptoms of peripheral neuropathy occur because the nerves are damaged in some way. This can occur at either the axon, which is “wire” from the nerve cell out to the body, or it can occur in the myelin sheath itself. The myelin sheath is like an insulator around the axon which acts to speed conduction of the nerve signal. For example, an axon with myelin connects like a broadband internet connection able to stream high definition video and an axon without myelin is like dial up service, slow with frequent interruptions. Myelin involvement often occurs in the setting of demyelinating diseases or some infections.

In addition to damaging the axon or myelin or both, peripheral neuropathy can also affect a variety of nerve types. Small nerves fibers are often damaged in diseases such as diabetes which leads to problems with pain, temperature, and sensation changes. Large nerve fibers are injured in such disease processes like Guillan-Barre syndrome which leads to profound muscle weakness. Nerve fibers that come directly from the brain, called cranial nerves, can also be injured by a variety of disease processes.

The type of symptoms you experience from peripheral neuropathy depend on the underlying cause and the type and location of the nerves damaged. For causes from metabolic disorders such as diabetes, the progession is usually slow and begins in the lower extremities. A change in sensation is often the first symptom people notice. This is worse at night. It progresses from there to involve decreases in the ability to sense temperature, vibration, and eventually leads to complete sensory loss. Oddly enough this is frequently accompanied by severe pain in the affected extremity which can be brought on by even minimal stimuli. At its ends stage, peripheral neuropathy can lead to skin breakdown, balance problems, and ultimately profound muscle weakness and wasting.
What are some of the definitions of medical terms used to describe peripheral neuropathy?

The follow is a list of common definitions:

Paresthesia: this is often described as numbness or tingling or the pins and needle type sensation.
Anesthesia: this is loss of all sensation, pain, temperature, touch. If you have this you could cut off your finger and not feel it at all.
Analgesia: this is loss of all painful sensation but you can still feel things such as touch and temperature.
Hyperesthesia: this is increased sensitivity to any kind of stimulus to the skin
Hypoesthesia: this is decreased sensitivity

How is peripheral neuropathy diagnosed?

The diagnosis of peripheral neuropathy includes an evaluation by a physician. This evaluation will include a history of your symptoms, a physical exam, and in some cases diagnostic testing.

The history of your symptoms will often lead to the diagnosis and can point to or pinpoint a cause. Important items will include when the symptoms started. Did they start suddenly or gradually or has it been a long slow process developing over an extended period of time. Is there just one episode or does it come and go. Other important factors include underlying medical disorders such as cancer, diabetes, kidney failure, dietary habits, trauma, employment exposures, and family history of a similar problem.

The physical exam helps to define the extent of the neuropathy and usually involves a head to toe evaluation with particular attention on the eye and neurologic portions of the exam. During this exam it is usually evident if you have a mononeuropathy or a polyneuropathy. After the history and physical exam diagnostic testing is often undertaken. There are three main classes of diagnostic tests used to aid in the diagnosis and treatment. These are laboratory studies, imaging studies, and nerve studies.

Laboratory studies will often include a complete blood count to look for signs of anemia, heavy metal poisoning, or cancer. Electrolytes, kidney function tests, and certain vitamin levels will often be checked to evaluated causes such as kidney failure, diabetes and other endocrine disorders, and nutritional deficiencies. In some cases screening tests for rare diseases such as porphyria or infections will also be done and at times may include a skin or nerve biopsy or a lumbar puncture (spinal tap).

Imaging studies may include but are not limited to CT scans and MRI of the affected area. MRI in particular can often tell, in the right context, if your symptoms are from nerve impingement or other structural disorder.

Finally, nerve conduction studies and electromyography(EMG) is often undertaken. In nerve conduction studies a probe is used to stimulate a nerve causing an electrical impulse to fire. The way in which this impulse is transmitted can often tell your doctor if it is the axon or the myelin that is damaged. With EMG electrical activity is measure with the muscle active and at rest. This can help distinguish between nerve and muscle injury.
What kind of treatments are available for peripheral neuropathy?

The approach to treating peripheral neuropathy can be broken down into three main areas.

First, correcting the underlying cause of the neuropathy is important. Peripheral nerves, to some extent can heal and regenerate, so if the cause is found early, and treatment is initiated then the disease process can be slowed, stopped, or sometimes even reversed. For example, while diabetes can cause peripheral neuropathy, early diagnosis with tight control of your blood sugar can prevent this complication from occurring and stop or even reverse it once it has started.

Second, it is important to create on optimal environment for healing within your body. This begins with adopting a healthy lifestyle. Sleep is essential for your body to heal itself and trying to get 8 hours of sleep a night is very important. Maintaining an optimal body weight through healthy diet and exercise is also necessary. Get rid of the junk that you eat focusing on fruits, vegetables, and whole grains while limiting processed and high fat foods. This is usually enough to correct any underlying nutritional deficiencies but you may also want to consider taking a multivitamin. Finally, limit or eliminate alcohol and definitely stop tobacco in any of its forms. 

Third, it is important to control the symptoms. The symptoms of peripheral neuropathy can be very difficult to control. Initial pain control with over the counter analgesics such as ibuprofen and acetaminophen is sometimes helpful but rarely sufficient. If pain is severe and chronic a variety of medications may be tried but there are no definitive guidelines give lack of evidence strongly favoring one treatment over another.

Tricyclic antidepressants. These medications are older antidepressants largely replaced now by the SSRI (selective serotonin reuptake inhibitors). An example is amitriptyline which has been shown to be of some benefit and is thought to work by affecting the way your nerves respond to pain. 

Antiepileptics. These are seizure medications such as phenytoin, carbamazepine, oxcarbazepine, lamictal, and topiramate. They have shown some benefit with the exception of topiramate. To some extent they work by blocking the ability of nerves to rapidly trigger and electrical response. 

Gabapentin. This drug is also a seizure medication but its mechanism of action is not definitively known. It is thought to help peripheral neuropathy by modulating pain signals in the the spinal cord. 

Tramadol: This is a pain medication which has been found to have some benefit beyond its ability to treat pain in helping with the symptoms of peripheral neuropathy. 

Lidocaine patches: Known also as lidoderm patches these are applied directly to the site of pain and help in select cases. 

Capsaicin: A topical preparation shown to have some benefit.

Surgical intervention: In extreme cases sometimes the nerve itself will be destroyed. This often only helps the pain for a brief period of time as peripheral nerves have an astounding ability to regenerate. Unfortunately, symptoms ultimately wind up worse then before the procedure. 

What does the future hold?

As with any disease prevention is always better then treatment. There are multiple ongoing investigations into the different ways in which the nerves are damaged. As these processes are identified it is hoped that additional treatment will be found. Other research areas include looking at how the body responds to pain from neuropathy and creating or finding treatments that will block this process at either the brain or in the spinal cord.

About The Author

Dr. N. McMullin M.D. uses plant extracts, infused oils, and essential oils to make neuropathol solutions for relief from peripheral neuropathy symptoms.

Syndicated by EzineArticles

https://www.dressamed.com/root/the-5-whats-and-how-of-peripheral-neuropathy/

Legal Arguments About Opioids

If you're taking opioids for your neuropathic pain, you may be interested in today's post from the trustworthy pain-topics.org (see link below). There is currently, in the USA, a great deal of controversy regarding prescribing and issuing opioids as pain killers. This is mainly due to the potential for their abuse. For further information on this issue, you can visit this article from The Body . The problem is that many patients with severe neuropathic pain may find their chemists and doctors being unable to issue them any more thanks to new legal requirements. This means that people who depend on their pain relieving qualities and are perfectly justified in taking them, may suffer because of a large underground abuse and addiction problem. More interesting articles on the same subject can be found on pain-topics.org, or by using the search facility to the right of this page.

Opioids on Trial – Part 2
Posted by SB. Leavitt, MA, PhD at 2/09/2013

This past week the U.S. Food and Drug Administration (FDA) held a hearing titled “Impact of Approved Drug Labeling on Chronic Opioid Therapy.” Ostensibly, the purpose was to obtain testimony on issues pertaining to the safe use of opioid drugs in treating chronic pain, but unofficially the meeting was a response to a petition last summer from PROP, or Physicians for Responsible Opioid Prescribing, requesting changes to the labeling of opioid analgesics. As much as anything, it seems that these pain relievers are on trial and the outcome judgments could severely impact the fates of all persons with pain in the United States and other parts of the world.

FDA Information Gathering

The public hearing on February 7-8, 2013, hosted by the FDA in Bethesda, Maryland, had the stated purpose of obtaining “information, particularly scientific evidence, such as study data or peer-reviewed analyses, on issues pertaining to the use of opioid drugs in the treatment of chronic pain. These issues include: diagnosis and understanding of patient pain, understanding and adhering to the labels of pain-treating products, limiting opioid prescriptions and use, and abuse and misuse of opioid medicines.”

It is widely assumed that the hearing was motivated by a citizen petition to the FDA last summer by PROP and the advocacy group, Public Citizen. What is generally referred to as the “PROP petition” has sparked heated debates among healthcare professionals and considerable fear among patients with pain.

The petition requests 3 changes by the FDA to opioid-product labeling: (1) strike the term “moderate” from the indication of opioid analgesics for noncancer pain (leaving “severe pain” as the only indication); (2) add a maximum daily opioid dose, equivalent to 100 milligrams of morphine for noncancer pain; and (3) add a maximum duration of 90 days for continuous (daily) opioid use for noncancer pain.

In response to the PROP petition, which had been posted at the U.S. Government Regulations website, there were 1,740 comments submitted as of February 5, 2013 (of which 688 were posted for public viewing). In fact, further comments may still be submitted by any interested persons to the docket (#FDA-2012-P-0818) until April 8, 2013 [access here].

The recent 2-day hearing was conducted by a 5-member panel of FDA officials under the leadership of Douglas Throckmorton, MD, deputy director of the FDA’s Center for Drug Evaluation and Research (CDER). The agenda listed 55 speakers who had registered in advance — anyone could request a time slot — and each was afforded 7 minutes for a presentation.

The FDA had stated that the hearing would be informal and the rules of evidence did not apply. Curiously, a number of speakers submitted audiovisual presentations of their testimony and were not physically present at the meeting, which was not stated as being permissible in the official notice of the hearing.

One presenter, a concerned parent, gave his own presentation and then also filled-in for several other parents who had time slots but did not appear at the meeting. During an open comment period at the end, two additional persons came forward. So, the FDA exhibited considerable flexibility in conducting the hearing and, surprisingly, few presentations required the full 7 minutes and the meetings ended early on both days. The agenda and webcast archives of the hearing presentations are available for viewing [here].

Opioids on Trial: Who has the Onus Probandi?

During the 2 days of testimony, there were fervent claims and pleas by patients, family members, advocates, healthcare providers, and researchers on both sides — for and against the PROP petition. It was obvious that this is a highly polarizing issue, with vastly different perspectives on the problems and disparate interpretations of the available scientific evidence.

Excellent first-hand observations and commentary regarding specific presentations on days 1 and 2 are available from Jeffrey Fudin, PharmD [here] and [here], and Kristina Fiore of MedPageToday [here] and [here].

All of the speakers expressed concerns about the problems of prescription opioid misuse, abuse, addiction, overdose, and deaths. Whether or not the changes requested in the PROP petition would resolve those problems, while assuring that persons with pain would still have access to much needed medication, was hotly contested.

Foremost among the more science-oriented presentations were disagreements over current best evidence for arriving at judgments regarding the necessity and validity of the recommended labeling changes. Along these lines, parallels of law and medicine, particularly when it comes to assessing evidence as proof in arriving at sound judgments affecting patient care, were discussed in a prior UPDATE [here].

In law, the burden of proof (onus probandi in Latin) refers to the obligation of a plaintiff or petitioner initiating an action or complaint to present evidence establishing their allegations or pleading at trial or a formal proceeding. This is adjudicated by a “trier of fact,” which may be a judge, jury, board of inquiry, or a select panel.

As for the PROP petition, the FDA is the trier of fact and the burden of proof rests foremost with the petitioners. There is no “defendant” in such cases, although, as noted above, it does seem here that opioids as a class of drugs have been put on trial. Also, there often is no “respondent” in petition cases, but a broad cross-section of advocates, healthcare providers, and concerned organizations came forward at the hearing (as well as in many submission to the docket) to contest the PROP petition.

A critical question is: Does the PROP petition satisfy the necessary onus probandi; that is, presenting sufficient evidence of adequate quality to serve as an acceptable level of proof favoring their requested opioid labeling changes?

The PROP petition initiative — led by Andrew Kolodny, MD, who is president of the organization — has been discussed and dissected in a previous UPDATE article [here] and Kolodny responded in a separate UPDATE [here]. The petition letter includes 9 points of evidence, which were critiqued in a Pain-Topics UPDATE by Bob Twillman, PhD [here].

Furthermore, the petition letter references 20 documents as evidence in support of the cosigners’ claims, and those citations are listed in Appendix A (see below). Most of that same evidence was referred to at the FDA hearing by various proponents of the petition in their presentations.

Much of the evidence has been critiqued in past UPDATES articles (as indicated after the respective citations below with links) and, for the most part, the evidence is of low-quality and questionable reliability or validity. Several of the evidence documents are secondary sources featuring the commentary or opinions of the respective authors or agencies, which probably would be considered in formal proceedings as being only hearsay evidence.

One recently-reported research study, introduced as evidence at the FDA hearing but not included in the petition itself, was a data-mining investigation from Canada that found an association of opioid analgesic dose and the risk of injurious automobile crashes among drivers taking those medications. However, as described in an UPDATE [here], there were significant limitations and biases in this study, and it provided only weak evidence that was largely unsupportive of the claimed increased risks of opioid therapy.

More could be said about some of the evidence cited in the petition that has not been previously critiqued in Pain-Topics UPDATES. As it is, PROP members no doubt would disagree with our unfavorable assessments of their evidence; however, the onus probandi is on them to demonstrate why and how their evidence is reliable and valid. Merely reiterating results and quoting data from government reports or articles in peer reviewed journals — with an assumption that those documents represent a suitable quality of evidence and should be uncritically accepted by the FDA and others as such — is presumptuous.

At best, the petition and its associated evidence raises “reasonable suspicion” that changes in opioid prescribing practices for chronic pain may be warranted, and some of the evidence suggests “probable cause” for further investigation. However, strictly from an evidence-based medicine perspective, the petition overall does not make a “clear and convincing” case to satisfy the burden of proof for accepting the requested labeling changes.

More Evidence to Consider

An important argument put forth by the PROP group — in their petition letter and in commentary at the FDA hearing — is that there is a lack of evidence supporting a favorable benefit-to-risk ratio for long-term opioid therapy in chronic noncancer pain. Similarly, one presenter at the hearing suggested that there is a lack of evidence that patients would suffer if there were less prescribing of opioids for chronic pain.

We have argued in various UPDATES that “an absence of evidence is not itself evidence” and that, if anything, further research is needed before passing judgment. However, we were wrong. There actually is much further research evidence available for consideration; but, of course, this was not included in the PROP petition or during the FDA hearing.

The 25 documents listed in Appendix B (below) present studies that examine opioid therapy of longer duration than the 90-day limit in the PROP petition. Many of the studies are prospective, randomized, controlled clinical trials of potentially reasonable quality. Various types of moderate-to-severe chronic noncancer pain are examined, using different opioid agents, and at widely-ranging doses.

Notices of these research studies have been variously submitted to the FDA docket and they merit closer examination and assessment from quality-of-evidence perspectives. Each has its limitations; however, at a minimum the studies generally suggest there is “some credible evidence” (as a level of proof) that at least subsets of patients with moderate or severe chronic noncancer pain may benefit from opioid analgesia during many months of treatment. And, these patients may experience prolonged significant pain relief with tolerable side effects, improvements in important quality of life measures, and modest needs for dose escalations, if any, over time.

The studies listed in Appendix B are probably not inclusive of all that may be available, and there is a need for more thorough systematic reviews and data meta-analyses of all the evidence. Several observations are worth noting…
In many of the studies, there often are sizable numbers of patients discontinuing opioid therapy. However, this seems to be a proverbial question of “is the glass half empty or half full?” During the FDA hearing, one presenter pointed to discontinuation rates as evidence of opioid inefficacy and adverse effects. Meanwhile, another speaker, looking at the same type of data, was impressed by the significant proportions of patients who do continue long-term on opioid therapy and find it of benefit for chronic noncancer pain. Same data — very different perspectives and interpretations.

While there have been anecdotal claims and small cases series of select patients with chronic pain who actually improve after discontinuation of long-term opioid therapy, there do not appear to be good quality studies involving substantial numbers of patients that broadly support this contention.

Also, there do not appear to be high-quality studies of extremely long-term opioid therapy for chronic noncancer pain, largely due to problems with followup over so many years. Yet, in 2010, there was a reported case series of 100 patients (ages 30-85 years, 61% male) who had been taking opioid medications for 10 to 35 years for a variety of noncancer pain conditions [see UPDATE here]. All had benefitted from this therapy and achieved better quality of life. Dosing in most patients remained stable during long periods of time and adverse effects were readily manageable medically. It must be conceded, however, that case series such as this are low-quality evidence, and further research is needed.

Challenges Ahead for FDA

It seems uncertain just how the FDA will proceed, but they no doubt face a daunting challenge ahead. As the trier of fact and adjudicating body the FDA must distinguish fact from hearsay opinion, separate science from pseudoscience, and distinguish poor-quality evidence from the good.

Clearly — based on the 2 days of hearings, the many submissions to the petition docket, and the abundance of other evidence — the problems surrounding opioid analgesics are serious, complex, and multifaceted. Action is needed, but there is great potential for doing harm rather than good.

The PROP petition has raised many important questions for consideration, along with some confusion and apprehension. In clarification of the petition’s intent, Kolodny suggested during the FDA hearing that the purpose is to prohibit drug companies from promoting long-term use of their opioid products for conditions where use has not been proven safe and effective. He stipulated that the petitioners are not claiming that long-term use of opioids for chronic pain or higher-dose opioids are always inappropriate, for all patients.

Furthermore, he affirmed that if the labeling changes are approved, practitioners still would be able to prescribe opioids “off-label” for any type of pain, at necessary doses, and for adequate periods of time. In fact, Kolodny suggested that “off-label” prescribing is often considered appropriate medical practice and even necessary in some cases, and that insurance carriers usually recognize this as such.

At the same time, others during the FDA hearing expressed concerns about the prudence of such practices. There were observations that off-label prescribing is discouraged in current medical education, and it would be a deterrent to conscientious practitioners who strive to rigorously adhere to rules as well as to those concerned about regulatory compliance and liability. And, off-label prescribing might be used by insurance carriers as justification for denying payment; an example of this already happening based merely on evidence in the unapproved petition was noted by one speaker.

Still, it seems that off-label opioid prescribing is the solution proposed by PROP for assuring adequate opioid availability for patients with chronic pain. Given that, an important question is: If the FDA were to approve the requested labeling changes in the PROP petition, would this also be a tacit and de facto endorsement by the FDA of off-label prescribing for meeting individual patient needs?

Rational, Balanced Solutions are Needed

A decision to accept or reject the PROP petition will leave one side or the other dissatisfied. However, the FDA may be in a position to propose balanced and rational compromise solutions that will address the important issues raised by the petition and help to assuage at least some of the current problems associated with opioid prescribing. For example,
It seems evident from the various presentations at the FDA hearing that more evidence-based understandings are needed regarding the concepts of opioid tolerance, hyperalgesia, withdrawal, dependence, addiction, drug interactions, and the pharmacogenomics of metabolism in different patients. Also, distinctions between cancer and noncancer pain, as well as moderate and severe pain need better clarification. The FDA could exert a leadership role in gathering the research and expert opinion necessary to further our understandings of those issues as they relate to safe and effective opioid prescribing for chronic pain.

Rather than changing labeling, the FDA does have the mechanism of “black box warnings,” which can be added to product information as necessary to highlight areas of particular concern, such as the need for prudent patient selection and monitoring, the necessity of periodic reevaluation for analgesic effectiveness and safety, and other concerns brought forward during the hearing and in comments to the docket. It seems that healthcare providers do attend to such warnings, even when they are less familiar with subtleties of product indications and many other details in the labeling.

Certainly, more and better prescriber education is needed, and the FDA mandated Risk Evaluation and Mitigation Strategies (REMS) for extended-release and long-acting opioid analgesics, as well as for select other opioid products, were an important step in that direction. Education programs and other actions associated with the REMS are just beginning to go into effect, so their impact is still undetermined. If necessary, the FDA has reserved the right to strengthen those efforts and, as many in the pain field have requested all along, the REMS could be extended to all opioid analgesics whether long- or short-acting.

Patient and public education on opioid safety are clearly inadequate, and effective approaches for minimizing fatal overdose risks are being neglected. FDA REMS initiatives stress the importance of patient education as a component of due diligence, but this often appears to be a secondary objective. Meanwhile, assertive and effective community-based programs like Project Lazarus [discussed in UPDATE here] have not gained nationwide traction, our own dedicated educational website for patients and caregivers — Opioids911-Safety [here] — has been underutilized, and the widespread distribution of the overdose antidote, naloxone, has been considered by the FDA and other government agencies, but has been languishing for unknown reasons.

These are but several possibilities for constructive action; others could no doubt be added to the list. Rather than adamantly pursuing their label-changing agenda, it might be more practical and beneficial if the PROP group were to partner with the FDA and the rest of the pain community to (a) gather better research evidence and objectively evaluate it, (b) develop appropriate protocols for identifying patients who would or would not benefit from opioid therapy for chronic pain, and (c) strengthen existing educational efforts and develop new programs as necessary.

As one speaker suggested during the FDA hearing, heading off in the wrong direction at this time could result in millions of patients getting hurt. And, that is not what PROP members or anyone else wants to happen.

http://updates.pain-topics.org/2013/02/opioids-on-trial-part-2.html

Useful Explanatory Video About Neuropathy Vid

Today's post and 15 minute video from askdrolsen.com (see link below) is a general explanatory post about neuropathy from the viewpoint of a chiropractor with special interest in neurology. It's a very useful video for people new to the disease or for family and friends of existing neuropathy patients. The information is accurate and simply explained and covers most of the questions people have. Worth a look for all people living with neuropathy.

Peripheral Neuropathy



Most people who suffer from peripheral neuropathy don’t have any idea what their full spectrum of treatment options are. Most believe that (a) they have to take medications that give some relief and have side effects or just don’t work or (b) that there isn’t anything else they can do. To start let’s get a big myth out-of-the-way – “only diabetics or multiple sclerosis sufferers get neuropathy”. There is a myriad of different causes of peripheral neuropathy.

Peripheral neuropathy is a problem with the nerves that carry information to and from the brain to the legs and feet. This produces pain, loss of feeling, and inability to control muscles. But already there’s a problem with this definition — just because you feel a symptom in your hands or feet doesn’t mean that’s where the problem is. This is a huge, gigantic misunderstanding and this is where diagnoses and treatment of most peripheral neuropathy goes wrong because peripheral neuropathy is in fact a complex web of neurological, hormonal, immune, and/or nutritional problems.
So with so many potential causes or combinations of causes of peripheral neuropathy it’s important that peripheral neuropathy sufferers explore them all as “one size diagnoses and treatment” does not fit them.

One of the most common causes of peripheral neuropathy is a functional disconnection syndrome affecting the parietal lobe of the brain. The right parietal lobe of the brain receives and processes all the signals that come from the nerves in your muscles and joints on both sides of your body. When the right parietal lobe is functioning properly you have normal sensation — no numbness, no tingling, no shooting pains. But if the parietal lobe starts to weaken or slow down then the signals don’t get processed correctly and you feel numbness, tingling and pain in both of your feet, and then months or years later in your hands. This is what happens when the functional disconnection syndrome occurs in the brain. Functional disconnection syndrome is an electrical imbalance in the frequency of firing between the two sides of the brain. The two parietal lobes should fire equally. When one starts to fire less frequently than the other (due to traumas, emotional stresses, inflammatory or toxic triggers) then neurons in the parietal lobe lose their firing “timing” and we get all sorts of symptoms like numbness, tingling, weakness, pins and needles, and pain — the symptoms of peripheral neuropathy.

Another major trigger of this condition is an autoimmune response against peripheral nerve tissue. Basically what happens is your immune system attacks and destroys nerve tissue. It can even attack brain tissue itself. These attacks can be triggered by food sensitivities, viruses, infections, high amounts of insulin (diabetics) and high amounts of inflammation. The immune system mistakenly destroys nerve tissue and causes all of the symptoms of peripheral neuropathy whether attacking brain or peripheral nerve tissue.

So to properly assess and treat peripheral neuropathy each system of the body must be reviewed and evaluated. Triggers must be eliminated and problems and imbalances in the hormonal, G.I. and immune systems must be corrected, also the various imbalances unique to the individual need to be addressed with a coordinated, non-drug approach all at the same time. If this is not done the sufferer often will spend months and years going from practitioner to practitioner evaluating the various above-mentioned “pieces of the puzzle” one at a time. Although the patient may occasionally “luck out” by accidentally addressing the correct cause this dis-organized approach to a problem as complex as peripheral neuropathy is usually doomed to fail and is the reason why medications and surgery yield poor long-term results when utilized as treatment options for the peripheral neuropathy patient.

http://www.askdrolsen.com/conditions-we-have-treated

More Information About Fibromyalgia Vid

Another short video from beatingneuropathy.tv (see link below) today, adds a little more information to Monday's post about lidocaine treatment for fibromyalgia. It may also be worth your while following up on Dr Hayes' suggestion to listen to his radio broadcast about fibromyalgia (link in the video).

Episode 28 – More on Fibromyalgia
Posted by John Hayes Jr Thursday, October 3rd, 2013

Dr. Hayes discusses fibromyalgia, its connection to neuropathy, and what its sufferers can do to take back their health.



http://beatingneuropathy.tv/2013/10/episode-29/

More About The Dangers Of Fluoroquinolones For Neuropathy Patients

Today's important post from peoplespharmacy.com (see link below) takes a fresh look at the current controversy about the antibiotics known as fluoroquinolones. These drugs have been on the market and prescribed for decades which begs the question as to why we weren't warned about the potential for nerve damage and the worsening of neuropathic symptoms earlier. It is entirely possible that your doctor or specialist may prescribe these antibiotics for a particular problem without being aware that they can cause severe nerve damage, In that case, always check the bottle or box or pamphlet for the words '...floxacin' or '...quinolone' in the name of the drug. It can be hidden; Ciprofloxacin for instance can often be called Ciproxin on the label. If you discover that your antibiotic is in fact from the fluoroquinolone family, go straight back to your doctor, discuss it and if necessary, ask for an alternative (there are plenty available). This article is definitely worth reading.

Could Your Antibiotic Cause You Permanent Nerve Damage?
October 7, 2013 in People's Pharmacy Alerts 
 
Did you know that the FDA has issued a safety notification about a class of popular antibiotics called fluoroquinolones (FQs)? The announcement involves the following drugs: 

Ciprofloxacin (Cipro)
Gemifloxacin (Factive)
Levofloxacin (Levaquin)
Moxifloxacin (Avelox)
Norfloxacin (Noroxin)
Ofloxacin (Floxin)

According to the FDA, over 21 million people get a prescription for one of these drugs each year. That makes this class of antibiotics among the most popular in the pharmacy. Doctors love to prescribe FQs because they are effective for a wide range of infections including bronchitis, pneumonia, sinusitis, urinary tract infections, prostatitis and skin infections.

These drugs have been around for decades. Cipro, for example, has been on the market for over 25 years. After all this time, one would think that the FDA would have a clear understanding of the benefits and risks of such drugs. In fact, you might assume that doctors would have been warned about complications of FQ drugs like Levaquin or Cipro from the very beginning. Au contraire. It comes as a great shock to patients to discover that serious fluoroquinolone warnings continue to be issued, decades after these drugs were originally approved.

The most recent FDA announcement relates to nerve damage, aka peripheral neuropathy. Here is the official safety communication issued on 8-15-2013:

"This serious nerve damage potentially caused by fluoroquinolones may occur soon after these drugs are taken and may be permanent... Peripheral neuropathy is a nerve disorder occurring in the arms or legs. Symptoms include pain, burning, tingling, numbness, weakness, or a change in sensation to light touch, pain or temperature, or the sense of body position. It can occur at any time during treatment with fluoroquinolones and can last for months to years after the drug is stopped or be permanent. Patients using fluoroquinolones who develop any symptoms of peripheral neuropathy should tell their health care professionals right away."

In other words, patients can experience this potentially irreversible nerve damage within days of starting drugs like ciprofloxacin or levofloxacin. Even if the drugs are stopped promptly, the side effects can last.

Doctors and pharmacists may not always describe the symptoms patients need to watch out for. And people may not associate weakness, numbness or tingling with an antibiotic, since it doesn't seem logical that a medicine designed to overcome an infection would damage nerves. Such symptoms may not seem that bad, but in some cases peripheral neuropathy can be permanently disabling.

OTHER KINDS OF NERVE DAMAGE

We first became aware of unusual problems brought on by fluoroquinolone antibiotics in July of 1994 after receiving this question:

"I often have side effects from medicines, but have never experienced anything like Floxin. I took it for a severe sinus infection followed by pneumonia last winter. After three days of utter misery and a rash on my back, I started hallucinating. Are there other people who have had a bad reaction to this antibiotic?"

We had to do some digging, but we finally discovered that FQs can cause "hallucinations, visual disturbances confusion, dizziness and seizures."

We talked to journalist Stephen Fried about his wife's experience with Floxin. In the book Bitter Pills, the Frieds describe how one Floxin pill for a urinary tract infection led to debilitating neurological symptoms that lasted for years.

At the time, a lot of doctors didn't believe such long-lasting neurological complications could happen so quickly. It has taken the FDA over 25 years to alert physicians to just such a possibility.

The same can be said about tendinitis or tendon rupture. This is another very serious adverse reaction triggered by FQ antibiotics. The first published report of an Achilles tendon problem appeared in 1983. Thereafter there were many case reports linking drugs like ciprofloxacin and levofloxacin to tendinitis and tendon rupture. These can also be disabling complications of FQ antibiotics. It took the FDA until 2008 to issue "black box" warnings about this problem, 20 years after Cipro was first introduced.

FLUOROQUINOLONE SIDE EFFECTS; COMPLICATIONS: 

Digestive distress, nausea, diarrhea, constipation, stomach pain, heartburn, vomiting
Headache, dizziness
Agitation, anxiety, irritability, restlessness, confusion
Insomnia
Tendon problems, tendinitis, tendon rupture
Retinal detachment
Nerve damage, peripheral neuropathy, nerve tingling, numbness
Allergic reactions, skin rash, anaphylaxis (life-threatening reaction requiring immediate medical attention!)
Super-infections including C. diff diarrhea
Hallucinations, psychosis, seizures
Depression, suicidal thoughts or actions
Irregular heart rhythms, torsades de pointes, QT prolongation
Kidney or liver damage
Blood disorders
Arthritis, muscle pain, weakness

READER REACTIONS:

Here are some stories from visitors to our website. Add your own FQ experience below. If these antibiotics have worked well for you without side effects we would like to hear about that. If you have suffered, we would like to see your story as well. Please comment below.

"I have taken Cipro a number of times over the years and wondered why my tendons, especially the Achilles tendon, were so inflamed. Finally read the side effects and saw it can be a serious side effect to the point of bursting the Achilles tendon. I carry a note with my insurance card in my wallet warning not to give me any of this family of antibiotics." C.G.

"It's been eight months and I've been to two specialists trying to determine if I have arthritis. They say I do not. I took Cipro and Levaquin within a one month period and it has been eight months since then, and I have pain and stiffness EVERY DAY. What started out as plantar fasciitis and wrist tendinitis then moved into my hips and elbows and is now in my upper back and shoulders.

"I ran a low grade fever for 6 months after taking these drugs. The symptoms started within two days of taking the last dose of Levaquin. I have not even addressed the fatigue, irritability and mood changes I experienced during the first three months after taking the drug. I was healthy, active and exercised regularly. Now I don't know what to do--stretching generally aggravates my pain. How can the FDA allow this drug to be prescribed?" Augsdi

"In 2000 I had an adverse reaction to Cipro: inflammation of most of my connective tissue to the point of needing help to get up out of bed or get dressed. I was unable to lift much and could not sit for more than 15 minutes due to the pain. My doctors could not believe it was the Cipro. It was 5 years before I was able to hike and ride my bike again." Jo

"The quinolone drugs, Cipro, Levaquin, Avelox, etc. are extremely strong and dangerous. When they go awry the adverse effects are serious, long term and often permanent.

"The awareness in the medical community of these dangers is extremely poor and often the concerns of patients suffering from adverse effects of these drugs are dismissed as 'not possible,' despite studies and literature citing these very effects i.e. neuropathy, tendon ruptures, neuromuscular damage, cartilage damage and others.

"I struggle to heal from 5 days of Cipro given a year ago and have met hundreds of people now who are going through similar struggles due to quinolone antibiotics. These drugs, though tolerated by many, should only be dispensed when there is no safer alternative due to the severity and permanence of adverse effects." Tao

http://www.peoplespharmacy.com/2013/10/07/popular-quinolone-antibiotics-can-cause-permanent-nerve-damage/

Some Good Advice About Neuropathy

Today's post from kiich.sharedby.co (see link below) is very useful and well-written information about neuropathy from a physical therapist, responding to discussions with one of his patients. His advice is spot on and the information he provides can be understood by everybody (in contrast to many neuropathy information sites). From someone new to neuropathy, to experienced patients who have suffered for years, a few minutes reading this will not be time wasted.

Are you suffering from peripheral neuropathy?
By Bob Cairo Special to the Coastal Point Date Published: March 20, 2015

A few weeks ago, a patient told me he wanted me to write an article about diabetic neuropathy. As I was thinking about it, it occurred to me that there are so many kinds of peripheral neuropathy that I wanted to make sure I help all of you who are struggling with it or might be soon.

It’s complicated, it’s painful and it can change your life in dramatic ways. Are you experiencing sharp or stabbing pain in your knees and ankles? Do your calves ache or are your feet numb? Do your legs feel like they are on fire?

Pain in our lower extremities is a very common issue, especially as we age. But, if you haven’t taken a fall, twisted a knee or done something that would easily identify exactly what’s causing your problem, you may be suffering from peripheral neuropathy. Understanding what it is and what you need to do if you or a loved one is diagnosed with peripheral neuropathy could have a lifelong impact on mobility and quality of life.

We all understand that our nervous system controls the proper function of every system in our bodies. The peripheral nervous system involves the nerves that lead from our brain and spinal cord to the rest of our body. When one of these nerves becomes diseased or damaged from a trauma or even repetitive stress, it’s called peripheral neuropathy.

Some 2 to 3 million Americans are struggling with a type of peripheral neuropathy. This is a problem that doesn’t discriminate in gender or age, but it’s particularly common in people older than 55. If you are a diabetic and you aren’t doing all that you should to control it, you are a high-risk candidate.

Because there are so many potential problems, I’m going to focus on the lower extremities, because that is one of the most common areas of impact.

It’s tricky to diagnose peripheral neuropathy, because there are so many potential causes, and doctors will tell you that not all the causes are known. We know that more than 50 percent of diabetics experience at least one type of neuropathy, and feet and legs are one of the biggest areas of impact.

We also know that some viruses and bacteria will attack the nerves. We know that alcoholism, vitamin deficiencies, traumas, some autoimmune diseases, infections and even tumors, whether benign or malignant, can be among the many potential causes.

People who are afflicted with a peripheral neuropathy in their lower extremities often talk about burning and sharp or stabbing pain. In many cases, there’s a tingling sensation. Sometimes, numbness and tingling comes on gradually in the feet and will spread to the legs.

Many people talk about the terrible discomfort associated with a simple touch, and some people lose feeling all together. Others lose coordination and start having a problem with falling, as a result. Muscle weakness is another potential symptom.

If you start to experience pain, weakness, tingling or any of the symptoms we were just talking about in your legs, knees, calves, ankles or feet, see a doctor immediately. Waiting to get help can be a terrible, costly decision, because the sooner you are diagnosed and treatment begins, the better your chances of getting those symptoms under control and stopping any additional damage occurring.

It’s a good idea to prepare for your doctor’s appointment by remembering to bring a list of all your medications with you and include any vitamins and supplements you might be taking.

It often helps to write down your symptoms and make sure you include any problems you might be experiencing. A problem that might seem unrelated to a symptom you are experiencing could actually be directly related. I’m sure you’ve heard this before, but it’s always better to write down your questions and leave some blank space to write down information your doctor is giving you as it happens. It can be so hard to remember everything that is said later on.

I also suggest you bring someone with you. There’s something to that old saying that two heads are better than one. You might miss something that is said, and having a second listener can be very helpful to keep all that information straight.

You can expect that your doctor will conduct a thorough examination and will likely perform some tests to determine the cause of your problem. If it’s peripheral neuropathy, your doctor may refer you to a neurologist. Your doctor will be looking to determine the cause of your neuropathy, the type of nerve problems and what damage has already taken place.

Clearly, the type of treatment you receive depends on the problem that’s causing the neuropathy. In some cases, medications may help.

For problems such as muscle weakness, you will likely be sent to a physical therapist to help you expand your range of motion and build muscle strength. Your doctor may also ask your physical therapist to work with you on building an exercise program to help with pain management and, in the case of diabetes, to help control your blood sugar.

If you are diabetic, make sure you are checking your feet regularly for any signs of trouble and regularly monitor your blood glucose levels. Don’t be surprised if your doctor makes other recommendations about your diet and suggests some actions you take at home to manage your peripheral neuropathy.

One final thought: If you or a loved one has been diagnosed with peripheral neuropathy, make it your job to learn everything you can about your particular condition. It’s important to be an active participant in your care plan. You want to be armed with the information you need to make informed decisions about your treatment as you work with your care team of professionals to get the best possible outcome.

Bob Cairo is a licensed physical therapist at Tidewater Physical Therapy. He can be reached by calling (302) 537-7260. 

http://kiich.sharedby.co/de4d996b4c7488eb/?web=9dbef0&dst=http%3A//www.coastalpoint.com/content/are_you_suffering_peripheral_neuropathy_03_20_2015