New Guidelines For Treating Painful Neuropathy

You know by now that when an article talks about diabetic neuropathy, unless it's discussing blood sugars or other specific diabetes issues, you can more or less apply the information to all forms of  sensory neuropathy. The causes may be different but the symptoms pretty much apply to all. Today's article comes from depressionforums.org (see link below) and discusses the very interesting guidelines issued by the American Academy of Neurology. It's good to see that they advise the use of the traditional neuropathy treatments "if clinically appropriate". This article was written in April, 2011 and therefore a year before Pfizer withdrew Lyrica (Pregabalin) promotion for diabetes and HIV-related neuropathy - the message is that doctors should always prescribe drugs "if clinically appropriate" and not just as a matter of course.

New AAN Guidelines on Painful Diabetic Neuropathy
Susan Jeffrey April 11, 2011 (Honolulu, Hawaii)

 — The American Academy of Neurology has released new guidelines on the treatment of painful diabetic neuropathy (PDN).

The document provides evidence-based guidance on use of a range of pharmacologic agents, including anticonvulsants, antidepressants, opioids, and others, as well as nonpharmacologic treatments, such as transcutaneous electrical nerve stimulation (TENS) and magnetic field treatment.

"We were pleased to see so many of the pain treatments had high-quality studies that support their use," said Vera Bril, MD, from the University of Toronto, Ontario, Canada, lead author of the guidelines. "Still, it is important that more research be done to show how well these treatments can be tolerated over time, since diabetic nerve pain is a chronic condition that affects a person's quality of life and ability to function."

The guidelines are published online April 11 in Neurology and were presented here at the American Academy of Neurology 63rd Annual Meeting. They were developed in collaboration with the American Association of Neuromuscular and Electrodiagnostic Medicine and the American Academy of Physical Medicine and Rehabilitation; the document will appear in the April issues of their respective journals, Muscle and Nerve and PMR.

Unreported, Untreated
It is estimated that PDN affects 16% of the more than 25 million people who have diabetes in the United States, the authors point out. The condition is "often unreported and more often untreated, with an estimated 2 out of 5 cases not receiving care," Dr. Bril noted.

"As we emphasize the use of evidence-based guidelines to treat different disorders, it becomes clear that this field is very confusing because of the volume of literature," Dr. Bril told a press briefing here. "So the guidelines have been developed and will provide a framework for physicians to use when treating their patients. Physicians can understand what the evidence is for the treatments they'll use; when there is evidence, when there isn't, or when the evidence is negative."

The process started in 2007, with more than 2200 papers on PDN; of these, 463 were deemed relevant to the guidelines. Author teams reviewed these papers and identified 79 considered "highly pertinent" to the guideline. Each of these reports was rated by teams of 2 with regard to class of evidence for effectiveness, and disagreements were arbitrated by a third member.
The only drug to earn a "Strong Evidence, Level A" rating was pregabalin, but several drugs and nonpharmacologic interventions met criteria for "Moderate Evidence, Level B" endorsement.
That only 1 drug met this level of evidence was a bit of a surprise, Dr. Bril noted. "One of the big factors that moved a study from class I to class II is that you needed at least 80% of the people in the study to complete the study," Dr. Bril said, and 2 class I studies were required for a Level A recommendation.

"I can tell you there was discussion internally about the rules because of the way it fell out, but it would be a little strange to be changing your rules for guidelines because of the findings in 1 guideline process," she said. "The others are Level B mostly because they didn't get 80% completing their studies."

The level of evidence is not driven by the effect size of the drug, she noted. "So pregabalin has a small effect on pain, but the studies were class I, and you could say people tolerated the treatment and stayed in" the pregabalin studies, Dr. Bril added. "So you can't make assumptions and change the rules because of what you're finding."
They also provide the recommended doses of agents considered useful in the document.

Strong Evidence (Level A)

• Pregabalin should be offered "if clinically appropriate."

Moderate Evidence (Level B)

• Anticonvulsants gabapentin and sodium valproate should be considered for PDN treatment. The authors note though that because valproate is potentially teratogenic, it should be avoided in diabetic women of child-bearing age, and due to its potential adverse effects of weight gain and worsening of glycemic control, "this drug is unlikely to be the first treatment choice for PDN."
• Anticonvulsants oxcarbazepine, lamotrigine, and lacosamide should probably not be considered.
• Antidepressants amitriptyline, venlafaxine, and duloxetine should be considered; however, "data are insufficient to recommend one of these agents over the others," they note.
• Opioids dextromethorphan, morphine sulphate, tramadol, and oxycodone should be considered for the treatment of PDN, they note. Again data were insufficient to recommend one of these over the others.

They note that the use of opioids for chronic nonmalignant pain has "gained credence over the last decade due to the studies reviewed in this article." Both tramadol and dextromethorphan were associated with substantial adverse events, including sedation with both agents and nausea and constipation with tramadol. The use of these agents can also be associated with development of novel pain syndromes, such as rebound headache, the authors note, and long-term use can lead to tolerance and frequent escalation of dose.

• For other pharmacologic interventions, they recommend that capsaicin cream and isosorbide dinitrate spray be considered to manage PDN, although they note that many patients can be intolerant to the adverse effects of capsaicin, which include burning pain on contact with warm or hot water or in hot weather.
• Clonidine, pentoxifylline, and mexiletine, on the other hand, should "probably not" be considered for use.
• For nonpharmacologic treatments, they recommend that use of TENS be considered but "probably not" electromagnetic field treatment, low-intensity laser treatment, or Reiki therapy.

Weak Evidence (Level C)

• They found weak evidence that adding venlafaxine to gabapentin may provide a better response and that the Lidoderm patch may be considered to treat PDN.

Insufficient Evidence (Level U)

• The authors found insufficient evidence to "support or refute" use of the anticonvulsant topiramate; the antidepressants desipramine, imipramine, and fluoxetine; or the combination of nortriptyline and fluphenazine.
• Similarly, there was insufficient evidence either way on the use of vitamins and α-lipoic acid or the combination of amitriptyline with electrotherapy for treatment of this condition.

Placebo Effect
In their summary document, the authors point out as "notable" that the placebo effect varied from 0% to 50% pain reduction in the studies reviewed for this guideline.
"The panel recognizes that PDN is a chronic disease and that there are no data on the efficacy of the chronic use of any treatment, as most trials have durations of 2 to 20 weeks," they write. "It is important to note that the evidence is limited, the degree of effectiveness can be minor, the side effects can be intolerable, the impact of improving physical function is limited, and the cost is high, particularly for novel agents."
Neurology. Published online April 11, 2011.

 Author(s)

Susan Jeffrey

Susan Jeffrey is the news editor for Medscape Neurology & Neurosurgery. Susan has been writing principally for physician audiences for nearly 20 years. Most recently, she was news editor for thekidney.org and also wrote for theheart.org; both of these Web sites have been acquired by WebMD. Prior to that, she spent 10 years covering neurology topics for a Canadian newspaper for physicians.

http://www.depressionforums.org/depressive-diseases-health-disorders/178-chronic-pain-depression/2275-new-aan-guidelines-on-painful-diabetic-neuropathy

Mutations In A Sodium Channel Reponsible For Painful Neuropathy

Not exactly a catchy title to catch your eye over the breakfast cereal but nevertheless, today's post from painresearchforum.org (see link below) is a fascinating look at how neuropathy may look under the microscope. Basically, research has found that there may be genetic reasons for mutations in one of the three sodium channels in nerves and nerve cells that normally control how excitable pain-sensing nociceptors might be. These mutations may stop that control and allow the pain signals to get out of hand. Having discovered that genetic influences may be at work, it's thought that drugs can be targeted more specifically to quieten that excitement down. It sounds complex and technical and is but that should never stop us trying to understand what's going on in our bodies that cause such uncomfortable symptoms. You can probably get the gist of what they're talking about here.

Third Sodium Channel Implicated in Painful Small-Fiber Neuropathy
Mutations in Nav1.9 render pain neurons hyperexcitable 
by Stephani Sutherland on 16 May 2014


Three voltage-gated sodium channels—Nav1.7, 1.8, and 1.9—all participate in tuning the excitability of pain-sensing nociceptors. Genetic changes that alter the function of two of the channels, 1.7 and 1.8, and boost nociceptor activity have been found in patients with painful small-fiber neuropathy (SFN), a common condition with often mysterious origins. Now, an international consortium of researchers has rounded out the Nav triad by identifying gain-of-function mutations in Nav1.9 in some cases of painful SFN. The new findings reveal a previously unsuspected genetic cause for painful peripheral neuropathy and further validate Nav1.9 as a potential target for new drugs aimed at quieting pain neurons. The study, a collaborative effort between US and European researchers, was published April 27 in Brain.

In a commentary accompanying the paper, David Bennett of the University of Oxford, UK, who was not involved in the current study, wrote that the researchers “present the first evidence for a causative role of missense mutations in Nav1.9 in painful neuropathy.” As a result, he wrote, “Mutations in Nav1.7, 1.8, and 1.9 have now all been associated with painful neuropathy as a consequence of dorsal root ganglion [DRG] cell hyperexcitability and as such are targets for the development of novel analgesics.”

For the study, neurologists Ingemar Merkies and Catharina Faber at the University Medical Centre, Maastricht, the Netherlands, and Giuseppe Lauria at IRCCS Foundation, "Carlo Besta" Neurological Institute, Milan, Italy, carefully characterized a cohort of 393 patients with pure or predominantly small-fiber neuropathy. They previously identified mutations in SCN9A and SCN10A, encoding Nav1.7 and Nav1.8, respectively, in some of the cohort (see PRF related news story on Faber et al., 2012; also Faber et al., 2012). The team now reports eight variants in SCN11A—the gene that encodes Nav1.9—in 12 of the remaining 345 subjects. The variants were all heterozygous, and seven caused amino acid sequence changes in the Nav1.9 protein. None of the eight variants were found in 694 chromosomes from healthy control subjects.

Stephen Waxman, Sulayman Dib-Hajj, and their team at Yale University School of Medicine, New Haven, and the Veterans Affairs Medical Center, West Haven, both in Connecticut, US, followed up on the genetic work with what Bennett described as “a detailed and elegant functional analysis” of two of the missense mutations. Each mutation was found in two patients; one resulted in a leucine-to-proline change at position 1158 (L1158P), and the other caused an isoleucine-to-threonine swap at position 381 (I381T).

First authors Jianying Huang, Chongyang Han, Mark Estacion, and Dymtro Vasylyev—whom Dib-Hajj called “four highly specialized and talented electrophysiologists”—carried out the analysis. Using patch-clamp recording techniques on isolated mouse dorsal root ganglia (DRG) neurons made to express only the human channels, the researchers determined that both mutations altered the channels’ gating properties. Importantly, DRG neurons expressing mutant channels alongside the rodent channel were significantly more prone to fire both spontaneous and evoked action potentials than those expressing wild-type human channels.

The neuronal excitability experiments could be misleading due to high expression levels of the mutant channels and/or the presence of the rodent channel. To address that problem, the authors used a sophisticated dynamic clamp technique, where they "injected” currents into mouse DRG neurons that lacked their own Nav1.9 to mimic physiological levels of wild-type human channels or a 50/50 combination of wild-type and mutant channels. The results confirmed that currents generated by the I381T mutant channels were capable of causing changes in cell excitability similar to those measured in the expression experiments, suggesting that the effects were “not an aberrant effect of overexpression of a mutant protein,” Waxman told PRF.

Recently, gain-of-function mutations in Nav1.9 were found in two families with a rare inherited episodic pain condition (see PRF related news story on Zhang et al., 2013), and the new work links Nav1.9 mutations to a more common condition, painful SFN. However, a different gain-of-function mutation has also been found in two people with insensitivity to pain (see PRF related news story on Leipold et al., 2013). In that study, the authors postulated that a constant, slight depolarization of the membrane potential induced by the Nav1.9 mutant would inactivate sodium channels and render cells unexcitable. Based on their electrophysiological studies, Waxman said his group found no evidence that a depolarized resting potential in DRG neurons reduced their excitability, leaving open the question of how the mutation described by Leipold et al. might lead to pain insensitivity.

Neurotoxic mutants?

SFN pain symptoms vary from patient to patient, but usually include burning pain and tingling that originates in the hands or feet, along with other unpleasant sensations. About half of SFN cases can be traced to nerve damage due to diabetes, cancer, toxins, or other insults. But for the rest of patients, SFN has unexplained origins. Could the newly identified Nav1.9 mutations cause SFN in some? Waxman told PRF, “The mutations unequivocally cause DRG neuron hyperexcitability, which is a major contributor to pain.”

SFN also features damage to small-diameter nerve endings, detectable with a skin biopsy. Waxman suggests that in addition to pain, overactivity of Nav1.9 or other mutant sodium channels could contribute to this unexplained neurodegeneration and that quieting the channels might curtail the damage. Bennett, too, suggested in his editorial that drugs aimed at quieting Nav1.9, besides acting as analgesics, “may have the added advantage of also being disease modifying.”

Together with last year's findings in rare disorders, the finding of Nav1.9 mutations in SFN breathes new life into that channel as a potential therapeutic target. Pharmaceutical companies are actively pursuing Nav1.7 and Nav1.8 as analgesic drug targets, but industry has thus far shied away from Nav1.9 because of the lack of a connection to human pain and also because of technical difficulties associated with studying the channel. Dib-Hajj told PRF, “Until now, people did not really know what to make of this channel.” In light of the new findings, though, Dib-Hajj said, “Now they can’t ignore it.”

Of course, efforts to develop a Nav1.9 blocker would be aimed not only at the few patients with mutations in the channel, but also at a much broader population suffering from SFN or even neuropathic pain more generally. “It is clear to us that Nav1.9 behaves as a threshold channel, that it is important to setting the resting membrane potential of neurons, and it controls excitability … in the case of the wild-type channel, too, not just mutants. So if you can attenuate Nav1.9 [activity], chances are you will ameliorate pain,” said Dib-Hajj. “That is based on biology, not wishful thinking.” Still, when it comes to a Nav1.9-specific blocker, Dib-Hajj said, “We predict that patients would benefit, but the proof will be in the pudding.”

Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California.

http://www.painresearchforum.org/news/40751-third-sodium-channel-implicated-painful-small-fiber-neuropathy

The Painful Reality Of Neuropathy

Today's post from positivelite.com (see link below) takes a look at how neuropathy really feels for those who have to live with it. Despite the increase in neuropathy cases across the world, there is a parallel decrease in understanding what nerve damage actually entails. This article tries to explain what it’s really like to suffer from this strange and unpredictable disease. Perhaps worth passing on to your friends and family.
 

The painful reality of neuropathy
Tuesday, 22 April 2014 Dave R. 

Occasionally, everybody tingles, or has numb fingers or toes, or feels the nerve at the back of their leg twitch to give them shooting pain. They may be woken by restless legs that shudder without reason, or recoil if they touch something too hot or too cold, or conclude they’ve got a trapped nerve somewhere on their bodies. These are all perfectly normal but nothing prepares you for the effects of your nervous system going into major short-circuit mode!

When that happens, you may well find out what it’s like to be one of the millions of people across the world who are living with neuropathy.

Neuropathy is nerve damage, disease or disruption. That’s simple enough isn’t it…and the cure is? That’s also simple…there isn’t one. However, those bare facts tell people who aren’t affected, absolutely nothing about what life is like with this mysterious, indistinct and difficult to treat condition. Most people have little or no concept of how nerves work and how essential they are to daily life anyway (why would you, when everything works as it should!) and therefore find it nigh on impossible to understand what happens when the system breaks down.

The neuropathy sufferer is then faced with the task of explaining his or her weird symptoms to a largely glassy-eyed and disbelieving audience. When the patient can’t put it into words himself, he or she quickly feels frustrated, not taken seriously and even under suspicion that they’re on a sympathy quest or even committing some sort of fraud.
In a nutshell…

Often resulting from damage or degradation to the nerve itself, its cells, or the (myelin) lining that protects the nerve, sufferers are subjected to a series of confusing, functional breakdowns which send out wrong signals, or no signals at all. It really can be compared to a short circuit in a domestic electrical system but the resulting feelings and sensations are pretty unique to the disease.

Now the mechanics of it all, why it happens and its 100-plus causes, with special reference to HIV, can be found by reading earlier posts:

‘What is neuropathy? A growing problem’

‘Why do People with HIV suffer from neuropathy?’

and ‘How neuropathy is currently treated’

It’s important to remember that neuropathy affects all sorts of people from all categories of society. It’s most common amongst diabetics and affects more than 20 million people in the USA alone but between a third and a quarter of all people living with HIV will eventually suffer neuropathic symptoms - but what does that mean? What does it feel like and why are its symptoms so difficult to explain to a largely disinterested public?

As I said before, there are over 100 causes and also over 100 types of neuropathy, so pinning down exactly how someone feels with the disease really depends on where your nerve damage is happening and what part of your body is being affected. That said, the vast majority of neuropathy patients have sensations they can instantly recognize; irrespective of the cause. Generally, neuropathy falls into one of the following four categories:

· Motor neuropathy

Motor means movement, so motor neuropathy is damage to the nerves that control muscular activity and movement in the body. It generally affects feet, legs, hands and arms but can also effect speech.

· Sensory neuropathy

Sensory means touch, so sensory neuropathy is damage to the nerves controlling what and how you feel. So it can affect how you feel pain, or even the lightest of touches.

· Autonomic neuropathy

Autonomic means involuntary, so autonomic neuropathy affects the nerves directing bodily functions you aren’t aware of and have little control over, such as breathing and heartbeat but also digestion (including bladder and bowel functions), sexual response and circulatory problems. It’s easily the neuropathy with the most serious ramifications.

· Combination neuropathies

A nightmare for many, when you have a combination of the above problems.
So where is neuropathy most likely to strike and how are you going to recognize it?

In general most people suffer problems in their feet first. Feet are at the end of the nerve pathways and the furthest away from the central nervous system. It’s maybe logical that problems happen there first. The nerves there are part of the peripheral nerve system. You can think of the nervous system as consisting of the spinal cord leading to the brain (central nervous system) and all the nerves radiating out from there are peripheral nerves. Some specialists regard the digestive system as being the 4th centre of nervous activity, controlling the stomach, bowel and excretory functions but these are generally only affected if you have autonomic neuropathy.

So back to the feet, where the majority of people first notice something going wrong but neuropathy is never an overnight happening – it can take years to develop and creeps up on you without you really noticing a pattern developing – part of the reason why it is so difficult to diagnose and treat.

At first, you may suffer a loss of feeling or numbness in a toe, or toes. Nothing remarkable there but it is a first sign. Then gradually, you begin to feel as though the toes are both numb and painful, along with tingling, or other strange sensations. It’s as though the toe is anaesthetised on the surface, yet just underneath it’s painful, or tingling. This set of feelings often spreads to the other padded areas of the foot or leg. People talk about feeling as if they are walking barefoot in snow; or barefoot on soft sand; or they have socks on filled with clay. It really is a weird feeling and very uncomfortable. Many people call it the ‘glove and sock’ sensation, where you are walking on bare feet, or have bare hands but feel that you’re wearing something on top. It can also perversely feel as though you’re walking on bare bones.

The problem is that the numbness can lead you to walk strangely, or lose your footing, or take miss-steps. You feel as though you’re doing the right thing to make your feet move in the right direction but they do something else and this can lead to stumbling and falling. Basically the wrong signals are being sent out and there’s a communication breakdown between the brain and the feet. Another parallel with an electrical short-circuit.

Not only this but your legs can feel heavy; or you feel that your muscles aren’t responding and becoming weaker. This especially affects the calves and in extreme cases can lead to muscular atrophy. Climbing stairs can be both painful and tiring and walking the streets can feel like an assault course, as you’re constantly tripping over loose pavings you would normally avoid, or just stumbling when you least expect it. Many people end up using a cane to act as a ‘third leg’; partly because of muscular weariness and partly to give the feeling of more security when you walk.

You sometimes feel as if your leg muscles are spasming and this can be because you unconsciously put strain on the wrong muscle as you try to walk properly. People often clench their feet in order to get a better grip on the ground beneath them, which naturally leads to loss of relaxation and muscular cramping. Balance becomes a major issue and people have often been accused of being drunk, or high because they’re walking like demented spiders.

All these feelings and sensations can spread to your hands and arms (more extremities on the peripheral nervous system) but that’s not a given. Many people suffer with foot and leg neuropathy without problems in their hands and arms and vice versa. If you have problems in your hands; you can lose control of your grip and dropping cups, keys etc. can be a costly irritation. You have to imagine the effect this has on people. They lose their trust and confidence in their own actions and are often frightened and confused as to what is happening and that isn’t taking into account neuropathy pain!
The pain neuropathy brings.

Without intending to sound overly-dramatic: - oh my god, where do I start!

The most difficult thing for friends, family and co-workers to understand is the pain neuropathy can bring. It’s like nothing else you’ve ever experienced. It can range from mild tingling or burning, to pain that can leave you screaming in agony, especially at night. It can feel as though the affected areas are on fire and burning sensations are perhaps the commonest after tingling. Tingling sounds innocent enough but it can be so severe that it’s extremely painful and then you long for the numbness that you began with.

People often complain of ‘electric shock’ symptoms and that doesn’t need too much explanation. Often the muscles will spasm, leading to cramps which together with the shocks, the burning and the tingling can lead people to literally crying or screaming the hours away.

It has to be said, everybody’s neuropathy is unique to themselves, so the symptoms you see here can be anything from mild to wild. It’s little wonder that opiates can be the only course of action in the end but even they have their limitations, leading to increased doses and addiction.

With all these sensations, you can experience the strangest reverses of feeling. Stepping on a pebble may feel like treading on broken glass and hot bath water can feel cold (or vice versa) leading to many cases of burn wounds. People with neuropathy need to use an unaffected part of their body to test textures and temperatures, or they can land in trouble. Even bed sheets that you normally hardly feel, can cause severe discomfort and many resort to invented strategies to keep sheets off their feet and legs at night.

Paradoxically, areas where you experience numbness can be the most painful. The surface may be numb but just underneath Dante’s Inferno is raging. Try explaining that to friends and family – unless they’ve experienced it, they just don’t understand what you’re telling them. “How can it be numb and painful at the same time? That doesn’t make sense.” The problem is that some or all of these symptoms can in the worst cases, lead to being confined to a wheelchair, or even death, if autonomic functions are severely impaired.

Many people living with neuropathy experience abnormal sweating, or don’t sweat at all. Waking up with the sheets drenched (as many older HIV patients will know) is very unpleasant. The nerves to the sweat glands are affected and this changes the pattern and frequency of sweating. The same goes for urinary problems and digestive malfunction. It’s very difficult to relate these to nerve damage but they are common symptoms of autonomic neuropathy. The nerves to blood vessels, intestines and bladder are damaged by the disease and give out faulty signals leading to abnormal behaviour in functions which we take for granted. You may feel bloated after eating small portions; you may have difficulty emptying a full bladder yet the brain tells you the bladder is empty. This sort of thing leads to secondary infections, constipation and diarrhea.

Sexual malfunction in both sexes is a common side effect of autonomic neuropathy and can be very upsetting. Blood pressure changes are also alarming results of this type of neuropathy, leading to all the consequences of too low or too high blood pressure.

“Patients who have chronic neuropathic pain [often] have more than one type of pain. For example, a man who has post-herpetic neuralgia at high and mid thorax may have constant ongoing pain that keeps him awake all night; mechanical allodynia and hyperalgesia that prevent him from wearing any clothing so he cannot be active and socialize; secondary myofascial pain in the shoulder so that use of that arm is limited; and after a few short weeks of his pain, the patient is by now sleep deprived, depressed, anxious, and very irritable." (Backonja and Galer, Neurol Clin 1998; 16).”

Hopefully, this article gives you some idea of what it’s really like to have neuropathy in your life. It’s a horrible disease because it’s so unpredictable. Some people go for years with only mild discomforts (a little tingling here, a little numbness there) but others suffer dreadfully and need to be on the heaviest medication to control the symptoms. The medication only helps to control symptoms (see earlier links for more information) it doesn’t cure anything.

Unfortunately, in 2014, although there are many more research studies at molecular level being carried out on things ranging from fish venom, via natural supplements, to the most sophisticated opioids, there’s no sign of a cure on the horizon. People have to live with neuropathy as best as they can and find the best treatment available to help their own nerve problems.

Diabetes is by far the most common cause but between a quarter and a third of all HIV patients will end up with neuropathy too, either thanks to medication or the virus itself attacking the nervous system. All people ask for if they tell you they have neuropathy is a little sympathy and understanding that their lives are difficult. Chronic pain is a feature of our age but the chronic pain of neuropathy is possibly one of the meanest of them all and not to be underestimated.

http://positivelite.com/component/zoo/item/the-painful-reality-of-neuropathy