All You Need To Know About Small Fibre Neuropathy

Today's post from ncbi.nlm.nih.gov (see link below) tells you all you need to know about small fibre neuropathy and how it's treated. It includes all the references because they are important to the relevance of all the facts and it's quite a read! However, if you've been diagnosed as having small fibre neuropathy, or suspect that your neuropathy may fall under that heading, it's worthwhile ploughing through it because you'll learn so much about what gives you so many problems in daily living. Small fibre sensory neuropathy (SFSN) is a disorder in which only the small sensory cutaneous nerves are affected and as such can be classified as being different to other forms of neuropathy but it's important to realise that the results are pretty much the same and that goes for the treaments too. It's so confusing for patients when they are confronted by so many terms describing their neuropathy. Here, we're talking about the small sensory nerves and other neuropathies apply to single nerves, or longer axons but whatever you've been given as a label, this post will apply to you in many ways. Worth a read but clear your head first! (n.b. the US spelling of fibre is 'fiber' - it's not a typo!)

Diagnosis and Treatment of Pain in Small Fiber Neuropathy
Alexandra Hovaguimian and Christopher H. Gibbons
Author information ► Copyright and License information ►
The publisher's final edited version of this article is available at Curr Pain Headache Rep
Abstract

Small fiber neuropathy manifests in a variety of different diseases and often results in symptoms of burning pain, shooting pain, allodynia, and hyperesthesia. Diagnosis of small fiber neuropathy is determined primarily by the history and physical exam, but functional neurophysiologic testing and skin biopsy evaluation of intraepidermal nerve fiber density can provide diagnostic confirmation. Management of small fiber neuropathy depends on the underlying etiology with concurrent treatment of associated neuropathic pain. A variety of recent guidelines propose the use of antidepressants, anticonvulsants, opioids, topical therapies, and nonpharmacologic treatments as part of the overall management of neuropathic pain. Unfortunately, little data about the treatment of pain specifically in small fiber neuropathy exist because most studies combine mixed neuropathic pain syndromes in the analysis. Additional studies targeting the treatment of pain in small fiber neuropathy are needed to guide decision making.

Introduction

Peripheral neuropathy is an expanding public health problem, seen in nearly 40 million individuals in the United States [1]. Many of these individuals will have specific damage to small myelinated and unmyelinated nerve fibers, either in isolation or in combination with injury to larger myelinated nerve fibers. There are a variety of diseases that may result in a small fiber neuropathy, including diabetes and other glucose dysregulation syndromes (eg, impaired glucose tolerance and metabolic syndrome), thyroid dysfunction, sarcoidosis, vitamin B12 deficiency, HIV, neurotoxic medications (including many chemotherapeutic agents and antiretroviral agents), celiac disease, paraneoplastic syndromes, and paraproteinemias [2•]. Despite extensive diagnostic evaluation, up to 50% of individuals with small fiber neuropathy ultimately may be given a diagnosis of “idiopathic” [3•]. Regardless of the underlying etiology, pain is a common and often problematic feature of small fiber neuropathies. Therefore, therapy is tailored toward identification and treatment of the underlying cause of the neuropathy, when possible, while simultaneously managing symptoms of pain.

Definition of Small Fiber Neuropathy

A small fiber neuropathy occurs when damage to the peripheral nerves predominantly or entirely affects the small myelinated (Aδ) fibers or unmyelinated C fibers. The specific fiber types involved in this process include both small somatic and autonomic fibers. The sensory functions of these fibers include thermal perception and nociception. These fibers also are involved in a number of autonomic and enteric functions.

Most small fiber neuropathies occur in a length-dependent fashion, resulting in loss of function in a stocking distribution in the lower extremities. When the condition is more advanced, a glove-like loss in the upper extremities also may occur. In rare cases, a non–length dependent neuropathy results in symptoms involving the trunk, face, proximal limbs, or other focal areas [2•, 3•].

Anatomically, the small nerve fibers may be damaged or destroyed in these conditions, resulting in a loss of small nerve fibers and/or abnormal nerve fiber morphology. However, the pathogenesis of injury to small nerve fibers is not well understood. Small nerve fiber neuropathies can occur without large nerve fiber involvement, but in some cases they occur concomitantly or progress to involve large nerve fibers.

Symptoms of Small Fiber Neuropathy

Symptoms of small fiber neuropathy can vary widely in severity. Many individuals report the gradual onset of distal symptoms that include vague disturbances of sensation in the feet. These symptoms may include the feeling of a wrinkle in a sock that cannot be removed or of small pebbles or sand in the shoe. Others may report a cold-like pain, tingling or a pins and needles sensation. More severe symptoms of small fiber neuropathy may include burning pain that often is persistent, although it may vary in intensity throughout the day. Many patients also report transient electric shock–like pain, usually lasting only seconds, but quite severe and potentially multiple times per day. Many symptoms worsen during periods of rest and at night. In addition to spontaneous pain, many individuals report allodynia and hyperesthesia. Patients with small fiber neuropathy frequently complain that the bedsheets are exquisitely painful, and therefore, wear socks or use “foot tents” to keep the sheets from making physical contact with the feet.

Small nerve fiber neuropathies also may result in autonomic and enteric dysfunction. Patients often do not identify the relationship of these symptoms to their sensory complaints; however, when asked, they may report dry eyes, dry mouth, postural lightheadedness, presyncope, syncope, abnormal sweating, erectile dysfunction, nausea, vomiting, diarrhea, constipation, early satiety, difficulty with urinary frequency, nocturia, and/or voiding [4, 5].

Examination Findings in Small Fiber Neuropathy

One of the hallmarks of a pure small fiber neuropathy is a normal or near normal physical and neurologic examination. The coordination, motor, and reflex examinations will be normal. Light touch, vibratory sensation, and proprioception also may be normal, resulting in diagnostic confusion in some situations. Patients may have decreased pinprick, decreased thermal sensation, or hyperalgesia in the affected region. There may be mildly decreased vibratory sensation in some individuals. Associated skin changes in affected areas may include dry, cracked, or shiny skin, with decreased moisture on the surface of these affected areas as well.

Causes of Small Fiber Neuropathy

Diabetes and prediabetes (including both impaired glucose tolerance and impaired fasting glucose) frequently are associated with pure small fiber neuropathy; however, concomitant large fiber involvement is seen more often [6]. Nearly half of all subjects with idiopathic small fiber neuropathy have abnormal 2-hour glucose tolerance tests or abnormal fasting glucose levels [6, 7]. The abnormal glucose testing may be seen despite normal glycosylated hemoglobin. Several studies have also established a link between pain in small fiber neuropathy and abnormal glucose metabolism [8, 9]. There also is a large overlap between prediabetes and metabolic syndrome. The metabolic syndrome is comprised of hyperlipidemia, hypertension, and obesity in addition to abnormal glucose metabolism with insulin resistance. Each of these separate factors appears to convey an increased risk of developing a small fiber neuropathy [10]. Individuals with diabetes and metabolic syndrome appear to have twice the risk of developing a small fiber neuropathy compared to those with diabetes alone [11]. Recent reports now are suggesting that the single largest contributing factor to neuropathy development is hyperlipidemia [12•, 13••]. Some patients with diabetes also may experience an acute painful small fiber neuropathy associated with rapid glycemic control, also referred to as insulin neuritis or treatment-induced neuropathy [14•].

Other conditions associated with acquired small fiber neuropathy include HIV [15, 16], inflammatory neuropathies (such as Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy) [17, 18], celiac disease [19, 20], hepatitis C [21], restless legs syndrome [22], complex regional pain syndrome type I [23], paraproteinemia [24], neurotoxic drug use [25–27], systemic lupus erythematosus [28], Sjogren’s syndrome [29], abnormal thyroid function [2•], amyloidosis, and paraneoplastic syndromes [30, 31]. This list is not comprehensive and there are many case reports describing small fiber neuropathies in other diseases. In addition, there are inherited conditions which cause small fiber neuropathies, such as Fabry’s disease and the hereditary sensory and autonomic neuropathies.

Diagnosis of Small Fiber Neuropathy

The history and physical examination findings still are considered the gold standard against which all tests are compared when making a diagnosis of a small fiber neuropathy. A detailed review of the symptoms, rate of progression, and complaints suggestive of autonomic fiber involvement is necessary. Generally, if a patient presents with a compelling history for a small fiber neuropathy and an appropriate clinical exam, further testing to confirm the diagnosis may be unnecessary. This scenario is particularly likely in the context of an associated disease, such as diabetes. However, in many cases, the diagnosis may be less clear and ancillary testing may provide additional guidance. Patients should always be screened for other treatable causes of small fiber neuropathy. Recently, scoring examinations have been developed, and may aid in diagnosis of small fiber neuropathies [32•]. In addition, the specific types of pain experienced by patients with small fiber neuropathy may need to be characterized. The Neuropathic Pain Symptom Inventory differentiates various aspects of neuropathic pain, and may aid in selection of treatments as clinical trials begin to select specific aspect of neuropathic pain as targets [33].

Quantitative Sensory Testing

Quantitative sensory testing (QST) is an extension of the physical examination that can provide a threshold for detection of thermal sensation, thermal pain, and vibratory sensation. QST has been used in a number of longitudinal studies and clinical trials of neuropathy and is widely available [34]. There are some well-recognized limitations to QST; abnormalities in either the central or peripheral nervous system can result in the same deficit. In addition, QST requires conscious integration from the patient, and in conditions of cognitive impairment (due to disease or medication), the reliability of the test results are in question. Finally, QST is unable to distinguish between feigned and true loss of sensation [35].

There are few trials utilizing QST in the study of isolated small fiber neuropathies, most trials include patients with large fiber involvement as well [34, 36]. Heat or heat-pain detection thresholds are considered the most useful and specific for evaluation of a small fiber neuropathy. Cold and cold-pain detection are transmitted through lightly myelinated Aδ fibers, while vibration detection thresholds are detected through large myelinated Aα and Aβ sensory fibers. Recent reports of contact heat evoked potentials (CHEPs), a device that provides rapid cycles of heat resulting in evoked potentials measured by electroencephalogram, show a linear correlation between CHEP amplitude and cutaneous nociceptive nerve fiber density [37]. Further study is required to determine the utility of new variations of QST on the diagnosis of a small fiber neuropathy.

Quantitative Sudomotor Axon Reflex Testing

There are a variety of methods to quantify sudomotor function. The most frequently utilized and well-known test is quantitative sudomotor axon reflex testing (QSART), a measure of postganglionic sympathetic cholinergic function. Local sweating is produced through iontophoresis of acetylcholine; this method uses a mild electrical current to draw acetylcholine (a charged substance) into the skin, causing activation of local sweat glands. The stimulation also triggers an axon reflex resulting in neighboring sweat glands, not stimulated by acetylcholine, to produce sweat. The axon reflex–mediated sweat output is detected by passing dry gas over the nonstimulated region and quantifying the change in humidity of the gas. A study of patients with small fiber neuropathy revealed that QSART was abnormal in 74% of patients, and that sudomotor dysfunction may be the earliest manifestation of a distal small fiber neuropathy [38]. Another study reported QSART to be abnormal in 73% of patients with painful feet from a small fiber neuropathy. A variety of other tests, including sweat imprint tests, thermoregulatory sweat testing, and quantitative direct and indirect sudomotor testing, also detect abnormalities in patients with a small fiber neuropathy. To date, no prospective controlled study has evaluated the ability of these tests to diagnose a small fiber neuropathy.

Skin Biopsy

Skin biopsy has become a widely accepted technique to investigate the structural integrity of small nerve fibers [39]. A standard 3-mm dermatologic punch biopsy can be taken from any location on the body, but typically is performed on sites of interest in evaluation of a distal small fiber neuropathy (the lateral distal leg, the lateral distal thigh, and the lateral proximal thigh to look for a length-dependent pattern). For clinical investigation, bright field immunohistochemistry is used with antibodies against protein gene product 9.5, a marker for all peripheral nerve fibers. The number of fibers crossing the dermal/epidermal junction is quantified through standardized means, and results are expressed as the number of intraepidermal nerve fibers per millimeter. Recently revised consensus statements have highlighted the utility of skin biopsy in the evaluation of small fiber neuropathy [40•]. The sensitivity (78%–92%) and specificity (65%–90%) of skin biopsy for diagnosing a small fiber neuropathy is fairly high across all studies. In early or mild cases of small fiber neuropathy, morphologic abnormalities of nerve fibers may aid in diagnosis if nerve fiber density is not reduced [41]. Unfortunately, there are no data on the utility of skin biopsy to diagnose the etiology of the small fiber neuropathy.

Electromyography and Nerve-conduction Studies

Electromyography and nerve-conduction studies are well-established neurophysiologic techniques used to assess the integrity of larger myelinated sensory and motor fibers. These studies often are normal in pure small fiber neuropathies. If there is question of possible larger fiber involvement causing symptoms or occurring concomitantly with a small fiber neuropathy, these studies can clarify if larger sensory and/or motor nerve fibers are involved.

Treatment of Pain in Small Fiber Neuropathy

Treatment of any underlying causative etiology of a small fiber neuropathy is likely to be the most effective treatment of pain, when possible. Many cases of small fiber neuropathy will remain idiopathic, or will still require treatment of pain. There is very limited evidence for specific medications in the treatment of pain from small fiber neuropathies. Most clinical studies have examined drugs in the treatment of many neuropathic pain syndromes (such as postherpetic neuralgia and painful diabetic neuropathy). In some trials, the spectrum of neuropathic pain can be broad and include diagnoses such as central neuropathic pain, radiculopathy, or carpal tunnel syndrome. These disorders may respond to treatment differently than pain from small fiber neuropathy. This is a challenge when developing treatment recommendations for small nerve fiber pain because comparative effectiveness across different pain states is not known.

This issue is further complicated by evidence suggesting that some diseases causing neuropathic pain respond differently to the same medications. Neither HIV nor chemotherapy-related neuropathic pain respond to treatments that are effective for other forms of neuropathic pain. It is unclear if these discrepancies are methodological or due to differences in the underlying disease state. In addition, head-to-head trials of medications and long-term outcome data for small fiber neuropathies are lacking. When possible, disease-specific treatment guidelines should be selected for management of pain in small fiber neuropathy (eg, diabetes, HIV, or chemotherapy).

In patients with idiopathic small nerve fiber neuropathy pain physicians must select treatments based on evidence of safety, efficacy in other neuropathic conditions, tolerability, drug interactions, comorbid conditions, and cost [42]. There are a number of recent consensus guidelines for the treatment of neuropathic pain [43, 44, 45•, 46, 47 48••]. None of the guidelines specifically examine treatment of pain secondary to small fiber neuropathy. Several provide recommendations based on patterns of pain or underlying disease. Most of these guidelines are based on reviews of available randomized clinical trials published in MEDLINE and the Cochrane database, although some used additional resources. The criteria used to establish the guidelines varied somewhat, although all used randomized control trials. Other variables such as safety, efficacy, tolerability, number needed to treat (NNT), side-effect profile, comorbid conditions, effect on quality of life, cost and, ease of use also were considered. Certain guidelines also addressed population-specific issues such as availability and genetic features. These guidelines were published between 2006 and 2010; the older publications do not include the most recent trials. There is significant agreement about medications among these recommendations, although classifications of first-, second-, and third-line agents vary. Table 1 highlights the recommendations of these recent guidelines and consensus statements [43, 44, 45•, 46, 48••].



Table 1

Summary of Guidelines

There are several different classes of medications commonly used to treat neuropathic pain. These include antidepressants, anticonvulsants, opioids, and topical treatments. Tricyclic antidepressants (TCAs) consistently are recommended as first tier drugs across all guidelines [43, 44, 45•, 46–48]. The criterion for study inclusion varies amongst the guidelines; however, the number of studies for neuropathic pain reviewed ranged from 2 to 17. The NNT was 2.1 to 2.5 based on the type of TCA. None of the studies specifically treated patients with small fiber neuropathy. TCAs consistently were selected as first-tier choices based on their efficacy and other factors such as cost and availability. Their mechanism of action is inhibition of serotonin and norepinephrine reuptake. TCAs also have anticholinergic effects that can cause significant side effects for some patients, and specifically should be avoided in elderly adults. They are contraindicated in patients with a significant cardiac history, glaucoma, or recent monoamine oxidase–inhibitor (MAOI) use. Guidelines note that safety and tolerability factors may limit the use of TCAs.

Serotonin–norepinephrine reuptake inhibitors (SNRIs) are another class of antidepressants commonly used for the treatment of neuropathic pain. Both duloxetine and venlafaxine are recommended as second-line agents in most guidelines. For duloxetine, most guidelines reviewed two to three studies [43, 44, 45•, 46, 47, 48••]. It has been found to be effective in painful diabetic neuropathy and the NNT was 5.2. It has not been studied for other forms of neuropathic pain; therefore, it is frequently recommended as second- or third-line treatment. It has a rapid onset of action and is generally well tolerated. It should be avoided in patients with uncontrolled narrow-angle glaucoma or those being treated with MAOIs. In rare cases it has been associated with abnormal bleeding, hepatotoxicity, and serotonin syndrome.

Venlafaxine is another SNRI that typically is recommended as a second-line agent. Two studies have found it to be effective for painful diabetic neuropathy and for mixed neuropathy with a NNT of 4.6 [43, 44, 45•, 46, 47, 48•]. In a study that compared imipramine and venlafaxine head to head, the imipramine group had a higher proportion of responders [49]. Generally, venlafaxine is well tolerated, but should be avoided in patients being treated with MAOIs. In some cases, it has been noted to increase blood pressure and cause ECG changes. Rare adverse events including bleeding, hyperlipidemia, and pulmonary complications (interstitial lung disease and eosinophilic pneumonia) have been reported. Due to differences in the NNT, TCAs are recommended over SNRIs in most guidelines except in elderly patients or others at risk for adverse events.

In addition to antidepressants, anticonvulsants also are routinely recommended for the treatment of neuropathic pain. Gabapentin frequently is utilized as a first-line treatment of neuropathic pain. Most guidelines reviewed two to four studies and the NNT was 3.9 to 4 [43, 44, 45•, 46, 47, 48••]. It is effective for neuropathic pain (specifically postherpetic neuralgia and painful diabetic neuropathy). The mechanism of action is believed to be via the voltage-gated α2δ calcium channel, modifying the release of excitatory neurotransmitters. It is well tolerated and not known to cause significant drug–drug interactions. In rare circumstances, it has been associated with Stevens-Johnson syndrome.

Pregabalin is another anticonvulsant frequently used for first-line treatment of neuropathic pain. In the included guidelines, two to six studies on pregabalin in different types of neuropathic pain (postherpetic neuralgia, painful diabetic neuropathy, or both) were reviewed. For some guidelines, several studies were excluded based on concern that the methodology included enriched enrollment. The calculated NNT was 4.2 [43, 44, 45•, 46, 47, 48••]. Pregabalin’s mechanism of action also is believed to be through the voltage-gated α2δ calcium channels and is a presynaptic inhibitor of the release of glutamate, substance P, and calcitonin gene–related peptide (CGRP). It also is typically well tolerated, but should be used with caution in patients with congestive heart failure. Angioedema rarely has been described as a side effect.

Topical lidocaine frequently is recommended as a first- or second-line treatment of focal neuropathic pain. These recommendations are typically for the lidocaine patch, although there also is evidence available for lidocaine gel. The guidelines included three or four studies (primarily for postherpetic neuralgia) and the NNT is 4.4 [43,44, 45•, 46, 47, 48••]. It is generally most effective for patients with focal regions of pain and offers the advantage of less systemic side effects and drug interactions. It also may be used for breakthrough pain. It is believed to act by decreasing neuronal membrane permeability to sodium ions. Topical lidocaine is more expensive than some of the other treatments, but is generally well tolerated. It should be avoided in regions of skin breakdown. Rare allergic or anaphylactic reactions can occur.

Lastly, opioids and tramadol frequently are recommended as second- or third-line medications across all guidelines. Among expert opinions, there is consistent concern about the use of opioids for nonterminal neuropathic pain due to dependence. Some guidelines review different types of opioids (oxycodone, morphine, methadone, and levorphanol) as well as different types of neuropathic pain (painful polyneuropathy and post-herpetic neuralgia). The number of studies included ranged from five to eight and the NNT ranged from 2.5 to 2.7 based on the type of neuropathic pain and the drug [43, 44, 45•, 46, 47, 48••]. Some guidelines suggest that opioids, typically oxycodone, be used for severe breakthrough pain either for acute exacerbations or during titration of another agent. While effective for pain, opioids pose the potential for many side effects as well as overdosing and dependence.

Tramadol is consistently recommended as a second- or third-line choice for treatment of neuropathic pain. Concerns for dependence also are raised with tramadol use. The number of reviewed studies ranged from two to three among the guidelines and included painful diabetic neuropathy, mixed polyneuropathy, or postherpetic neuralgia. The NNT ranged from 3.4 to 4.8 based on the type of neuropathic pain and criteria applied [43, 44, 45•, 46, 47, 48••]. Tramadol and its active metabolite bind to central μ-opiate receptors and inhibit ascending pain pathways. Tramadol also causes serotonin and norepinephrine–reuptake inhibition, another potential mechanism of pain relief. Side effects of tramadol can include dyspnea and respiratory depression, and it is rarely associated with myocardial infarction, pancreatitis, seizure, and serotonin syndrome. It should be avoided in patients who are actively using central nervous system depressants such as alcohol, hypnotics, opioids, or psychotropic drugs. In addition, tramadol does have the potential to interact with most antidepressant medications, and care is required due to the potential duplicative serotonin- and norepinephrine-reuptake inhibition. Also, up to 10% of Caucasians are poor cytochrome P450 2D6 metabolizers and, therefore, are unable to metabolize the drug effectively, resulting in poor efficacy [50].

In the only published study specifically examining treatment of small fiber neuropathy, both gabapentin and tramadol were found to be effective [51]. This study used an enrichment crossover design. Participants were included if they had biopsy-proven small fiber neuropathy and were self-identified as gabapentin responders. Patients first were treated with single-blinded gabapentin at their prestudy dose as well as matching diphenhydramine placebo, 50 mg, capsules for 1 week. Participants with a pain intensity score of 7.5 or higher were then allowed to continue to the second phase, in which patients were tapered off their gabapentin dose during the first week and continued on the diphenhydramine placebo for 2 weeks. Pain scores were assessed during the second week, and those participants with a pain score of 3 or higher and a 30% or greater increase from their initial phase pain scores then were randomized into a double-blind crossover phase. During the last phase of the trial, patients were randomized to three 2-week double-blind treatment periods with1-week washout periods between each treatment phase. Overall, 18 participants were treated in a randomized crossover design with 3 treatments: gabapentin at their prestudy dose, tramadol, 50 mg four times daily, and diphenhydramine 50 mg at bedtime. Three participants withdrew before completing all three treatment periods. There was a statistically significant improvement in pain scores for both gabapentin and tramadol groups when compared to diphenhydramine. The NNT for gabapentin was 4.6. The NNT for tramadol was 4.0. There was no statistically significant difference between the average pain scores during the gabapentin and tramadol treatment phases. There were no reported significant adverse events in either treatment group.

Other classes of medications have been used for the treatment of neuropathic pain including antiarrhythmics. This class typically is excluded from expert panel recommendations due to the large number of potential side effects. Selective serotonin reuptake inhibitors also are excluded as first- or second-line recommendations due to limited data on efficacy. For detailed descriptions of the guidelines, included studies, drugs and dosing, please refer to the recently published guidelines for neuropathic pain listed in Table 1 [43, 44, 45•, 46, 47, 48••].

Nonpharmacologic options also are important for pain management. Some patients may benefit from cool or warm soaks, soft socks, and foot tents. Other treatments such as transcutaneous electrical nerve stimulation, acupuncture, physical therapy and massage also have been used, but have not been examined in clinical trials for small fiber neuropathic pain [43, 44, 45•, 46, 47, 48••].

Conclusions

Small fiber neuropathy frequently is associated with neuropathic pain. The clinical history and physical examination often are sufficient to make the diagnosis of a small fiber neuropathy; however, additional functional and pathological tests may help to confirm the diagnosis. Patients should be carefully screened for reversible causes of small fiber neuropathy. A variety of medications for treatment of pain exist, and there are a number of available consensus guidelines that can aid clinicians in selecting appropriate treatments. For some conditions, such as painful diabetic neuropathy, there are additional treatment guidelines available. However, additional studies specifically targeting the pain in small fiber neuropathy are necessary to support clinical decision making. With the advent of new medications coming to market, further review of the literature will be necessary.

Acknowledgement

This work was supported in part by a grant from the National Institutes of Health (NINDS K23 NS050209 [CHG]).

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34. Peltier A, Smith AG, Russell JW, Sheikh K, Bixby B, Howard J, Goldstein J, Song Y, Wang L, Feldman EL, Singleton JR. Reliability of quantitative sudomotor axon reflex testing and quantitative sensory testing in neuropathy of impaired glucose regulation. Muscle Nerve. 2009;39:529–535. [PMC free article] [PubMed]
35. Freeman R, Chase KP, Risk MR. Quantitative sensory testing cannot differentiate simulated sensory loss from sensory neuropathy. Neurology. 2003;60:465–470. [PubMed]

36. Cruccu G, Sommer C, Anand P, Attal N, Baron R, Garcia-Larrea L, Haanpaa M, Jensen TS, Serra J, Treede RD. EFNS guidelines on neuropathic pain assessment: revised 2009. Eur J Neurol. 2010;17:1010–1018. [PubMed]

37. Chao CC, Tseng MT, Lin YJ, Yang WS, Hsieh SC, Lin YH, Chiu MJ, Chang YC, Hsieh ST. Pathophysiology of Neuropathic Pain in Type 2 Diabetes: Skin Denervation and Contact Heat Evoked Potentials. Diabetes Care. 2010;33:2654–2659. 2010. [PMC free article] [PubMed]

38. Low VA, Sandroni P, Fealey RD, Low PA. Detection of small-fiber neuropathy by sudomotor testing. Muscle Nerve. 2006;34:57–61. [PubMed]

39. Lauria G, Bakkers M, Schmitz C, Lombardi R, Penza P, Devigili G, Smith AG, Hsieh ST, Mellgren SI, Umapathi T, Ziegler D, Faber CG, Merkies IS. Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst. 2010;15:202–207. [PubMed]

40. Lauria G, Hsieh ST, Johansson O, Kennedy WR, Leger JM, Mellgren SI, Nolano M, Merkies IS, Polydefkis M, Smith AG, Sommer C, Valls-Sole J. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol. 2010;17:903–909. [PubMed] This is a critical review of all the available data on the use of skin biopsies for the assessment of small fiber neuropathy.

41. Gibbons CH, Griffin JW, Polydefkis M, Bonyhay I, Brown A, Hauer PE, McArthur JC. The utility of skin biopsy for prediction of progression in suspected small fiber neuropathy. Neurology. 2006;66:256–258. [PubMed]

42. Dworkin RH, 'Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, Kalso EA, Loeser JD, Miaskowski C, Nurmikko TJ, Portenoy RK, Rice AS, Stacey BR, Treede RD, Turk DC, Wallace MS. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007;132:237–251. [PubMed]

43. Attal N, Cruccu G, Baron R, Haanpaa M, Hansson P, Jensen TS, Nurmikko T. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2009 revision. Eur J Neurol. 2010;17:1113–1e88. [PubMed]

44. Dworkin RH, O'Connor AB, Audette J, Baron R, Gourlay GK, Haanpaa ML, Kent JL, Krane EJ, Lebel AA, Levy RM, Mackey SC, Mayer J, Miaskowski C, Raja SN, Rice AS, Schmader KE, Stacey B, Stanos S, Treede RD, Turk DC, Walco GA, Wells CD. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. 2010;85:S3–S14. [PMC free article] [PubMed]

45. Moulin DE, Clark AJ, Gilron I, Ware MA, Watson CP, Sessle BJ, Coderre T, Morley-Forster PK, Stinson J, Boulanger A, Peng P, Finley GA, Taenzer P, Squire P, Dion D, Cholkan A, Gilani A, Gordon A, Henry J, Jovey R, Lynch M, Mailis-Gagnon A, Panju A, Rollman GB, Velly A. Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag. 2007;12:13–21. [PubMed] This is a comprehensive medication review of different agents used to treat neuropathic pain.
 
46. Acevedo JC, Amaya A, Casasola OL, Chinchilla N, De GM, Florez S, Genis MA, Gomez-Barrios JV, Hernandez JJ, Ibarra E, Moreno C, Orrillo E, Pasternak D, Romero S, Vallejo M, Velasco M, Villalobos A. Guidelines for the diagnosis and management of neuropathic pain: consensus of a group of Latin American experts. J Pain Palliat Care Pharmacother. 2009;23:261–281. [PubMed]

47. Bohlega S, Alsaadi T, Amir A, Hosny H, Karawagh AM, Moulin D, Riachi N, Salti A, Shelbaya S. Guidelines for the pharmacological treatment of peripheral neuropathic pain: expert panel recommendations for the middle East region. J Int Med Res. 2010;38:295–317. [PubMed]

48. Attal N, Cruccu G, Haanpaa M, Hansson P, Jensen TS, Nurmikko T, Sampaio C, Sindrup S, Wiffen P. EFNS guidelines on pharmacological treatment of neuropathic pain. Eur J Neurol. 2006;13:1153–1169. [PubMed] This is a very thorough review of the treatment of neuropathic pain, highlighting the strength and weakness of pharmacologic agents across a spectrum of diseases and calculating the number needed to treat.

49. Sindrup SH, Bach FW, Madsen C, Gram LF, Jensen TS. Venlafaxine versus imipramine in painful polyneuropathy: A randomized, controlled trial. Neurology. 2003;60:1284–1289. [PubMed]

50. Kroemer HK, Eichelbaum M. "It's the genes, stupid". Molecular bases and clinical consequences of genetic cytochrome P450 2D6 polymorphism. Life Sci. 1995;56:2285–2298. [PubMed]

51. Ho TW, Backonja M, Ma J, Leibensperger H, Froman S, Polydefkis M. Efficient assessment of neuropathic pain drugs in patients with small fiber sensory neuropathies. Pain. 2009;141:19–24. [PubMed]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086960/

The Need For Answers About Neuropathy

Today's post from medscape.com (see link below) reports on an expert's honest opinion about the current treatment options for neuropathy. The article is titled 'diabetic neuropathy' but applies to all neuropathies whatever the cause. It's refreshing to hear a qualified speaker finally admitting that current treatments are just inedaquate but until something better comes along, we have to make do with what we have. He goes on to look at the pros and cons of various current medications but admits what we all know, that the current list of medications is more of a plaster over the wound than a cure or means of nerve repair. Worth reading.

Diabetic Peripheral Neuropathy: An Unmet Clinical Need
Lisa Nainggolan January 08, 2014 Medscape Medical News - Conference News


MELBOURNE, Australia — Pharmaceutical options for diabetic peripheral neuropathy are sorely required, says one expert in the field.

Speaking at the International Diabetes Federation World Diabetes Congress 2013 in Melbourne last month, Rayaz A. Malik, MBChB, FRCP, PhD, from the Central Manchester University Teaching Hospitals and University of Manchester, United Kingdom, said: "We have no licensed treatment for diabetic neuropathy. We have witnessed failure after failure of numerous clinical trials despite great experimental data. None of these drugs has been translated into therapies we can prescribe to our patients."

One issue is that many of the trials of such agents have included patients who already have quite advanced neuropathy. The lack of simple, objective, sensitive tests to assess early nerve damage and repair is a limiting factor, said Dr. Malik. "The currently advocated tests, such as neurophysiology, focus on the large fibers, instead of the more abundant and clinically relevant small fibers," he noted.

"We need to critically look at the way we run these clinical trials and the end points used. If you have a test that is not sensitive enough for assessing early improvement, then despite million-dollar trial programs, the drug fails."

Neuropathy: A Microvascular Complication, Often Painful

Dr. Rayaz A. Malik

Dr. Malik, who specializes in treating diabetic peripheral neuropathy, explained that type 1 and type 2 diabetes are the commonest causes of painful neuropathy in the Western world, with 50% of patients with diabetes suffering from neuropathy, which can be painless or painful. Others causes of neuropathy include HIV neuropathy and chemotherapy-induced neuropathy (CIPN).

Around 20% of patients with diabetic neuropathy will suffer from pain, "which can be anything from mild discomfort to debilitating, can't-sleep-at-night pain, predominantly in the lower limbs and feet — sharp, jabbing pains, to the point where some patients can't even have bed sheets over their feet." He estimates that 5% of patients are "very badly affected."

As well as the pain, other complications of neuropathy include falls and foot ulcers, with the latter leading to digit, foot, or limb amputation if not managed correctly. The development of infections and ulcers can be reduced with good screening and surveillance programs.

Dr. Malik said it has become clear that neuropathy is "a microvascular complication" of diabetes, "just like nephropathy and retinopathy," and recent data have indicated that cardiovascular risk factors such as blood pressure and lipids are in fact stronger predictors of whether a patient will develop peripheral neuropathy than glucose control.

"Glucose control is advocated but at best has been shown to prevent progression in type 1 diabetes (in the DCCT studies) but not in type 2 diabetes [data from UKPDS, ACCORD, ADVANCE, and VADT]."

Improved blood-pressure control has been shown to work "in 2 small trials," he added, one with the ACE inhibitor trandolapril (Mavik, Abbott Laboratories) (Lancet.1998;352:1978-1981) and the other with a combination of the ACE inhibitor delapril and the calcium-channel blocker manidipine (Hypertension. 2011;58:776-783).

New UK Guidance for Diabetic Neuropathy Pain

There are treatments for the pain associated with neuropathy, however, although this is merely symptom relief and does not address the underlying nerve damage.

The therapeutic choices for pain relief are tricyclic antidepressants, selective serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine, and the antiepileptics gabapentin and pregabalin (Lyrica, Pfizer), Dr. Malik explained to Medscape Medical News.

Although the efficacy of all of these agents has been proven compared with placebo in randomized clinical trials, the evidence for gabapentin and tricyclic antidepressants in particular is "limited," he noted. And there have been very few head-to-head trials comparing these different treatments.

In fact, the treatment of painful diabetic neuropathy is "far from adequate, but…we make do with at least something, and at best 50% of patients get 50% pain relief," he observes. Side effects are also an issue, said Dr. Malik, especially from the centrally acting agents; these include "sedation, nausea, and off-target anticholinergic effects of the tricyclics such as postural hypotension and urinary retention."

Only duloxetine and pregabalin are actually licensed for use in diabetic neuropathy pain, he pointed out, with use of gabapentin and tricyclics being off-label for this condition. Most organizations worldwide recommend a choice of one of these agents, with slight variations in terms of which is first-, second-, or third-line choice of therapy.

In fact, in the United Kingdom, the National Institute for Health and Care Excellence (NICE) has just issued new guidance stating that duloxetine, pregabalin, gabapentin, and tricyclic antidepressants "can now all be considered as first-line agents," he explained. Until recently, duloxetine was indicated as first-line therapy for diabetic painful neuropathy there.

The new UK guidance — the pharmacological management of neuropathic pain in adults in nonspecialist settings — covers all types of neuropathic pain, not just diabetic.

The American Diabetes Association (ADA) has also recently drawn attention to the difficulties of treating diabetic painful neuropathy in its annually revised clinical-practice guidelines Standards of Medical Care in Diabetes — 2014. This year's report has a newly expanded section on diabetic neuropathy, going into greater detail about the various treatments and their limitations.

The section encourages physicians to be more persistent in urging patients to stay on pain medications long enough to give them a chance to work and using an individualized "trial-and-error" approach with different drugs and drug combinations.

"Neuropathy is a difficult condition to treat, and the meds we have aren't that good... This is an area that really requires communication between the care team and the patient," Richard Grant, MD, MPH, a research scientist at the Kaiser Permanente Division of Research, Oakland, California, and chair of the ADA Professional Practice Committee, told Medscape Medical News last month.

Fenofibrate and Corneal Confocal Microscopy

One building story is the potential role of triglycerides in diabetic peripheral neuropathy. Fenofibrate (Lipidil, Abbott), a triglyceride-lowering agent, has just been approved in its first market worldwide, Australia, for the treatment of diabetic retinopathy based on data from the FIELD study. The same study also showed that fenofibrate reduced minor amputations by 50%, explained Dr. Malik, noting that amputations were a prespecified end point of this trial.

Dr. Malik said some doctors do currently use fenofibrate for diabetic peripheral neuropathy, off-label, but that to gain an indication specifically for this use "will require a large clinical trial using the right end points."

Companies are reluctant to fund trials with amputations as an end point, as the studies take too long, he explained. "Instead, neuropathy end points have predominantly been clinical neurological examination for deficits (very variable and poorly reproducible) or neurophysiology (which assesses only large fibers that constitute 10% of nerve fibers and is also not very reproducible)."

Another reason many trials have failed in this field is that the patients included already had advanced neuropathy when they participated, he noted.

"More sensitive and quantitative measures of early nerve repair are needed to identify patients who are responding to treatment, providing a signal to continue, rather than abort a trial prematurely," he stressed.

One potentially useful technique that his team and others around the world have been pioneering is called corneal confocal microscopy (CCM). "This is an ophthalmic instrument that allows us, in a noninvasive way, to assess nerve fiber structure very sensitively."

Another sensitive technique is skin biopsy, but this has the disadvantage of being invasive. "When you have 2 tests with similar sensitivity: skin biopsy or CCM, which is totally noninvasive, the latter seems to be the logical route to go down."

Dr. Malik added that CCM can also show repair of nerves "even in patients with advanced neuropathy who have undergone pancreas and renal transplantation." The technique can also be employed in in a range of other neuropathies.

A review on this emerging technique, "An Eye on the Foot," on which he was senior author, was published in September last year (J Diabetes Sci Technol. 2013;7:1179–1189).

http://www.medscape.com/viewarticle/818838

Two Videos About Neuropathy Medical Cannabis And HIV Vid

Today's two YouTube videos presented by Dr. Donald Abrams, are pretty much a follow-up to yesterday's post and are directed at people living with both HIV and neuropathy. They set about justifying the use of medical marijuana to relieve nerve pain. The first video concentrates on Dr Abram's experiences of medical cannabis and HIV/Aids wasting syndrome and serves more as a background to the Part Two video. The second video, talks about how he discovered the benefits of cannabis for people living with both HIV and neuropathy.
The transcripts are shown below each video.

Dr. Donald Abrams Tells Us How Medical Marijuana Helps AIDS Patients - Pt 1

Transcription
There are patients able to overcome their nausea and vomiting from their chemotherapy and perhaps even be cured of these malignancies by using cannabis. But what really started me in my research was in my work with HIV AIDS patients. Again seeing them being eaten alive if you will by the AIDS wasting syndrome, which was a common sort of end of life phenomenon that we had before we discovered effective anti retroviral drugs and about the time Delta-9 THC was approved, thats the drug durnabinol or marinol, for treatment for this wasting syndrome in HIV patients. We began to hear from these patients that they actually preferred smoking the cannabis because of their ability to titrate the effect better than swallowing a pill. We know now that cannabis taken by mouth either as baked product or the medication Delta-9 THC has much different absorbs ion and kinetics. It takes a much longer time to reach a much lower peak and then it stays in the system for quite a while. Whereas when it is inhaled, either smoked or vaporized, the peak plasma concentration is actually reached in about 2 minutes and then falls over the next 30 minutes. So the effect happens more rapidly and perhaps dissipates more rapidly. When taken by mouth, the Delta-9 THC, then main psychoactive component is metabolized in the liver to a 11 hydroxy form that is also psychoactive. So when eaten as either a baked product or as the pill the Delta-9 THC creates this psychoactive metabolite that makes people have even more of a psychoactive effect that when it is smoked. And for many patients this is unpleasant. So in 1992 I was challenged, if I may, to study smoked marijuana in patients with the Aids wasting syndrome and to compare it to marinol or durabinol which had been just approved for that indication. And that began a bit of a sort of struggle with our government to be able to conduct a clinical trial. But ultimately after a number of years we did get a million dollars and 1400 government cannabis cigarettes to do a clinical trial. It wasnt any more in patients with the AIDS wasting syndrome, because by this time we had effective anti-retroviral drugs and that syndrome had disappeared. And with the national institute on drug abuse they have actually a congressional mandate that they can only study substances of abuse as substances of abuse. So they were never going to allow me or to give me marijuana to study as a possible therapeutic agent. The study I ultimately got funded for was to study whether or not it was safe. For patients with HIV on the new potent anti-retroviral regimes to use cannabis. Because there had been a report in the literature of a patient using ecstasy or MDMA and dying from an overdose of ecstasy when taken with these antiviral drugs. So the question I posed and the government allowed me investigate, was is it safe for patients on the anti-retroviral drugs to smoke cannabis or to take the cannabis pill while they were taking the protease inhibitors.

Dr. Donald Abrams Tells Us How Medical Marijuana Helps AIDS Patients - Pt 2

Uploaded on 5 May 2010


Transcription
So we did that study, and we showed that there was no damage to the level of the aids drug in the blood stream to the patients immune system or to the level of the virus in their blood stream over 21 days of smoking a government cigarette 3 times a day. And that led us then to move on and do other research looking to see if whether or not cannabis had any medicinal benefit for patients with HIV. Particularly we were fortunate in California when we had a budget surplus that one of our state senators established a center for medicinal cannabis research at the university of California. And that center worked out a deal with NIDA so that NIDA the only legal source of marijuana for research in the country would supply investigators who had been favorably peer reviewed by the University of California Center for Medicinal Cannabis Research to do clinical trials looking at the effectiveness of smoked marijuana. So I submitted a study to look at marijuana in patients with the painful HIV related peripheral neuropathy, which is the damage to the nerves in the hands and feet. For which we really didnt have any treatment. Opioid analgesics dont work well. We tried acupuncture. Most people use anti seizure medications. And these also could interact with the levels of the aids drugs. So we proposed a study to see if smoked cannabis could alleviate the pain of this peripheral neuropathy and ultimately we wound up doing a placebo-controlled trial where 25 patients smoked real cannabis from the government and 25 smoked cannabis that had the active ingredient had been extracted. And we showed the group that smoking the real cannabis had a decrease not only in their peripheral neuropathy pain in an experimental pain that we created in the patients by heating their skin to 104 degrees and then applying caparison cream on top of their skin. So that study funded by the Center for Medicinal Cannabis Research actually was the one of the first modern studies to be done that showed in a randomized placebo control fashion that cannabis does have a medicinal use and that is for treatment of HIV related peripheral neuropathy. And when we looked at our results the effectiveness of cannabis in that situation is comparable to the effectiveness of the drug that is most commonly used the anti seizure medications. Now do I think the government will change cannabiss schedule 1 classification which means it has no accepted medical use, on the basis of a study of 25 patients smoking cannabis and 25 smoking placebo. No, I think I have been around long enough to know thats not gonna do it.

https://www.youtube.com/watch?v=oAOGESbo22k and
https://www.youtube.com/watch?v=Qfs6RMFYBec

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Covering The Basics About Neuropathy

Today's post from postindependent.com (see link below) is a short, general information article about neuropathy, specifically designed for those new to the disease, or family and friends who want to know more about what's so clearly affecting someone in their circle. For that reason, it's short and concise and you will need to do much more research from now on but it does cover the basics and will be helpful to those wanting a quick explanation of what's going on. Definitely worth a read; if not for yourself, maybe for someone you know.

Aging column: What you should know about neuropathy
Judson Haims February 1, 2016

Neuropathy in its simplest definition is nerve disease or damage. It is a relatively common condition and is not isolated to any particular part of the body. Injury, infection, exposure to toxins and alcohol/drugs can all contribute to neuropathy.

Neuropathy affects:

• Sensory nerves, which control sensation. Effects of this type of neuropathy often include impaired sense of touch, reflex and balance.

• Motor nerves, which govern movement. These nerves, if affected, contribute to issues of muscle twitching, weakness and atrophy.

• Autonomic nerves, which influence internal organs. Bladder control, blood pressure, digestion and sweating abnormalities are associated with this type of disorder.

TYPES OF NERVOUS SYSTEMS

The central nervous system (CNS) is contained within the brain and spinal cord. Neuropathy occurring within the CNS is often associated with spinal cord injury, scaring of tissue surrounding nerves, alcohol abuse and Parkinson’s.

The peripheral nervous system is the largest nervous system of the human body. The nerves that run through our arms, hands, fingers, legs feet and toes are peripheral nerves — they transmit sensory information back to the CNS of the brain and spinal cord.

While neuropathy can commonly occur in your central nervous system, it more often affects the peripheral system.

According to the National Institutes of Health, “An estimated 20 million people in the United States have some form of peripheral neuropathy, a condition that develops as a result of damage to the peripheral nervous system — the vast communications network that transmits information between the central nervous system (the brain and spinal cord) and every other part of the body. Symptoms can range from numbness or tingling, to pricking sensations (paresthesia) or muscle weakness.

“Areas of the body may become abnormally sensitive, leading to an exaggeratedly intense or distorted experience of touch (allodynia). In such cases, pain may occur in response to a stimulus that does not normally provoke pain. Severe symptoms may include burning pain (especially at night), muscle wasting, paralysis, or organ or gland dysfunction. Damage to nerves that supply internal organs may impair digestion, sweating, sexual function and urination. In the most extreme cases, breathing may become difficult, or organ failure may occur.”

DIAGNOSIS

In the United States, the most common cause of peripheral neuropathy is diabetes. According to the American Diabetes Association, 60 to 70 percent of people with diabetes will develop neuropathy.

Peripheral neuropathy is often difficult to diagnose. Because it can affect many different parts of the body, it is sometimes hard to determine the specific cause of symptoms. Often, medical professionals will start by running blood tests, physical exams, reviewing medical history and examining family neurological diseases.

Further testing may include nerve and skin biopsies, nerve function tests, and CT/MRI imaging. An electromyogram (EMG) study may also be suggested. EMG studies are used to evaluate and measure the electrical activity of muscles at rest and during contraction. Nerve conduction studies measure the ability of sensor y and motor nerves and how well they send electrical signals.

Prevention

Although people with diabetes often experience neuropathy issues, one of the best steps to taking an active role in minimizing your exposure to peripheral neuropathy is keeping your blood sugar levels under control. This requires constant monitoring by anyone that may have neuropathy concerns however, for those with diagnosed diabetes the A1C test should be taken at least twice a year.

Maintaining good foot care plays a very important part in minimizing risks of neuropathy. Properly trimming toenails, wearing dry and clean socks, wiggling your toes, moving your ankles up and down multiple times a day, and wearing shoes that are comfortable and fit well may assist in mitigating many foot problems.

Great information about peripheral neuropathy can be found at the Foundation for Peripheral Neuropathy, the American Diabetes Association, and the Brain Resources and Information Network division of the National Institute of Neurological Disorders and Stroke.

If you have experienced loss of sensitivity in your hands and/or feet, or have noticed balance concerns, a visit to your doctor may be a good idea.

Judson Haims is the owner of Visiting Angels Home Care in Garfield County. His contact information is, www.visitingangels.com/comtns, 970-328-5526.

http://www.postindependent.com/news/20441999-113/what-you-should-know-about-neuropathy