Anti Epileptics For Neuropathy An Australian View

Today's post from nps.org.au (see link below) is a very interesting look at the workings of anti-epileptic drugs in the treatment of neuropathy. It's always interesting to look at how different countries approach the treatment of chronic pain and/or neuropathy. In Australia, it's generally recommended that neuropathy patients are treated with a progressive scale of treatments, beginning with non-drug options and moving on, if necessary, via anti-depressants and anti-epilepsy drugs to opiates. This ties into a general world-wide approach to the disease but the article agrees that neuropathy is hard to treat, whatever you use to control the symptoms. Regarding anti-epileptic drugs, it concludes that the only two that are effective (however limited) are gabapentin and pregabalin. However, once again, this ignores Pfizer's own advice that pregabalin (Lyrica) is not suitable for particular groups of neuropathy sufferers (HIV- and diabetic neuropathy patients for instance) and it does seem strange that that advice from the makers is being overlooked across the world. This may partly be due to that fact that doctors see some successes with neuropathy patients being treated with Pregabalin but that doesn't take into account whether the drug is actually good for you or not. Whatever the issues around pregabalin, this is an interesting article for those already on anti-epileptics, or about to begin using them.

Treating neuropathic pain with anticonvulsants — which ones work?
Published in Health News and Evidence Date published: 10 January 2014

Summary
 
Neuropathic pain is a common form of chronic pain, with an array of drugs available for its treatment, including anticonvulsants.

A recent Cochrane review assessed the evidence around efficacy and safety for 10 anticonvulsant drugs used to treat neuropathic pain and found evidence of efficacy for only 2 — gabapentin and pregabalin.
The study provides support for the use of pregabalin and gabapentin in treatment of neuropathic pain, but was not able to distinguish between the 2 drugs in terms of efficacy for the treatment of painful diabetic neuropathy or postherpetic neuralgia. Nor was the study able to identify patients most likely to benefit from treatment with either drug.
Gabapentin and pregabalin are TGA-approved in Australia for the treatment of neuropathic pain. Currently, pregabalin is PBS subsidised when prescribed for neuropathic pain, and gabapentin is subsidised for this indication only under the RPBS. 

Practice points
Use a comprehensive clinical assessment to determine the cause of pain, its nature and severity, and the effect of the pain on the patient.1
Provide each patient with an individual management plan based on this assessment.1
Use a multidisciplinary approach to management that includes patients in decision making, and consider non-drug treatments first.1,2
Consider the TCA amitriptyline as first line if drug treatment is required.3
Consider next an anticonvulsant such as pregabalin or gabapentin if first line is unsuccessful.3
Conduct early and regular clinical reviews of patients on drug treatment.4
Refer patients whose pain relief is inadequate to a pain specialist, a multidisciplinary pain clinic or a palliative care service.3,5
Chronic pain in Australia

Chronic pain affects 1 in 5 Australian adults,6,7 with incidence increasing with age. Much of the burden of patient management falls on general practitioners.1

Chronic pain is Australia's third most costly health condition after cardiovascular diseases and musculoskeletal conditions.8 The total cost of chronic pain to the Australian economy was reported to be $34 billion in 2007, including $7 billion in health system costs.8

Neuropathic pain

Neuropathic pain is a form of chronic pain, and is difficult to treat effectively.3

Neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory system9 and is usually described as burning, painful, cold or electric shocks. These symptoms may occur alongside tingling, pins and needles, numbness or itching.3,10

Causes include nerve damage, which can be followed by changes to the central nervous system.11 This condition can present for months or years, causing significant, disabling, moderate to severe pain.11
Neuropathic pain: Australian guidelines

Australian guidelines recommend that patients with chronic pain, such as neuropathic pain, have an individualised management plan. This plan should be linked to a comprehensive patient assessment to determine the cause of pain, its nature and severity as well as the effect of the pain on the patient.1

There is no generally accepted 'stepwise' approach to treatment of neuropathic pain. Australian guidelines recommend non-drug approaches first.1,5 Many drugs are available for the treatment of neuropathic pain, with TCAs and anticonvulsants the drugs of choice.3,5 However, comparative studies are limited, there is no evidence for differences in the relative efficacies of individual drugs5,11 and these treatments are often associated with adverse events.

Guidelines recommend starting drug therapy for neuropathic pain with a TCA (such as amitriptyline) or an anticonvulsant.3,5 The anticonvulsants gabapentin and pregabalin are recommended by Therapeutic Guidelines as a second-line treatment of neuropathic pain after the TCA amitriptyline.3 The dose of the drugs can be escalated at weekly intervals if tolerated, but it may take several weeks to achieve clinical efficacy.

*TCAs are an established treatment for neuropathic pain but are not approved by the TGA for this indication.
Efficacy and safety of anticonvulsant drugs for neuropathic pain: Cochrane review

The Cochrane Collaboration recently reviewed the efficacy and safety of 10 anticonvulsant drugs for the treatment of neuropathic pain and fibromyalgia.11 This was not a new systematic review of individual studies,11 but compiled data from the 10 previous Cochrane reviews published between 2009 and 201312-21 and comprising 17,955 participants (with at least moderate pain) from 91 studies.11-21

These studies were placebo controlled, double blind, randomised controlled trials. Results were presented for each different drug for 3 different neuropathic pain conditions — painful diabetic neuropathy, postherpetic neuralgia and central neuropathic pain — and for fibromyalgia. This article will focus on the findings related to neuropathic pain.

Evidence of pain reduction for gabapentin and pregabalin only

This Cochrane review reported on efficacy as well as patient impression of improvement, and investigated outcomes including patient-reported pain relief of 50% or more and Patient Global Impression of Change (PGIC).11 Results were reported in terms of whether patients were more likely to achieve the benefit with the treatment than by taking placebo.11

A reduction in pain intensity of 50% or more is considered to be a clinically relevant benefit.3

The Patient Global Impression of Change (PGIC) is a measure of global improvement with treatment where participants rate their improvement from 'very much improved' to 'very much worse' with 'no change' as the mid-point.22

Among the 10 anticonvulsants studied, evidence of pain reduction was only found for gabapentin and pregabalin.11 People taking either of these drugs were more likely to report pain relief of 50% or more for painful diabetic neuropathy and postherpetic neuralgia than those taking placebo†.11 People taking pregabalin for the treatment of central neuropathic pain were also more likely (compared to placebo) to report pain relief of 50% or more†.11

The number of patients who would need to be treated with pregabalin or gabapentin for one patient to see this improvement was estimated to range from 4 to 10 for >=50% reduction in pain.11 Therapeutic Guidelines advises that for pain treatment to be considered to be effective, the number needed to treat for one person to achieve an outcome should be between 2 and 5.3
Further findings

The Cochrane review also found that people taking gabapentin for painful diabetic neuropathy or postherpetic neuralgia were more likely to rate their improvement as 'excellent' or 'very good or excellent' than those people taking placebo*.11

People taking lacosamide or pregabalin for painful diabetic neuropathy were more likely to rate their improvement as 'very good or excellent' than those people taking placebo*.11 The data suggest that the benefit with pregabalin may be dose dependent, as a benefit was seen with the 600mg/day dose but not the 300mg/day dose. Data for other drugs was not presented.11
*These results were statistically significant. The rating of improvement by patients was determined using the PGIC.

Carbamazepine: an accepted treatment for neuropathic pain but insufficient evidence of effect

Carbamazepine is an accepted treatment in Australia for neuropathic pain but is not TGA-approved for this indication.5

This Cochrane review found that evidence of efficacy for carbamazepine was of low quality and consequently likely to be subject to a number of biases that would overestimate efficacy.11 Most studies with carbamazepine were less than 4 weeks' duration, in contrast to studies with other drugs that were of 10-12 weeks or longer.11
Safety

The risk of adverse events in people taking anticonvulsant drugs is high, with CNS adverse events relatively common and often dose dependent, particularly for pregabalin and lacosamide.11 In this Cochrane review, available data showed that only oxcarbazepine statistically significantly increased the risk of a serious adverse event in people taking anticonvulsants for either neuropathic pain or fibromyalgia compared to those taking placebo.11

Limitations of the study

This Cochrane review benefits from, and is also limited by, the fact that the data are taken solely from previous Cochrane reviews. While this ensures that each study included is of a comparative and high standard, it also means that some trials would have been omitted.11 For example, levetiracetam does not feature in a Cochrane review and therefore was not assessed in this study, although it has been tested in other randomised controlled trials.11
Conclusions: pregabalin and gabapentin are the preferred anticonvulsants

While all evidence considered in this Cochrane review was described as 'second tier' or lower due to the potential for biases to overestimate efficacy, the results provide support for current Australian guidelines.3
Treatment best practice and implications for patients
Assess the nature of the pain experience and inform people of realistic outcomes with treatment.23,24
Provide each patient with an individualised management plan based on a comprehensive clinical assessment of their pain.1
The primary treatment goal in most cases is to make the pain tolerable — not usually to eliminate the pain.23
Aim for medium-term drug therapy with a drug holiday after 6 months. Patients who relapse during a drug holiday can resume treatment.
Conduct early and regular clinical reviews.

This Cochrane review supports the use of pregabalin and gabapentin as part of a management plan for neuropathic pain, but is not able to distinguish between their efficacies for treatment of painful diabetic neuropathy or postherpetic neuralgia. Drug therapy is best used as part of a multifaceted, multidisciplinary, active self-management approach to the physical, psychological, social and vocational impacts of neuropathic pain.2

Analgesic failure is common in the treatment of neuropathic pain and there is currently no evidence to inform which patients are most likely to benefit from what drugs and indeed the order in which drugs should be taken to optimise outcomes.11 However, patients who do not respond to one drug may respond to another, even within the same drug class.5 Combination drug therapy may be needed by many patients.24,25 A specific combination of treatments cannot be recommended due to the limited number of studies for any combination therapy, as well as other study factors, such as the limited trial size and duration.25

More information is available from NSW Health.

Refractory, severe neuropathic pain

Assistance from a pain specialist and a multidisciplinary pain service may be required for refractory, severe neuropathic pain, as treatment options are complex.2
Further information
Pregabalin (Lyrica) for neuropathic pain (NPS Medicinewise RADAR: April 2013).26
Information for patients

Patient information leaflet: Key points for patients about chronic pain (Therapeutic Guidelines).

References

1. eTG complete [Internet]. Therapeutic Guidelines: Analgesic. Melbourne: 2012. [Online] (accessed 19 December 2013).
2. Australian Pain Society. Evidence-based recommendations for the pharmacological management of neuropathic pain. Position Statement, June 2008. [Online] (accessed 20 October 2012)
3. eTG complete [Internet]. Therapeutic Guidelines: Neurology. Melbourne: 2011. [Online] (accessed 19 December 2013).
4. National Institute for Clinical Excellence (Nice). Neuropathic Pain: The pharmacological management of neuropathic pain in adults in non-specialist settings. NICE Clinical Guideline 173. Manchester: National Institute for Clinical Excellence, 2013. [Full text]
5. Rossi S e. Australian Medicines Handbook, 2013. Adelaide.
6. Hogg MN, Gibson S, Helou A, et al. Waiting in pain: a systematic investigation into the provision of persistent pain services in Australia. Med J Aust 2012;196:386-90. [PubMed]
7. Blyth FM, March LM, Brnabic AJ, et al. Chronic pain in Australia: a prevalence study. Pain 2001;89:127-34. [PubMed]
8. Access Economics Pty  Ltd. The high price of pain: the economic  impact of persistent pain in Australia. Sydney Deloite Access Economics, 2007 [Full text]
9. Jensen TS, Baron R, Haanpaa M, et al. A new definition of neuropathic pain. Pain 2011;152:2204-5. [PubMed]
10. Votrubec M, Thong I. Neuropathic pain — a management update. Aust Fam Physician 2013;42:92-7. [PubMed]
11. Wiffen PJ, Derry S, Moore RA, et al. Antiepileptic drugs for neuropathic pain and fibromyalgia — an overview of Cochrane reviews. Cochrane Database Syst Rev 2013;11:CD010567. [PubMed]
12. Birse F, Derry S, Moore RA. Phenytoin for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2012;5:CD009485. [PubMed]
13. Corrigan R, Derry S, Wiffen PJ, et al. Clonazepam for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2012;5:CD009486. [PubMed]
14. Gill D, Derry S, Wiffen PJ, et al. Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2011:CD009183. [PubMed]
15. Hearn L, Derry S, Moore RA. Lacosamide for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2012;2:CD009318. [PubMed]
16. Moore RA, Straube S, Wiffen PJ, et al. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev 2009:CD007076. [PubMed]
17. Moore RA, Wiffen PJ, Derry S, et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2011:CD007938. [PubMed]
18. Wiffen PJ, Derry S, Lunn MP, et al. Topiramate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2013;8:CD008314. [PubMed]
19. Wiffen PJ, Derry S, Moore RA. Lamotrigine for acute and chronic pain. Cochrane Database Syst Rev 2011:CD006044. [PubMed]
20. Wiffen PJ, Derry S, Moore RA, et al. Carbamazepine for acute and chronic pain in adults. Cochrane Database Syst Rev 2011:CD005451. [PubMed]
21. Zhou M, Chen N, He L, et al. Oxcarbazepine for neuropathic pain. Cochrane Database Syst Rev 2013;3:CD007963. [PubMed]
22. Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 2005;113:9-19. [PubMed]
23. Moulin DE, Clark AJ, Gilron I, et al. Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag 2007;12:13-21. [PubMed]
24. Dworkin RH, O'Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 2010;85:S3-14. [PubMed]
25. Chaparro LE, Wiffen PJ, Moore RA, et al. Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database Syst Rev 2012;7:CD008943. [PubMed]
26. National Prescribing Service. Pregabalin (Lyrica) for neuropathic pain. RADAR; April 2013. [Full text]

http://www.nps.org.au/health-professionals/health-news-evidence/latest-issue/treating-neuropathic-pain

Neuropathy Knowledge What Is An Axon

Today's post from sciencedaily.com (see link below) is the seventh part of a series from the same source providing readers with explanations and information about many of the medical terms they hear when researching neuropathy, or sitting in the doctor's surgery and talking about it. Today it explains the word 'axon' and gives related definitions of other words associated with its workings in the nervous system. Worth following the links if you have the time.

Axon
Science Daily via Wikipedia

An axon, or nerve fiber, is a long slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma.

Axons are in effect the primary transmission lines of the nervous system, and as bundles they help make up nerves.

Individual axons are microscopic in diameter - typically about one micrometre across - but may extend to macroscopic lengths.

The longest axons in the human body, for example, are those of the sciatic nerve, which run from the base of the spine to the big toe of each foot.

These single-cell fibers may extend a meter or even longer. In vertebrates, the axons of many neurons are sheathed in myelin, which is formed by either of two types of glial cells: Schwann cells ensheathing peripheral neurons and oligodendrocytes insulating those of the central nervous system.

For more information about the topic Axon, read the full article at Wikipedia.org, or see the following related articles:


Myelin — Myelin is an electrically insulating phospholipid layer that surrounds the axons of many neurons. It is an outgrowth of glial cells: Schwann cells ...  read more


Neural development — The study of neural development draws on both neuroscience and developmental biology to describe the cellular and molecular mechanisms by which ...read more


Pupillary reflex — In medicine, the pupillary reflex or pupillary light reflex, is the reduction of pupil size in response to light. It is a normal response and ...  read more


Sensory neuron — Sensory neurons are nerve cells within the nervous system responsible for converting external stimuli from the organism's environment into internal ... read more


Neuron — Neurons (also known as neurones, nerve cells and nerve fibers) are electrically excitable cells in the nervous system that function to process and ...  read more


Sympathetic nervous system — The sympathetic nervous system (SNS) is part of the autonomic nervous system (ANS), which also includes the parasympathetic nervous system (PNS). The ...  read more


Neurobiology — Neurobiology is the study of cells of the nervous system and the organization of these cells into functional circuits that process information and ...  read more


Nociceptor — A nociceptor is a sensory receptor that sends signals that cause the perception of pain in response to potentially damaging stimulus. Nociceptors are ...  read more


Chemical synapse — Chemical synapses are specialized junctions through which cells of the nervous system signal to one another and to non-neuronal cells such as muscles ...  read more


Nervous system — The nervous system of an animal coordinates the activity of the muscles, monitors the organs, constructs and also stops input from the senses, and ...  read more

http://www.sciencedaily.com/articles/a/axon.htm

An Honest Reflection Of The Current State Of Neuropathy Treatment

Today's post from medscape.com (see link below) may depress the hell out of you because it's basically an analysis of the failures with neuropathy treatment and diagnostic testing over the last decades. At least Medscape are honest here and don't try to pull the wool over our eyes with promises of exciting new developments in the field of nerve damage control. There are exciting new developments and this blog highlights them when they emerge but as the co-author rightly states: "As a clinician, I'm frustrated that current drugs have no benefit for the underlying nerve damage. We have witnessed failure after failure of clinical trials of disease-modifying drugs, because the end points are not fit for that purpose." Says it all really! That said, as patients, we have to remain optimistic and we have to report individual failures as they happen, so that enough evidence can be built up to confirm or reject any particular drug's effectiveness. We also need to continue to explore options from the alternative circuits. All we're interested in really is reducing our daily discomfort and it has to be said, progress in that area has largely been patient-led during the last decades because standard drug treatments are pretty much the same as they've been for decades and they are largely ineffective. This blog does take issue with the recommendation of Pregabalin as a first-line treatment but apart from that, the article presents a scenario that we can all recognise and reflects our frustrations as patients too.
 

New ADA Guidance Charts Success, Failure in Diabetic Neuropathy
Miriam E Tucker January 09, 2017

Notably missing from the first US guidelines to address diabetic neuropathy in more than a decade is any recommendation for disease-modifying treatments, since none are currently approved by the US Food and Drug Administration (FDA).

Indeed, many candidate drugs for diabetic neuropathy have failed in trials, and one of the new guideline authors believes novel end points — particularly measures of small-nerve fiber damage and repair — that could better assess a potential drug's efficacy need to be employed in clinical studies.

Coauthor Rayaz A Malik, MBChB, FRCP, PhD, of Weill Cornell Medicine-Qatar, Doha and New York, told Medscape Medical News, "As a clinician, I'm frustrated that current drugs have no benefit for the underlying nerve damage. We have witnessed failure after failure of clinical trials of disease-modifying drugs, because the end points are not fit for that purpose."

Such assessments of small-nerve fiber damage should also be used for earlier diagnosis of diabetic neuropathy, says Dr Malik.

"Although about 20% of patients have painful neuropathy and can present to their doctor, the majority have painless neuropathy, which is silent and is diagnosed only when it is too late and the patient has already developed a foot ulcer," he continued.

"Given that the 5-year mortality of a patient with a foot ulcer is worse than most cancers, there is a need to identify early neuropathy. Yet currently advocated tests, like the monofilament, identify only patients with advanced neuropathy. Why do we have robust methods for detecting early retinopathy and nephropathy, but not neuropathy?"

Published in the January issue of Diabetes Care, the new ADA position statement revises ADA's last neuropathy guideline, published in 2004.

The new document covers prevention and management of distal symmetric polyneuropathy (DSPN), diabetic autonomic neuropathies including cardiovascular autonomic neuropathy (CAN), as well as less common forms of neuropathy.

The aim is to provide state-of-the-art information for clinical management of the condition but to also acknowledge the current lack of disease-modifying drugs.

Most Patients Don't Need Sophisticated Testing or Opioids

Lead author of the new guidelines, Rodica Pop-Busui, MD, PhD, of the University of Michigan, Ann Arbor, told Medscape Medical News that there are two key clinical messages in the new document: the first is that electrophysiologic testing or referral to a neurologist is rarely needed for diagnosing neuropathy and the second is that opioids for the pain of diabetic neuropathy should be considered only as a very last resort and not as first- or second-line therapy,

"The purpose of the document is to provide clinicians with evidence-based tools to understand how to diagnose, monitor, and manage some of the aspects related to diabetic neuropathy.…It provides a tool to help them confidently diagnose neuropathy on their own and avoid expensive unnecessary tests or referrals," Dr Pop-Busui said.

The statement also covers neuropathy prevention, including glycemic control and lifestyle modification. Assessment for DSPN, the document advises, should be undertaken at diagnosis of type 2 diabetes, 5 years after diagnosis of type 1 diabetes, in those with prediabetes and symptoms of peripheral neuropathy, and every year thereafter.

Modalities for assessment should include careful history and either temperature or pinprick sensation to assess small-fiber function, along with tuning fork for vibration sensation, and 10-g monofilament testing for ulceration risk.

Electrophysiologic testing or referral to a neurologist is rarely necessary, except in atypical situations."There were several neurologists on the writing group, in addition to endocrinologists. We reached the same conclusion — that referral is not needed for typical cases of diabetic neuropathy — and we have provided a stepwise approach to get an idea of whether a patient has typical symptoms and signs," Dr Pop-Busui noted.

For treating neuropathic pain, the document advises the FDA-approved pregabalin or duloxetine as first-line treatment and various nonapproved agents, including gabapentin or tricyclic antidepressants, as second-line. Due to the high risks of addiction and other complications, opioids are advised only for patients with severe pain who don't respond to other medications, and referral to specialized pain clinics is advised in such cases.

Recommendations are also provided for assessment of cardiovascular, gastrointestinal, and urogenital autonomic neuropathies in patients with microvascular and neuropathic complications.

Included are considerations for excluding other conditions or drug effects that could be mimicking the symptoms, use of short-term metoclopramide for treatment of gastroparesis, assessment of patient-specific neuropathy-related end points, such as falls and mobility, and assessment of less common neuropathies.

"Hopefully readers will find this document very useful. We tried to make it very easy to read, with pearls that are all evidence-based.…We want to give them the tools to be able to see a complicated patient with diabetic neuropathy relatively easily in their office," Dr Pop-Busui explained.

Why Aren't There Any Drugs to Treat Neuropathy?

In the document's final section "Neuropathy Clinical End Points for Research and Clinical Trials," the authors point out that "multiple clinical trials for these conditions have failed."

They cite as contributing factors "a lack of agreement and uniformity in the use of the most sensitive DSPN measures that capture the natural history of the disease and detect repair in the specific nerve-fiber populations, as well as the inclusion of appropriate patient populations."

For DSPN drug trials in particular, the statement recommends the use of validated clinical instruments for assessing symptoms and disability, along with advice to "consider" using electrophysiology and measures of small-fiber damage and repair, such as intraepidermal nerve-fiber density or corneal confocal microscopy.

Dr Malik has long maintained that one of the main impediments to better neuropathy treatment in both clinical practice and research has been the focus on measures of symptoms and large-fiber dysfunction, rather than assessment of small-fiber damage and repair that occurs earlier and could therefore serve as a more appropriate target for early intervention and for the development of drugs to treat neuropathy.

"I honestly believe there are many drugs that have failed because of this. If you test small fibers they repair sooner than large fibers. If you do a clinical trial lasting only 1 or 2 years you actually might not see the benefit of that drug because you're not looking at the small fibers….Big Pharma has invested huge amounts of money in disease-modifying drugs, but they've all failed," Dr Malik asserted.

He blames advisors to the FDA for not "moving away from symptoms, signs, and neurophysiology" and for not allowing small-fiber assessment to be at least a secondary end point in drug trials "to give disease-modifying therapies a fighting chance."

He believes that many promising drugs like the aldose reductase inhibitors, nerve growth factor, C-peptide, and the novel investigational peptide ARA 290 (Araim Pharmaceuticals) could well be approved for DSPN if small-fiber evaluation were included as an end point.

However, Dr Pop-Busui pointed out, other candidate drugs have failed due to toxicity — notably the aldose-reductase inhibitors — although one of those (epalrestat) is currently licensed for DSPN in some countries in Asia.

Also, she noted that there has been difficulty in identifying an appropriate animal model for human diabetic neuropathy.

"We are working very hard to try to identify the right targets that can be developed into more successful phase 2 and phase 3 trials....This is a very complex question," she said.

What's the Best Tool for Research and Clinical Practice?

Dr Malik has conducted extensive research demonstrating the utility of corneal confocal microscopy, a tool originating from ophthalmology that has been shown to predict the development of peripheral neuropathy in patients with diabetes and even prediabetes.

Corneal confocal microscopy could serve both clinically and as a surrogate end point in clinical trials as a noninvasive alternative to skin biopsy for the assessment of early small-fiber damage and repair. This is the type of tool needed for drug development, he believes.

"No drug company is going to invest in a 5-year clinical trial. What you need is something that will give you a signal that nerves are beginning to repair within 12 months, which then allows you to continue and show that other tests like [quantitative sensory testing] and neurophysiology also improve," he explained.

"The monofilament and neurological examination are very good at picking up advanced neuropathy and identifying the high-risk foot but are terrible at detecting early neuropathy and indeed nerve repair," he added.

But such tools still play an important role in clinical practice, Dr Pop-Busui stressed.

"Some tools may be ancient but in fact provide extremely important information. These tools can be carried in a physician's pocket and used in a few minutes. Yes, we are using technology in many aspects of diabetes management, but in diabetic neuropathy, the clinical exam is very important."

And she pointed out that use of tools such as corneal confocal microscopy at this point is unlikely to change clinical practice.

"We don't have preventive treatments, so we wouldn't do anything different. We would still treat their glucose and other risk factors. We don't have other pathogenic treatments as we talk right now."

For the current document, she said, "The task given to us was to help physicians and patients to have the best effective care of the complication with all the information critically evaluated. In medicine things change all the time. If the evidence changes, we will update the document."

FDA Still Working on Development Programs for Agents for DSPN

Both Drs Pop-Busui and Malik participated in a February 2013 FDA public workshop, "Clinical Development Programs for Disease-Modifying Agents for Peripheral Neuropathy."

In response to a Medscape Medical News query about the outcome of that meeting and the status of the end-points issue, an FDA spokeswoman responded: "The FDA has taken into account the information discussed at the 2013 public workshop and the comments received as we continue to work with industry on clinical development programs for disease-modifying products for the management of peripheral neuropathy. We will provide updates on this topic as appropriate."

The guidelines authors have no relevant financial relationships.

For more diabetes and endocrinology news, follow us on Twitter and on Facebook.

Diabetes Care. 2017;40:136-154. Article

http://www.medscape.com/viewarticle/874162

DYNAMIC MOTION OF HIV AS IT READIES AN ATTACK

Researchers at Weill Cornell Medical College have developed technologies that allow investigators, for the first time, to watch what they call the "dance" of HIV proteins on the virus' surface, which may contribute to how it infects human immune cells. Their discovery is described in the Oct. 8 issue of Science, and is also a part of a study published the same day in Nature.

The new technology platform opens new possibilities for devising an approach to prevent HIV infection, says Dr. Scott Blanchard, an associate professor of physiology and biophysics at Weill Cornell, and one of three co-lead authors on the Sciencestudy. He is also an author on the Nature paper that describes a three-dimensional structure of one of the shapes, or conformations of the HIV protein.

"Making the movements of HIV visible so that we can follow, in real time, how surface proteins on the virus behave will hopefully tell us what we need to know to prevent fusion with human cells -- if you can prevent viral entry of HIV into immune cells, you have won," says Dr. Blanchard, who is also associate director of Weill Cornell's chemical biology program.

"What we have shown in the Science study is that we now have the means to obtain real-time images of processes happening on the surface of intact HIV particles, which we now plan to use to screen the impact of drugs and antibodies that can shut it down," he says.

"We desperately need solutions to prevent HIV infection, which, to date, has infected or killed more than 70 million people worldwide," Dr. Blanchard says. If this technology proves useful in HIV management, it could potentially be used to decode infection processes for other viruses, he says.

Using Light to Watch HIV Dance

In the Science study, Dr. Blanchard worked with Dr. Walther Mothes, a HIV specialist at the Yale University School of Medicine, and with Dr. James Munro, who was Dr. Blanchard's first graduate student and who is now an assistant professor at Tufts University School of Medicine. Drs. Mothes and Munro are the two other co-lead investigators.

Dr. Blanchard adapted an imaging technique that uses fluorescence to measure distance on molecular scale -- single-molecule fluorescence resonance energy transfer (smFRET) imaging -- to study viral particles. His group developed fluorescent molecules (fluorophores) -- which he dubs "beacons" -- and the team inserted them into the virus's outer covering, known as the envelope. With two of these special beacons in place, smFRET imaging can be used to visualize how the molecules move over time, when the virus proteins change conformation. The approach provides a measure of distances, on the order of a billionth of an inch, between two beacons glowing in different colors, and this can be used to detect shape shifting as it occurs and the attached beacons move.

The team used the technology to study motions of proteins on the surface of the HIV virus (called envelope proteins) that are key to the virus's ability to infect human immune cells carrying CD4 receptor proteins. (CD4 receptor proteins help HIV bind to a cell.) The envelope consists of three gp120 and gp41 proteins positioned close together, and referred to as "trimers," that open up like a flower in the presence of CD4, exposing the gp41 subunit that is essential for subsequent aspects of the mechanism that causes infection.

"There are 10-20 such envelope trimers on the surface of each HIV particle, and they mutate rapidly, thereby evading typical immune responses. This is why it is so difficult for humans to mount an effective immune response and why it is challenging for researchers to develop vaccines targeting the HIV envelope proteins," Dr. Blanchard says. The researchers were able to study proteins from two different strains of HIV, which contained beacons that did not alter the biology of the particles.

Then they watched.

They saw that the gp120 proteins' virus particles changed shape constantly and that the timing and nature of their movements were both similar and distinct. "This answered the first big question of how opening of the envelope trimer is triggered," Dr. Blanchard says. "Many scientists believe that the particles remain in one conformation until they come across a CD4-positive cell. But we saw that the proteins dance when no CD4 was present -- they change shape all the time."

The researchers were then able to watch how the viruses responded when synthetic CD4 was introduced. They also saw that antibodies known to exhibit some effectiveness acted to prevent gp120 from opening, and that these effects correlated with a decrease in the virus' ability to infect cells. Similar things happened when they introduced a small molecule now under development to prevent HIV infection.

"The practical outcome from this technology is that we can begin to understand how the biological system moves. So far we have detected three different conformations of the envelope trimer. We are working now to improve the technology to achieve the imaging precision we need to make broadly effective therapies," Blanchard says.

Technologies Work Hand in Hand

The Nature study, led by researchers at the National Institute of Allergy and Infectious Diseases, used X-ray crystallography to capture a three-dimensional structure of one of the conformations revealed in the Science paper. The protein constructs used in this investigation were originally developed by a team of researchers headed by Dr. John Moore, professor of microbiology and immunology at Weill Cornell.

"The antibodies used in the crystallography study are ones that we observed to stop the dance of the HIV envelope proteins, pushing the trimer assembly into a quiescent, ground state," Dr. Blanchard says.

"This concrete, atomic resolution picture of what the pre-fusion machinery looks like and where these antibodies bind provides an important step forward to understanding HIV's biology," he says.

Dr. Blanchard believes both techniques -- smFRET and X-ray crystallography -- can work hand in hand to help scientists describe the functions of molecules from the perspective motion, including the other two distinct conformations identified in the smFRET study.

"The approach is really a breakthrough for science because most research is done in a test tube where billions of molecules are present, all behaving independently. It is very difficult to extract direct information about these types of movements from indirect observations," such as those that don't use imaging technology, he says. "The single-molecule approach allows practical, interpretable, real-time information to be obtained about molecular processes in complex biological systems."

An Opioid Without Side Effects For Nerve Pain Is That Possible

Today's post is from genengnews.com (see link below). Don't you just love reading an article that contains a sentence like: “Unlike the conventional opioid fentanyl, this agonist showed pH-sensitive binding, heterotrimeric guanine nucleotide–binding protein (G protein) subunit dissociation by fluorescence resonance energy transfer, and adenosine 3′,5′-monophosphate inhibition in vitro.”!! However, with this sort of text, you have to remember that the ordinary neuropathy patient is essentially not the target audience here and this sort of article needs to be read with a sort of 'skim' technique that gives you the gist of what's being said, while skipping over the techno-speak. The article talks about a new form of opioid that is being developed that does the pain-killing job very effectively but doesn't have the side-effects that the media and politicians just can't cope with at the moment. We have to applaud research in the opioid field that doesn't begin with a skull and crossbones declaration that 'all opioids are bad'. Here they are genuinely recognising the benefits of opioids while trying to eliminate the potential harmful side effects. The whole world seems to be searching for opioid alternatives at the moment (powerful lobby - the anti-opioidals!) when the logical thing to search for is opioid adaptations that make them more user-friendly. Worth a read - you'll get the message I promise you.

Opioid Acts Only on Hurt Tissues, Skips Side Effects 
March 6, 2017 Gen News Highlights

  A new opioid can target “disease-specific” (pathological rather than physiological) conformations of receptors and ligands by selectively activating opioid receptors where acidic conditions prevail, as in tissues affected by inflammation or injury. Thus, the opioid brings pain relief at the site of inflammation and does not affect healthy tissues, such as those of the brain or intestinal wall, thereby avoiding side effects. [G. Del Vecchio & V. Spahn/Freepik]

Opioids, like sledgehammers, are powerful but blunt tools. When they are used to flatten pain, opioids may give other things a pounding, too. The problem is conventional opioids act on inflamed or damaged tissues as well as healthy tissues. Consequently, while opioids may relieve pain, they may also cause serious side effects, such as drowsiness, nausea, constipation, and dependency—and in some cases, respiratory arrest.

In hopes of finding a way to craft finer painkilling tools, scientists based at Charité-Universitätsmedizin Berlin scrutinized different ways opioids can interact with opioid receptors. These scientists, led by Prof. Dr. Christoph Stein, were on the lookout for “disease-specific” opioid receptor-ligand conformations. That is, the scientists plan was to exploit pathological (rather than physiological) conformation dynamics in the design of new opioids, and thereby create drugs that would target damaged or inflamed tissues yet bypass healthy tissues.

"By analyzing drug–opioid receptor interactions in damaged tissues, as opposed to healthy tissues, we were hoping to provide useful information for the design of new painkillers without harmful side effects," said Prof. Dr. Stein.

Prof. Dr. Stein’s team was aware that previous strategies in drug development had focused on central opioid receptors in noninjured environments, even though many painful syndromes (such as arthritis, neuropathy, and surgery) are driven by peripheral sensory neurons and are typically accompanied by inflammation with tissue acidosis. Ultimately, the team decided that this alternative mechanism of action—the binding and activation of peripheral opioid receptors—could be preferentially exploited by a new class of opioids. The key was the occurrence of acid conditions.

By following through on this idea, the scientists designed a new opioid that, unlike clinically used opioids, best activates the receptors in acidified tissues. When the new opioid was evaluated in a rat model of inflammatory pain, it exerted strong pain relief essentially without the side effects of standard opioids.

Details appeared March 3 in the journal Science, in an article entitled, “A Nontoxic Pain Killer Designed by Modeling of Pathological Receptor Conformations.” The article describes how the scientists used computer modeling to analyze morphine-like molecules and their interactions with opioid receptors. In particular, computer modeling was used to simulate an increased concentration of protons, thereby mimicking the acidic conditions found in inflamed tissues.

“By computer simulations at low pH, a hallmark of injured tissue, we designed an agonist that, because of its low acid dissociation constant, selectively activates peripheral μ-opioid receptors at the source of pain generation,” wrote the article’s authors. “Unlike the conventional opioid fentanyl, this agonist showed pH-sensitive binding, heterotrimeric guanine nucleotide–binding protein (G protein) subunit dissociation by fluorescence resonance energy transfer, and adenosine 3′,5′-monophosphate inhibition in vitro.”

The authors observed that their novel opioid produced injury-restricted analgesia in rats with different types of inflammatory pain without exhibiting respiratory depression, sedation, constipation, or addiction potential. These results, the authors suggested, mean that treating postoperative and chronic inflammatory pain should now be possible without causing side effects. Doing so would substantially improve patient quality of life.

“In contrast to conventional opioids, our NFEPP-prototype appears to only bind to, and activate, opioid receptors in an acidic environment,” explained the study's first authors, Dr. Viola Spahn and Dr. Giovanna Del Vecchio. “This means it produces pain relief only in injured tissues, and without causing respiratory depression, drowsiness, the risk of dependency, or constipation."

"We were able to show that the protonation of drugs is a key requirement for the activation of opioid receptors," the authors concluded. Their findings, which may also apply to other types of pain, may even find application in other areas of receptor research. Thereby, the benefits of improved drug efficacy and tolerability are not limited to painkillers, but may include other drugs as well.

http://www.genengnews.com/gen-news-highlights/opioid-acts-only-on-hurt-tissues-skips-side-effects/81253978

Magnetic Therapy an option for Neuropathy

Today's short post from Discovery: fit&health (see link below) reinforces the need for people with neuropathic pain to consider carefully, if a treatment is going to help or not. Many clinics offer therapies and treatments involving magnets and make extravagent claims as to their success rate. These can be expensive and may well work for some but many medical experts would disagree. The conclusion of this article is that more research is needed but in the meantime, you need to get advice from your own doctors before parting with your hard-earned cash.

Magnet Therapy and Diabetic Neuropathy

Magnets have used for centuries in China, India, and Egypt for their alleged healing powers. In the late 1800s, American advertisements offered magnetic belts and insoles as a cure for sleeplessness, hysteria, and indigestion. Such claims continue today, yet exactly how or if they work remains unknown.

One theory suggests that magnets can work with the body's own magnetism, similar to a magnetic resonance imaging (MRI) procedure. An MRI scanner creates a strong magnetic field, which causes the atoms within body tissues to shift. Based on that premise, it would seem possible for therapeutic magnets to heal damaged nerves.

Some researchers believe the magnets increase blood flow, "nourishing" a painful area, helping it heal, while others say magnets "repolarize" nerve impulses, changing the perception of pain.

Whatever the reason, magnetic insoles, mattress pads, pillows, bracelets, Belts, and even hairbrushes are a $5 billion industry worldwide, thanks to consumers who swear by them as a safe, noninvasive therapy for all types of chronic pain from tendonitis to migraine headaches.

Mainstream medicine, however, isn't buying it. For every study that shows the potential benefits of using magnets, it seems there's another that shows none at all. One of the more compelling studies appeared in the American Journal of Pain Management in January 1999. In it, Dr. Michael Weintraub, a neurologist at New York Medical College in Valhalla, N.Y., studied the effects of magnets on diabetic and nondiabetic patients with chronic foot pain.

His results showed 90 percent of the diabetics found magnetic footpad insoles significantly reduced chronic foot pain. While the numbers look impressive, critics say the study was too small to mean much. Meanwhile, another study done at the Veterans Affairs Hospital in Prescott, Ariz., published in the March 2000 Journal of the American Medical Association, found that adults with long-term back pain got absolutely no significant pain reduction from magnet therapy.

Despite the controversy, most experts agree the therapy warrants more research. In fact, the National Center for Complementary and Alternative Medicine at the National Institutes of Health believes the potential of magnetic healing worthwhile enough that it funded two ongoing studies on magnets and pain.

http://health.howstuffworks.com/medicine/tests-treatment/magnet-therapy-and-diabetic-neuropathy.htm

SINGLE NEURON HUB ORCHESTRATES ACTIVITY OF AN ENTIRE BRAIN CIRCUIT

The idea of mapping the brain is not new. Researchers have known for years that the key to treating, curing, and even preventing brain disorders such as Alzheimer's disease, epilepsy, and traumatic brain injury, is to understand how the brain records, processes, stores, and retrieves information

New Tel Aviv University research published in PLOS Computational Biology makes a major contribution to efforts to navigate the brain. The study, by Prof. Eshel Ben-Jacob and Dr. Paolo Bonifazi of TAU's School of Physics and Astronomy and Sagol School of Neuroscience, and Prof. Alessandro Torcini and Dr. Stefano Luccioli of the Instituto dei Sistemi Complessi, under the auspices of TAU's Joint Italian-Israeli Laboratory on Integrative Network Neuroscience, offers a precise model of the organization of developing neuronal circuits.

In an earlier study of the hippocampi of newborn mice, Dr. Bonifazi discovered that a few "hub neurons" orchestrated the behavior of entire circuits. In the new study, the researchers harnessed cutting-edge technology to reproduce these findings in a computer-simulated model of neuronal circuits. "If we are able to identify the cellular type of hub neurons, we could try to reproduce them in vitro out of stem cells and transplant these into aged or damaged brain circuitries in order to recover functionality," said Dr. Bonifazi.

Flight dynamics and brain neurons

"Imagine that only a few airports in the world are responsible for all flight dynamics on the planet," said Dr. Bonifazi. "We found this to be true of hub neurons in their orchestration of circuits' synchronizations during development. We have reproduced these findings in a new computer model."

According to this model, one stimulated hub neuron impacts an entire circuit dynamic; similarly, just one muted neuron suppresses all coordinated activity of the circuit. "We are contributing to efforts to identify which neurons are more important to specific neuronal circuits," said Dr. Bonifazi. "If we can identify which cells play a major role in controlling circuit dynamics, we know how to communicate with an entire circuit, as in the case of the communication between the brain and prosthetic devices."

Conducting the orchestra of the brain

In the course of their research, the team found that the timely activation of cells is fundamental for the proper operation of hub neurons, which, in turn, orchestrate the entire network dynamic. In other words, a clique of hubs works in a kind of temporally-organized fashion, according to which "everyone has to be active at the right time," according to Dr. Bonifazi.

Coordinated activation impacts the entire network. Just by alternating the timing of the activity of one neuron, researchers were able to affect the operation of a small clique of neurons, and finally that of the entire network.

"Our study fits within framework of the 'complex network theory,' an emerging discipline that explores similar trends and properties among all kinds of networks -- i.e., social networks, biological networks, even power plants," said Dr. Bonifazi. "This theoretical approach offers key insights into many systems, including the neuronal circuit network in our brains."

Parallel to their theoretical study, the researchers are conducting experiments on in vitro cultured systems to better identify electrophysiological and chemical properties of hub neurons. The joint Italy-Israel laboratory is also involved in a European project aimed at linking biological and artificial neuronal circuitries to restore lost brain functions.

An Older Persons Struggle With Neuropathy Vid

Today's video comes via the neuropathyassociation Facebook page (see link below) and shows  a real life story of an older lady suffering from severe neuropathy. Sometimes we need to see this sort of video to understand what people with neuropathy are going through in their daily lives and sometimes, after watching it, we may realise that our own situation is perhaps not as bad as we think. Certainly worth 4 minutes of your time.


Circle of Care
Angela Macropoulos (a caregiver in our community) submitted this video featuring her mother Josephine Macropoulos' ongoing neuropathy fight to the American Academy of Neurology Foundation for its 2011 Neuro Film Festival.



https://www.facebook.com/NeuropathyAssociation

Cannabis And Neuropathy An Evaluation

Today's post from cannabisoils.ca (see link below) is a rational and well-balanced assessment of the benefit medicinal cannabis can bring to neuropathy patients. There has been so much hysteria in the media, especially in North America, where cannabis is often linked to the war on hard drugs, that articles such as this are what we as patients, most need to evaluate our own treatment options. The last paragraph is perhaps the most telling.
 

Medicinal Cannabis and Painful Sensory Neuropathy  
Article by: Igor Grant, MD

Painful peripheral neuropathy comprises multiple symptoms that can severely erode quality of life. These include allodynia (pain evoked by light stimuli that are not normally pain-evoking) and various abnormal sensations termed dysesthesias (e.g., electric shock sensations, “pins and needles,” sensations of coldness or heat, numbness, and other types of uncomfortable and painful sensations). Common causes of peripheral neuropathy include diabetes, HIV/AIDS, spinal cord injuries, multiple sclerosis, and certain drugs and toxins. Commonly prescribed treatments come from drugs of the tricyclic and selective serotonin reuptake inhibitor (SSRI) antidepressant classes, anticonvulsants, opioids, and certain topical agents. Many patients receive only partial benefit from such treatments, and some either do not benefit or cannot tolerate these medications. The need for additional treatment modalities is evident.

Animal studies and anecdotal human evidence have for some time pointed to the possibility that cannabis may be effective in the treatment of painful peripheral neuropathy [1]. Recently, the Center for Medicinal Cannabis Research (CMCR) at the University of California [2] completed five placebo-controlled phase II clinical trials with smoked or inhaled cannabis [3-7]. Another study reported from Canada [8]. Patients included people with HIV neuropathy and other neuropathic conditions, and one study focused on a human model of neuropathic pain. Overall, the efficacy of cannabis was comparable to that of traditional agents, somewhat less than that of the tricyclics, but better than SSRIs and anticonvulsants, and comparable to gabapentin (see figure 1).



Figure 1. Common analgesics for neuropathic pain.
*to achieve a 30% reduction in pain.
Number needed to treat (NNT) = 1/(E-P), where E is the proportion improved in experimental condition and P is the proportion improved on placebo. Example: If 60% “improve” (according to a given definition) in the experimental condition, while 30% “improve” in the placebo condition, then NNT = 1/(.6-.3) = 3.3. Data adapted from Abrams et al. [3] and Ellis et al. [4].

The concentrations of tetrahydrocannabinol (THC) in these studies ranged from 2 to 9 percent, with a typical concentration of 4 percent resulting in good efficacy. Side effects were modest and included light-headedness, mild difficulties in concentration and memory, tachycardia, and fatigue. Serious side effects (e.g., severe anxiety, paranoia, psychotic symptoms) were not observed. Mild cognitive changes resolved within several hours of drug administration.

While these were short-term trials with limited numbers of cases, the data suggest, on balance, that cannabis may represent a reasonable alternative or adjunct to treatment of patients with serious painful peripheral neuropathy for whom other remedies have not provided fully satisfactory results. Because oral administration of cannabinoids (e.g., as dronabinol, marketed as Marinol) can result in inconsistent blood levels due to variations in absorption and first-pass metabolism effects, inhalational (or potentially sublingual spray, e.g., nabiximols, marketed as Sativex) administration remains preferred to oral administration.

Cannabis as a smoked cigarette, while demonstrating efficacy, poses a number of challenges, inasmuch as it remains illegal under federal law, even though it is permitted in an increasing number of jurisdictions on physician recommendation. Figure 2 provides a schematic approach for physician decision making in jurisdictions where medicinal cannabis is permitted [9]. See figure 2

This decision tree suggests key points that a physician should consider in making a determination. In the case of a patient assumed to have persistent neuropathic pain, the first determination to be made is that the patient’s signs and symptoms are indeed consistent with a diagnosis of neuropathy. Assuming a patient does not respond favorably to or cannot tolerate more standard treatments (e.g., antidepressants, anticonvulsants) and is willing to consider medicinal cannabis, the physician proceeds to compare risk and benefit. Among these considerations is whether the patient has a history of substance abuse or a serious psychiatric disorder that might be exacerbated by medicinal cannabis. Even the presence of such a risk does not necessarily preclude the use of medicinal cannabis; rather, coordination with appropriate substance abuse and psychiatric resources is necessary, and, based on that consultation, a risk-benefit ratio can be formulated. In patients for whom the ratio appears favorable, the physician should discuss modes of cannabis administration including oral, smoked, or vaporized. Once risks and benefits are evaluated and discussed with the patient, cannabis treatment may commence as with other psychotropic medications, with attention being paid to side effects as well as efficacy. Attention must also be paid to possible misuse and diversion, which can then trigger a decision to discontinue the treatment.

In summary, there is increasing evidence that cannabis may represent a useful alternative or adjunct in the management of painful peripheral neuropathy, a condition that can markedly affect life quality. Our society should be able to find ways to separate the medical benefits of making a treatment available to improve lives when indicated from broader social policy on recreational use, marijuana legalization, and unsubstantiated fears that medicinal cannabis will lead to widespread cannabis addiction.
http://www.cannabisoils.ca/medicinal-cannabis-and-painful-sensory-neuropathy/

Is Ketamine An Option For Neuropathic Pain

Today's post from zen-haven.com (see link below) is a realistic look at the reality of neuropathic pain but becomes subjective when considering the use of ketamine to control it. Ketamine has a bad rap. It's widely known as a party drug and is on many countries' banned lists. It is used under controlled conditions in hospital situations after surgery but many mainstream doctors will raise their eyebrows at the idea of it as a neuropathic pain controller. Yet the article is correct in that theoretically, the way ketamine works it could well help reduce chronic nerve pain. The suggestion is that a hospital administered infusion may give reasonably long lasting relief but the conclusion that this will then give the nervous system time 'to repair itself' is optimistic at best. The drug may well play a part in reducing neuropathic pain but the nerve damage can't logically be 'repaired' due to its administration - so far, no drug can repair nerve damage.

Navigating the Murky World of Neuropathic Pain
Posted on August 11, 2013 by Soren Dreier
Author: Christine Lin

As human beings, we instinctively avoid pain—the sting of nettles, the burn of a hotplate, the pinching of door hinges. Pain is useful because it communicates immediate danger and helps us keep out of it. However, some pain is chronic, as neuropathic pain often is.

Neuropathic pain derives from the central nervous system or peripheral nervous system. It is pain that comes from the nerves, as opposed to common muscular aches and arthritic pain. Sometimes it is triggered by traumatic accidents.

In support forums, patients suffering from neuropathic pain describe their symptoms as “burning all over,” “shooting pains in the arms and legs,” “agony,” and “unbearable.” Many of them recount their experiences in seeking relief “frustrating,” that they’ve “tried everything,” or that “not one doctor can give me an answer.”

Neuropathic pain, as a broad category of conditions that include neuralgia, phantom limb syndrome, complex regional pain syndrome (CRPS), and central pain syndrome, is a little-understood realm in medicine. We don’t always know its causes. And current treatment methods are mediocre at best.

Even its occurrence rate among the general population is hard to discern.

In 2008, a study of neuropathic pain incidences in the Dutch population found it has an annual incidence of almost 1 percent of the general population and affects women and middle-aged persons more often.

A 2005 survey of three U.K. cities puts the rate at 8 percent, while a 2006 one conducted in France came up with 5 percent.

Chronic pain affects more than day-to-day functioning. A study last year published in the Journal of Neuroscience found that people with chronic back pain or CRPS have smaller hippocampi than healthy people.

The hippocampus plays a crucial role in processing information, memory, and spatial navigation.

Current Treatments Hit-or-Miss

While researchers are slowly forming a better idea of what causes neuropathic pain, the research has been hard to translate into medical practice, leaving many patients feeling hopeless. Part of the reason is that there are likely a variety of causes that depend on the patient’s history of injury, lifestyle, and drug history.

Tricyclic antidepressants and anticonvulsants are the common, first-line drugs used to treat neuropathic pain.

According to a 2005 study, tricyclic antidepressants will give relief to one in every two to three patients with peripheral neuropathic pain, which is superior to serotonin noradrenaline reuptake inhibitors (SNRIs), which are successful in one in every four to five, and selective serotonin reuptake inhibitors (SSRIs), good for one in every seven patients.

Anticonvulsants have not been found to be more effective than tricyclic antidepressants with an efficacy rate about the same as that of SNRIs.

Emerging Treatment

Patients who fail to find relief may have a new treatment option to turn to.

A 2006 study in the American Journal of Therapeutics found that 85 percent of neuropathic pain patients who underwent outpatient ketamine infusion saw improvements in their conditions. Just over half of the study participants reported continued relief one month after discontinuing treatment.

Known more popularly for its abuse as a club drug, ketamine has been recognized and used for several decades as an anesthetic. It works to stop the transmission of pain by blocking N-methyl-D-aspartate (NMDA) receptors. Recent research has identified hyperactivity of these receptors as a possible factor in generating neuropathic pain.

Few medical establishments in the United States administer ketamine infusions. While it does not cure neuropathic pain conditions, treatment can put the patient into remission long enough to give the nervous system a chance to repair itself.

Read More: Here

http://zen-haven.com/navigating-the-murky-world-of-neuropathic-pain/

Is Acupuncture An Option For Your Nerve Damage

Today's post from time.com (see link below) follows on from yesterday's post and adds a little more information to the argument as to whether acupuncture may help relieve your neuropathic symptoms or not. It's a sensibly written and short description of how acupuncture works and offers no guarantees but as the acupuncturist points out at the end; “...if you’re being prescribed opioids, or you’re considering surgery, you lose very little by trying acupuncture first.” Worth a quick read if you're worried about the amount of chemicals you're swallowing in order to keep the pain down.

You Asked: Does Acupuncture Work? 
Markham Heid @markhamh June 29, 2016

For certain conditions—particularly pain—there’s evidence it works. Exactly how it works is an open question.

You hear the term “acupuncture,” and visions of needles may dance in your head. But the 3 million Americans (and counting) who have tried it know there’s a lot more to the treatment than pokes and pricks.

A typical visit to an acupuncturist might begin with an examination of your tongue, the taking of your pulse at several points on each wrist and a probing of your abdomen. “They didn’t have MRIs or X-rays 2,500 years ago, so they had to use other means to assess what’s going on with you internally,” says Stephanie Tyiska, a Philadelphia-based acupuncture practitioner and instructor.

These diagnostic procedures inform the placement of the needles, Tyiska says. But a visit to an acupuncturist could also include a thoughtful discussion of your diet and personal habits, recommendations to avoid certain foods or to take herbal supplements and an array of additional in-office treatments—like skin brushing or a kind of skin suctioning known as “cupping”—that together fall under the wide umbrella of traditional Chinese medicine.

But does it work? Figuring out whether each one of these practices may be therapeutically viable is a challenge, and determining how all of them may work in concert is pretty much impossible. Combine them with acupuncturists’ frequent references to “qi,” or energy flow, and it’s easy for a lot of people to dismiss the practice as bunk.

Not so fast, though. A recent meta-analysis, which examines existing research on a topic, compared acupuncture treatment to standard medical treatment (the kind involving a doctor’s exam and drugs) for musculoskeletal pain, chronic headaches, and osteoarthritis. It also compared real acupuncture to “sham” acupuncture, a procedure where needles are inserted at random to make patients believe they were receiving acupuncture when they were not. “There are many poorly designed acupuncture studies out there, so we tried to include only the best trials,” says Andrew Vickers, a biostatistician at Memorial Sloan Kettering Cancer Center who coauthored the meta-analysis.

When comparing legit acupuncture to standard care, there was a statistically significant benefit to acupuncture, Vickers says. “We saw a measurable effect there,” he explains. “If acupuncture were a drug, we’d say the drug works.”

When Vickers and his team compared legitimate acupuncture to sham acupuncture, that benefit persisted, but shrank. There are a lot of ways to interpret this, Vickers says. “It could be acupuncture has a large placebo effect, or it could be that pressure points”—the precise locations at which needles are inserted—“are less important than acupuncturists claim,” he explains.

Many people equate placebo effects with scams. “The term placebo has always had this very negative connotation,” says Vitaly Napadow, director of the Center for Integrative Pain Neuroimaging at Harvard Medical School. But Napadow says our poor opinion of placebo needs revising. The human body has built-in systems for stoking or calming pain and other subjective sensations. “If a placebo can target and modulate these endogenous systems, that’s a good and a real thing,” he says.

But acupuncture may have effects even more profound than placebo. Napadow has conducted dozens of brain imaging studies on acupuncture in an effort to determine just how the treatment may or may not calm pain or related conditions like headache or arthritis. He says there are lots of ways acupuncture might work, and the specific mechanism may depend on the type of condition you’re trying to treat.

One possibility is that being jabbed with a needle induces a tiny injury, causing your immune system to respond by sending inflammatory proteins and other infection-fighting, would-healing chemicals to the source of that injury. “There’s the idea that by inducing many of these very small injuries, you’re ramping up the immune system so that it can deal with bigger problems,” Napadow says.

It’s also possible that the increased flow of blood and immune system chemicals to the poke site could help clear away accumulated cellular byproducts that may trigger or worsen a condition like plantar fasciitis or tendonitis, he says. “Or the needles might activate nerve receptors in the skin, which then pass info up into your spinal cord and brain,” he says. “That information might trigger a change in brain physiology, like the release of endorphins or those sorts of neurotransmitters that could lessen the sensation of pain associated with something like fibromyalgia.”

His research has borne out some of these potential mechanisms. One of his studies showed that after traditional acupuncture, opioid receptors were more available, or receptive, to the body’s natural pain-quelling chemicals. There was no such change after sham acupuncture.

It basically means opioid receptors were more available or receptive to the types of body hormones and chemicals that help quell pain.

Napadow says that more research has looked into the effect of expectancy on acupuncture outcomes—or whether people who believe the treatment will work experience more benefit than those who don’t. The evidence suggests that expectancy doesn’t improve acupuncture’s effectiveness. “Often it’s the guy who says his wife made him try it who has the greatest benefit,” he says.

Couple these promising findings with the fact that acupuncture is a low-cost treatment option with very few side effects, and Napadow says it makes sense to consider it a helpful partner to Western medicine—especially when it comes to chronic pain-related ailments for which Western medicine often relies on painkillers. “It won’t cure cancer,” he says. “But it could be effective for managing side effects of radiation or chemotherapy—things like pain or neuropathy or nausea.”

Tyiska, the Philadelphia-based acupuncturist, makes a similar argument. “I don’t tell people to stop seeing their doctors,” she says. “But if you’re being prescribed opioids, or you’re considering surgery, you lose very little by trying acupuncture first.”

http://time.com/4383611/acupuncture-alternative-medicine-pain/

Sensus An Alternative Electrotherapy For Neuropathic Symptoms

Today's post from sensusrx.com (see link below) announces a new portable, wearable electro-sensory unit comparable to the better known TENS units. From reading the promotion, it certainly sounds easier, more convenient and more sophisticated but you should always be aware that these electrotherapy devices don't work for everybody at the same levels and may disappoint the buyer. That said, many people swear by them so it's best to discuss it thoroughly with your doctor or specialist and do your own research before taking the plunge.
 

How is SENSUS Optimized for Painful Diabetic Neuropathy?  SENSUS Blog Tuesday, February 3rd, 2015

SENSUS was designed to meet the unique needs of those suffering from neuropathic pain conditions such as painful diabetic neuropathy (PDN). People with diabetes and PDN often have physiology that responds differently to electrotherapy than that of someone without diabetes. For instance, nerve degeneration and elevated skin resistance to electrical stimulation are typical in those with diabetes. Effective pain relief may therefore require a more powerful device with higher stimulation output. Most conventional TENS devices do not have the capability of delivering the stimulation characteristics that are needed for those with diabetic peripheral neuropathy and therefore may have limited efficacy and utility for treating PDN.

SENSUS is a wearable pain relief device designed to provide the user the freedom to be active while they are receiving therapy. Conventional TENS units include multiple individual electrodes connected to lead wires, which may be awkward to place for pain in the lower legs and feet and it would inhibit the user’s mobility. The SENSUS and integrated electrode are placed on the upper calf. The device is slim enough to be worn discreetly under clothing so the user can go about their daily activities while therapy is being provided.

Since PDN often disrupts sleep, traditional TENS devices are not an option for night time pain relief because they cannot be used during sleep. SENSUS is the only nerve stimulator approved by the FDA for use during sleep so it is an option for around the clock pain relief.

Finally, most people with diabetes have complicated treatment programs involving multiple medications and devices such as blood glucose meters. Consequently, many of them will want to avoid an addition to their therapeutic regime that is unnecessarily complicated. Unlike conventional TENS devices, SENSUS is highly automated and can be setup by at home in just a few minutes. Therapy is initiated and stopped by pressing the sole button on the device and will automatically run throughout the day without any management on the part of the user.

The SENSUS Pain Management System has been optimized for people with diabetes, and includes advanced technology to enhance convenience while maximizing pain relief.

Posted by NeuroMetrix in Painful Diabetic Neuropathy

http://www.sensusrx.com/blog/index.html?blogid=42

An HIV Neuropathy Personal Story

Today's post is a video interview with a person living with both HIV and neuropathy from 1html.net (see link below). Even though everyone's story is different, personal to themselves and reveals different experiences of HIV; it will strike a chord with many people if only because of the effects stress can have on your well-being. The transcript of the video is reproduced below.




Transcript

Pamela Curry: Hello! My name is Pamela Curry. I became HIV positive via sexually transmitted means. I was going to a hospital to go about a procedure and they tested me for HIV and that's when I tested positive and of course I remember where it came from. Because I most of the time practiced safe sex, but he was so unpleasant that he was playing that slide and so the time over I got it from. At first I was angry, upset and that got even worse when I lost my job two weeks later because the company I worked for was self insured and unfortunately this is a right to work state. So when the paper work got to the home office, they found a reason to terminate me. Now because I want a fixed income, I have to seek out housing that will accept housing assistance for persons with HIV AIDS. And a lot of companies won't take that. So that means you have to live in somewhat less lower standard than you what may have been accustomed to before. Since testing positive -- to mention the word stress I break out into shingles. I have very severe attacks of shingles. In recent years I have felt personal neuropathy that I started at beginning. So then there are mornings where I can't get out of bed and I have to crawl to the bathroom. I was trying to compose myself and get myself to a position where people will not notice before I go venturing outside. Female Speaker: You take a number of medications?Pamela Curry: A little -- this pill twice a day. I have my medicine carrying it right here, here is about 20 pills. Some of them are -- one in particular typically causes nausea, sometimes frequent diarrhea. The most severe it comes over you just like that, but it is medication related and I know what meds call it, but I have to have them. So you deal with it the best you can. When you are HIV positive you are more susceptible to lots of infections and that includes common infections that 20 like -- Herpes, 20% population has it but not all of them, because it is not active. When you are HIV positive your immune system is compromised and you are going to have outbreaks more frequently and that will also -- I have the shingles more frequently. I have to take a higher dose of Valtrex to try to prevent it and even with the higher dose of Valtrex that doesn't mean you are not going to have a break out. It means you have to go to specialist instead of just your general practitioner and always use a protected sex. I know the current -- Administration's guidelines are to teach abstinence only and you are supposed to talk about the failure rate of condoms are 14%. But a condom only fails 14% and abstinence only, only works a 100% when it is practiced to 100%. And reality is 80% of teenagers do not continue to practice abstinence a 100% of the time. They are going to have sex and if haven't provided them with the tools to protect themselves, that become a risk.

http://www.1html.net/19360/Pamela_Curry_Hello_My_name_is_Pa.html