Peripheral Neuropathy

Peripheral Neuropathy: Pathogenic Mechanisms and Alternative Therapies

Abstract
Peripheral neuropathy (PN), associated with diabetes, neurotoxic chemotherapy, human immunodeficiency virus (HIV)/antiretroviral drugs, alcoholism, nutrient deficiencies, heavy metal toxicity, and other etiologies, results in significant morbidity. Conventional pain medications primarily mask symptoms and have significant side effects and addiction profiles. However, a widening body of research indicates alternative medicine may offer significant benefit to this patient population. Alpha-lipoic acid, acetyl-L-carnitine, benfotiamine, methylcobalamin, and topical capsaicin are among the most wellresearched alternative options for the treatment of PN. Other potential nutrient or botanical
therapies include vitamin E, glutathione, folate, pyridoxine, biotin, myo-inositol, omega-3 and -6 fatty acids, L-arginine, L-glutamine, taurine, N-acetylcysteine, zinc, magnesium, chromium, and St. John's wort. In the realm of physical medicine, acupuncture, magnetic therapy, and yoga have been found to provide benefit. New cutting-edge conventional therapies, including dual-action peptides, may also hold promise.


Introduction
Prevalence

Peripheral neuropathy (PN) - characterized by pain, numbness, and tingling in the extremities and slow nerve conduction - affects a significant percentage of the U. S. population and can be extremely debilitating. A 1999-2000 report, National Health and Nutrition Examination Survey (NHANES), of 2,873 men and women ages 40 or older (419 with diabetes), found a PN prevalence of 14.8 percent. PN was defined as at least one insensitive area on the foot with monofilament testing; it was also assessed by self-reported symptoms. The incidence of PN was significantly higher (62%) in the subset with diabetes. The incidence of PN also increased significantly with age. NHANES found 8.1 percent of the 40-49 year age group had PN, compared to 34.7 percent of individuals over age 80.


Etiological Factors
Peripheral neuropathy manifests as axonal degeneration. Diagnosis of PN involves a complete evaluation to determine the extent of the neurological deficit as well as a complete history and physical examination to determine the possible etiology. Despite thorough history and physical exam, etiology remains a mystery in approximately 50 percent of cases.

Peripheral neuropathy can be the result of genetics, chronic disease, environmental toxins, alcoholism, nutritional deficiencies, or side effects of certain medications.

Among chronic diseases, diabetes mellitus is the most common cause of PN. Mechanisms involved in diabetes-associated PN are discussed in depth in a later section. Other endocrinological abnormalities that can result in neuropathy include hypothyroidism and acromegaly. The neuropathy associated with hypothyroidism commonly manifests as carpal tunnel syndrome. Other manifestations resemble diabetic neuropathy, with tingling paresthesias in a stocking- glove distribution. PN of acromegaly (excess growth hormone) includes carpal tunnel syndrome and sensorimotor polyneuropathy. Human immunodeficiency virus (HIV) also results in PN, usually involving distal, nonpainful paresthesias, decreased ankle reflexes, and abnormal pain and temperature perception. Amyloidosis is another chronic disease resulting in PN.

Environmental neurotoxins that can cause peripheral neuropathy include exposure to mold in water-damaged buildings, solvents such as n-hexane and methyl n-butyl ketone, and heavy metals, including thallium, arsenic, lead, mercury, and germanium. Peripheral neuropathy is common among chronic alcohol abusers, with prevalence as low as nine percent and as high as 50 percent. Alcohol-associated PN is related to a combination of factors, including malnutrition, nutrient deficiencies (thiamine in particular), and direct neurotoxicity of alcohol. Medications that commonly result in PN include the chemotherapy drugs cisplatin, suramin, paclitaxel, and docetaxel, as well as cholesterollowering statin drugs, HIV antiretroviral drugs, and thalidomide.


Pathogenesis of Peripheral Neuropathy
Diabetic Peripheral Neuropathy


PN affects 30 percent of hospitalized and 20 percent of non-hospitalized individuals with diabetes. The mechanisms underlying PN depend on etiology. Diabetes, being the most common etiological factor, is also the most studied in terms of pathogenesis. While conventional theory holds that prolonged hyperglycemia results in the complications associated with diabetes, including neuropathy, a recent study found PN can manifest even in individuals with abnormal glucose tolerance, a pre-diabetic condition. The study found that in a group with chronic idiopathic polyneuropathy, subjects were twice as likely to have abnormal glucose tolerance than age-matched controls from the general population.

The pathophysiology of diabetic neuropathy includes increased oxidative stress yielding advanced glycosylated end products (AGEs), polyol accumulation, decreased nitric oxide/impaired endothelial function, impaired (Na+/K+)-ATPase activity, and homocysteinemia. Not only are nerve cells more likely to be destroyed in a hyperglycemic environment, but repair mechanisms are also defective. Reduced levels of neurotrophic agents, including nerve growth factor and insulinlike growth factor, have been noted in experimental diabetes.

Oxidative Stress/Protein Glycosylation

Diabetes results in increased products of oxidation. In hyperglycemia, glucose combines with protein, yielding glycosylated proteins, which can become damaged by free radicals and combine with fats, yielding AGEs that damage sensitive tissues. In addition, glycosylation of antioxidant enzymes can render the defense system less efficient.

Significant evidence points to increased oxidative stress in diabetic PN, either because of enhanced production of reactive oxygen species (ROS) or defective scavenging of free radicals. A study compared markers of oxidative stress in 189 people with diabetes (105 with PN, 22 with PN plus cardiac autonomic neuropathy [CAN], and 22 with no PN or CAN) with 85 controls. Markers of oxidative stress included plasma 8-iso-prostaglandin F2a, superoxide anion generation, and lag time to peroxidation by peroxynitrite. Subjects with PN or PN plus CAN demonstrated significant elevations of all three markers, as well as significant decreases in the protective antioxidant vitamins C and E.

The effect of pro-oxidants has been examined in experimental diabetic neuropathy. In one study,
rats exposed to two pro-oxidant interventions - either the drug primaquine or a vitamin E-deficient diet
- demonstrated decreased nerve conduction velocity (NCV), nerve growth factor in the sciatic nerve, and neuropeptides compared to diabetic rats not exposed to additional oxidative stress.

Sytze van Dam provides a review of the pathophysiology of oxidative stress in PN, including
a summary of additional in vitro and animal research.


Polyol Accumulation
Glucose is able to passively diffuse without insulin into certain types of cells, including nerve
cells. Once inside the cell, glucose is converted to sorbitol and other polyols by the enzyme aldose reductase. Because polyols do not passively diffuse out of cells, they concentrate within cells such
as neurons, creating an osmotic gradient that allows excess sodium and water to follow.

It is now believed that, in addition to osmotic effects, polyol-pathway linked metabolic changes are
involved. Fructose is also a byproduct of polyol-pathway activation via the sorbitol dehydrogenase-driven conversion of sorbitol to fructose. High fructose levels result in increased AGE precursors, another source of oxidative stress.

Accumulation of sorbitol and fructose in nerve cells has been shown to decrease (Na+/K+)-ATPase activity. In addition, free carnitine and myo-inositol content in the caudal nerves of diabetic rats were significantly decreased with polyol accumulation. Providing the rats with an aldose reductase inhibitor
decreased the depletion of both myo-inositol and carnitine in caudal nerves and preserved (Na+/
K+)-ATPase activity in the sciatic nerve, adding further evidence that metabolic derangements are
associated with polyol-pathway hyperactivity.

Nitric Oxide Deficiency/Impaired Endothelial Function: The Arginine Connection
Vascular factors have also been implicated in the pathogenesis of diabetic PN. Nerve blood flow is diminished in experimental diabetic neuropathy, and numerous studies indicate it may be mediated by alterations in nitric oxide metabolism. One such study examined nerve blood flow and nitric oxide synthase (NOS) activity in the microvasculature serving peripheral nerves in diabetic rats. Hyperglycemia resulted in a significant diminution of nerve blood flow compared to controls. N-nitro-L-arginine, an inhibitor of NOS, also resulted in decreased nerve blood flow. L-arginine reversed the effects of NOS inhibitionand restored blood flow to the nerves.

An animal study also found disruptions in neuronal nitric oxide synthase (nNOS) in experimental diabetes. Decreased nNOS expression was associated with increased neuropathic pain.

Nitric oxide plays an important role in controlling (Na+/K+)-ATPase activity, a diminution of which has been implicated in the pathogenesis of PN. Experimental analysis revealed hyperglycemia results in an excess of endothelial superoxide radicals that result in reduced stimulation of NO on (Na+/K+)-ATPase activity; this effect is inhibited by L-arginine. Another animal study, however, did not find a relationship between altered NO activity and the development of sensory PN. The Sorbitol Pathway D-Glucose Aldose Reductase NADPH H+ NADP+ D-Sorbitol NAD+NADPH H+ Sorbitol Dehydrogenase D-Fructose


Review Peripheral Neuropathy
Alternative Medicine Review u Volume 11, Number 4 u 2006 Page 297 Erectile dysfunction (ED) in diabetic men correlates with reduced NO activity and resultant endothelial dysfunction. A study of 60 men with diabetes (30 with ED) found a further correlation with peripheral neuropathy. Heat/pain perception was abnormal in 40 percent of diabetics with ED but in only 10 percent of diabetics without ED, while warmth perception was abnormal in 50 percent of those with ED compared to 30 percent without ED.29 These results indicate a probable connection between abnormal NO activity and neuropathy in a clinical setting.

A Connection Between Increased Polyol Activity and Decreased NO Activity?
The interrelationships between the various pathogenetic aspects of diabetic PN are poorly understood.
An animal study attempted to elucidate a possible connection between aldose reductase activity (enhanced polyol pathway activity) and decreased NO activity. The researchers found NO to be an important mediator of nerve (Na+/K+)-ATPase and aldose reductase activity on NCV. NADPH is a cofactor for both NOS and aldose reductase. Therefore, the authors theorize that hyperglycemia increases activity of aldose reductase, subsequently decreasing NOS activity via cofactor competition. Hyperhomocysteinemia Diabetes and its complications are associated with elevated homocysteine levels. A group of 65 subjects with type 2 diabetes were divided into two groups, those with neuropathy (n=43) and those without neuropathy (n=22). The frequency of hyperhomocysteinemia (≥15 μmol/L) was significantly higher in the group with neuropathy (13/43) compared to those without neuropathy (1/22). Of the three vitamin cofactors for homocysteine metabolism (vitamins B6 and B12 and folate), plasma vitamin B12 levels demonstrated a downward trend in the neuropathy group, whereas there were no differences in vitamin B6 or folate levels between the two groups.


Hyperhomocysteinemia is associated with impairment of endothelial function, providing a mechanism for its possible involvement in diabetic complications, including neuropathy. Researchers propose a synergistic effect between AGEs and homocysteine, resulting in endothelial damage. In a group of 75 type 1 diabetics, those with hyperhomocysteinemia had significantly higher plasma thrombomodulin levels (a sign of endothelial damage; 62.2 ng/mL versus 38.2 ng/mL) and higher prevalence of neuropathy (57% versus 41%). Not all studies have found a correlation between high homocysteine levels and diabetic neuropathy. In a study of 629 people (266 with normal glucose tolerance, 167 with impaired glucose tolerance, and 162 with type 2 diabetes) no definitive correlation was found between hyperhomocysteinemia and PN.

Alcohol-related Neuropathy
Neuropathy associated with chronic liver disease/alcoholism appears to be associated with direct toxic effects of alcohol, malnutrition, thiamine deficiency, and genetics. Ammendola et al found the strongest correlation was between incidence of axonal neuropathy (most commonly of the sural nerve) and total lifetime dose of ethanol, compared to other parameters examined (malnutrition and family history of alcoholism). Other B-vitamin deficiencies, including folate deficiency, have also been associated with cases of alcohol-related neuropathy.


Thyroid/Pituitary Neuropathies

Mucinous deposits in soft tissue resulting in nerve compression and carpal tunnel-like symptoms have been implicated in neuropathy associated with hyperthyroidism.3 Neuropathy associated with excess
growth hormone or acromegaly has been associated with subperineurial-tissue proliferation and diminished myelinated and unmyelinated fibers.


AIDS-associated Neuropathy
Peripheral neuropathy affects as many as one-third of individuals with acquired immunodeficiency syndrome (AIDS), most commonly manifested as distal, symmetrical polyneuropathy. A study of 251 HIV-positive individuals found the incidence of neuropathy was significantly correlated with extent of immune deficiency (reflected in low CD4 counts) and malnutrition (decreased weight, hemoglobin, and serum albumin).

Peripheral Neuropathy Review

PN associated with AIDS resembles PN caused by vitamin B12 deficiency. Kieburtz et al report a prevalence of vitamin B12 deficiency (20%) in HIV-infected patients with PN.33 Others have reported no association between vitamin B12 deficiency and AIDS-related PN.4,34 Other proposed mechanisms (aside from antiretroviral drugs, addressed below) for the high incidence of PN in AIDS include increased oxidative stress and inflammatory cytokine production, and impaired repair mechanisms caused by decreased S-adenosylmethionine.

Drug-induced Neuropathy

Factors that render peripheral nerves susceptible to drug toxicity include a leaky blood-peripheral nerve barrier (compared to the blood-brain barrier) and genetics.

Antiretroviral Agents

Antiretroviral drugs used to treat individuals with HIV are implicated in PN. One study of 147 HIV-positive adults found exposure to didanosine (ddI) or stavudine (d4T) significantly increased the risk of developing PN (odds ratio of 3.21 and 7.66, respectively);36 zalcitabine (ddC) can also cause neuropathies. It is believed the neuropathies occur in part because of drug-induced mitochondrial defects. In a rabbit model, ddC resulted in demyelination via Schwann cell mitochondrial toxicity.37 High lactic acid levels are associated with the use of antiretroviral drugs and may be used to differentiate druginduced versus AIDS-related neuropathy in people with HIV.

Cancer Chemotherapeutic Agents
Numerous cancer chemotherapy drugs are associated with neurotoxicity and PN.
High cumulative doses of cisplatin result in incidence of PN as high as 70-100 percent, with more conventional lower doses resulting in a PN rate of 12 percent. Impaired DNA repair mechanisms are believed to be the cause of PN in this population. Taxoids such as paclitaxel and docetaxel result in peripheral neuropathy, particularly at high doses. The mechanism is unknown but large arrays of disordered microtubules, a major effect on tumor cells, may be a cause of neurotoxicity. Vinca alkaloids may exert neurotoxic effects by inhibiting microtubular assembly. Lipid-lowering Drugs PN is one of the less common side effects of the class of cholesterol-lowering drugs that inhibit 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase - the so-called statin drugs. A case-control study using automated databases found a significant increase in neuropathy in people taking lipid-lowering drugs as a whole (odds ratio: 1.27); statins (odds ratio: 1.22), and fibrates (another class of lipid-lowering drugs; odds ratio: 1.54). Potential mechanisms include interruption of cholesterol synthesis, resulting in disruption of cholesterol-rich neuronal membranes, or inhibition of coenzyme Q10 synthesis (also inhibited by HMG CoA reductase), resulting in neuron mitochondrial damage. A suspected case of diabetic neuropathy in a patient with type 1 diabetes on a statin drug completely resolved when the statin drug was withdrawn - indicating the neuropathy was from statin use, not diabetes. On the other hand, statin drugs may actually restore normal nerve function in diabetic neuropathy. In a study of mice with type 2 diabetes and neuropathy, the statin drug rosuvastatin restored nerve function and vascularity, at least in part by restoring nNOS, which improved microcirculation. Cancer Chemotherapeutic Agents Associated with Peripheral Neuropathy Cisplatin and its analogs 5-Fluorouracil  5-Azacytedine Vinca alkaloids (vincristine, vinblastine, etc.) Taxoids (paclitaxel, docetaxel) Cytarabine Etoposide Gemcitabine Hexamethylmelamine Ifosphamide Misonidazole Suramin VM-26 Copyright © 2005 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 10, Number 4 December 2005 Review Peripheral Neuropathy Alternative Medicine Review u Volume 11, Number 4 u 2006 Page 299 Conventional Treatment of PN Treatment of peripheral neuropathy depends, in part at least, on the cause of the neuropathy. In the case of drug-induced neuropathy, removing the offending agent or decreasing the dose can result in resolution of the symptoms. In other cases, such as in the case of alcohol-related neuropathy, correcting a deficiency (in this case B vitamins, particularly thiamine) is essential. Initially, it is often necessary to provide thiamine intravenously. Because of the prevalence of PN in diabetes, much of the research has focused on diabetic neuropathy. Conventional treatments include antidepressants (tricyclics - TCAs and serotonin selective reuptake inhibitors - SSRIs), anticonvulsants, antiarrhythmics (sodium-channel blockers; mexiletine), N-methyl-Daspartate (NMDA) receptor antagonists, five-percent lidocaine patches, opioid and non-opioid analgesics, and aldose reductase inhibitors (such as sorbinil or zenarestat). A review of placebo-controlled and comparative studies examined the efficacy and safety of several classes of drugs for neuropathy, including SSRIs, TCAs, NMDA-receptor antagonists, sodium-channel blockers, narcotic analgesics (tramadol, oxycodone), and first- and second-generation anticonvulsants (e.g., carbamazepine, sodium valproate, and gabapentin). The authors concluded that gabapentin showed the greatest efficacy with the fewest side effects and potential drug interactions. Other anticonvulsants in early stages of testing for PN include pregabalin (better absorbed than gabapentin)45 and lacosamide. Alternative Treatments for Peripheral Neuropathy alpha-Lipoic Acid Clinical Effects of Alpha-lipoic Acid (ALA) for Diabetic Peripheral Neuropathy ALA, among the most well-researched nutrients for peripheral neuropathy, has been used as a treatment for PN in Europe for decades. Three largescale, double-blind, placebo-controlled trials - the Alpha-Lipoic Acid in Diabetic Neuropathy (ALADIN) studies - have examined various routes of administration, dosages, and neurological effects of ALA. The first ALADIN study (n=328 type 2 diabetics) found three weeks of intravenous (I.V.) ALA at 600 or 1,200 mg daily was superior to placebo for reducing symptoms of neuropathy measured by several pain-score questionnaires; the 600-mg dose yielded slightly better results with fewer side effects. ALADIN II examined nerve conduction parameters as well as Neuropathic Disability Score (NDS) in a two-year trial of 65 patients with type 1 or 2 diabetes. Patients were assigned to one of three treatment groups: 600 mg ALA twice daily, 600 mg ALA once daily plus placebo once daily, or double placebo. After receiving the treatments I.V. for five days, subjects were placed on oral administration of the respective treatments. ALA resulted in significant improvement in some nerve conduction parameters but not in NDS compared to placebo. In the seven-month ALADIN III trial, 509 PN subjects with type 2 diabetes received 600 mg I.V. ALA daily for three weeks, followed by 600 mg orally three times daily for six months; 600 mg I.V. ALA daily for three weeks, followed by placebo three times daily for six months; or double placebo. While no significant differences were noted in subjective symptom evaluation among the groups, treatment with ALA was associated with improvement in nerve function. In the randomized, double-blind, placebocontrolled Symptomatic Diabetic Neuropathy (SYDNEY) trial, 120 type 2 diabetic patients with PN were administered 600 mg I.V. ALA (n=60) or placebo (n=60), five days/week for a total of 14 treatments.  At the end of the trial, the ALA group reported significant improvement in overall symptoms, including lancinating and burning pain, numbness, and tingling compared to the placebo group; improvement in one nerve conduction parameter was also reported. A meta-analysis of four placebo-controlled trials (n=1,258) - ALADIN I and III, SYDNEY, and a fourth unpublished trial (Neurological Assessment of Thioctic Acid; NATHAN II), all with the same protocol of 600 mg ALA administered I.V. for three weeks - found a continuous daily improvement in symptom scores beginning on the eighth day of treatment. Several smaller studies confirm the potential benefit of ALA for diabetic peripheral neuropathy. Like the first ALADIN study, one small study lasted only three weeks. Type 2 diabetics with symptomatic Copyright © 2005 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 10, Number 4 December 2005 Peripheral Neuropathy Review Page 300 Alternative Medicine Review u Volume 11, Number 4 u 2006 PN were given 600 mg ALA (n=12) or placebo (n=12) orally three times daily. Even with the study's short duration, burning pain and NDS improved significantly in the ALA group compared to placebo.

A smaller oral dose was also found effective in an uncontrolled study of 26 type 2 diabetics with PN. An oral daily dose of 600 mg ALA for three months resulted in reversal from symptomatic to asymptomatic neuropathy; five patients had no signs of neuropathy based on symptom evaluation or NCV.

A small study of 10 subjects with diabetic PN found 600 mg I.V. ALA for three weeks resulted in improved nerve function as well as decreased symptom scores. In this study, nerve microcirculation was examined by measuring capillary blood cell velocity (CBV). In normal healthy volunteers, cooling of one hand results in a decrease in CBV in the contralateral hand. In this small sample of 10 subjects no such reaction occurred. However, after three weeks of ALA treatment, response to cooling was observed with significant reduction in CBV. In addition, there was a significant reduction in neuropathy symptom scores.

In another small study of diabetics with PN, some of these same researchers further confirmed that one of the mechanisms of action of ALA involves improved microcirculation to the nerves, and that this effect occurs acutely, even after one I.V. infusion of ALA.

A Russian study found ALA was most effective in patients with mild neurological symptoms and a short history of diabetes.

ALA has also been found to be effective for diabetics with cardiac autonomic neuropathy at an oral dose of 800 mg daily for four months, and for diabetic mononeuropathy of the cranial nerves at a dose of 600 mg I.V. for 10 days followed by 600 mg/day orally for 60 days. Mechanisms of Action of ALA for the Treatment of Diabetic PN A clinical study was conducted to determine the effect of ALA on nitric oxide production in 16 individuals with diabetic neuropathy. Prior to ALA supplementation total plasma concentrations of nitrates and nitrites - a reflection of NO production - were two-fold lower in diabetic subjects than in healthy volunteers. ALA supplementation - 600 mg I.V. five days/week and 600 mg orally on weekends for three weeks, followed by 600 mg ALA orally for the remaining 20 days - resulted in normalization of NO metabolite levels as well as improvement in clinical symptoms and electrophysiological signs of neuropathy.

Theoretically, increased NO production would result in increased circulation to the neurons. Several in vitro and animal studies have helped elucidate the mechanisms of action of ALA for diabetic PN. In an in vitro study, sciatic nerve was incubated in glucose, resulting in a four-fold increase in lipid peroxidation. Addition of ALA as the R(+) form, the S(-) form, or the racemic mixture resulted in significant reductions in lipid peroxidation as measured by TBARS. There were no differences in effectiveness of the various forms of ALA.60 Another in vitro study confirmed ALA's effect on decreasing lipid peroxidation in a high-glucose environment. In addition, ALA was found to decrease protein glycosylation (measured by glycosylated hemoglobin) and increase (Na+/K+)-ATPase activity.61 The effect of ALA on lipid peroxidation was confirmed in a study of people with diabetic PN. A daily dose of 600 mg ALA for 70 days resulted in significant reductions in serum lipid peroxides that had been elevated compared to non-diabetic controls.

Several studies examining the mechanism of ALA have been conducted on streptozotocin-diabetic rats with neuropathy. ALA was found to increase glucose uptake by nerve cells,63 nerve myo-inositol, 63, 64 glutathione levels, 64, 65 (Na+/K+)-ATPase activity, 64 and nerve blood flow, 65 and normalize NAD:NADH ratios.

Acetyl-L-Carnitine (ALC)/L-Carnitine ALC for Treatment of Peripheral Neuropathy Associated with HIV Infection with HIV has been associated with a secondary deficiency of the amino acid L-carnitine. This deficiency may be due to malabsorption and other gastrointestinal disturbances, renal loss, shifts
in metabolism,66 and use of antiretroviral drugs.

Antiretroviral drugs are a major cause of peripheral neuropathy in HIV-positive individuals, potentially due to a drug-induced deficiency of L-carnitine or ALC. As mentioned previously, severe axonal peripheral neuropathy can occur in subjects treated with the nucleoside analogues ddI, ddC and d4T (d-drugs), probably due to their action of Copyright © 2005 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 10, Number 4 December 2005 Review Peripheral Neuropathy Alternative Medicine Review u Volume 11, Number 4 u 2006 Page 301 reducing mitochondrial DNA content. In a non-randomized study, serum L-carnitine and ALC levels in 12 HIV-positive individuals, with axonal peripheral neuropathy on various combinations of ddI, ddC, and d4T, were compared to 21 subjects on ddI or zidovudine (AZT) without neuropathy, 10 HIV-negative subjects with axonal or demyelinating autoimmune neuropathies, and 13 healthy individuals, the latter three groups serving as controls. Subjects with PN on antiretroviral d-drugs had significantly lower ALC levels compared to the control groups; there were no significant differences in L-carnitine levels among the groups.

Another larger study did not support these findings. Free carnitine, ALC, and total carnitine were measured in a group of 232 HIV-positive individuals with PN. Although there were a significant number
in the study group with lower total and free carnitine levels compared to healthy controls, there were no significant differences in ALC levels. There were also no significant differences between exposure to
antiretrovirals or extent of neuropathy and carnitine levels.

Although ALC deficiency in HIV-positive individuals with PN associated with d-drug antiretrovirals remains an open question, preliminary evidence points to a potential therapeutic effect of ALC in this population. In a study of 21 HIV-positive subjects with PN, 1,500 mg oral ALC twice daily for up to 33 months resulted in improved symptoms of neuropathy in 76 percent of subjects. In addition, periodic skin biopsies examining histological innervation found improvements beginning after six months of treatment.

Another small, short-term study examined the effect of 500 mg or 1 g ALC administered I.V. or intramuscularly (I.M.) daily for three weeks to HIVpositive individuals. Pain intensity was measured before and after treatment, and 10 subjects reported symptom improvement, five reported no change, and one reported a worsening of symptoms.71 Larger, long-term, placebo-controlled studies are indicated to determine the possible benefit of ALC for PN associated with HIV. Potential mechanisms of action of ALC may include counteracting the drug-induced mitochondrial damage by direct antioxidant effects, promotion of free fatty acid transport across the mitochondrial membrane improving cellular energy metabolism, correcting a deficiency, or enhancing the response to nerve growth factor.

ALC for the Treatment of Cancer Chemotherapy-induced Neuropathy As mentioned previously, cancer chemotherapy drugs, including the taxanes (paclitaxel, docetaxel), platinum drugs (cisplatin, oxaliplatin, carboplatin), and vinca alkaloids (vincristine, vinblastine) are associated with significant neurotoxicity, particularly if prescribed in high doses. The associated peripheral neuropathy can be disabling and can persist for years after discontinuation of the drug. Other cancer chemotherapeutic agents with potential neurotoxicity are listed above in. Acetyl-L-carnitine has been tested in clinical and animal studies for the treatment of chemotherapy- induced peripheral neuropathy. In one study, 26 patients with cisplatin- or paclitaxel-induced PN were given I.V. infusions of 1 g ALC daily for 10-20 days. The severity of PN was assessed by the World Health Organization (WHO) Toxicity Grading List at baseline and at the end of treatment. All five cisplatin- treated patients experienced at least one grade improvement in neuropathy symptoms, while eight of 12 patients in the paclitaxel group and eight of 10 in the combination paclitaxel/cisplatin group experienced at least one grade improvement in symptoms.

Oral doses of ALC have also been found effective for chemotherapy-induced PN, although improvement may take longer than with I.V. or I.M. routes of administration. Twenty-five patients with paclitaxel- or cisplatin-induced PN of grade 3 or greater during chemotherapy or grade 2 or greater persisting for at least three months post-chemotherapy, based on National Cancer Institute Common Toxicity Criteria (NCI-CTC), were given 1 g ALC three times daily for eight weeks. Sensory symptoms improved in 15 of 25 patients (1 grade in nine; 2 grades in six); motor symptoms improved in 11 of 14 reporting motor neuron dysfunction. Symptomatic relief persisted long after discontinuation of ALC - for an average of 13 months in 12 of 13 surviving patients. In addition, significant improvement was noted in sensory nerve action potentials and sensory NCV in 21 and Copyright © 2005 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 10, Number 4 December 2005 Peripheral Neuropathy Review Page 302 Alternative Medicine Review u Volume 11, Number 4 u 2006 22 subjects, respectively. The one patient in the study who experienced a worsening of symptoms was also receiving the drug vinorelbine.

Several animal studies support the use of ALC for chemotherapy-induced PN and help elucidate possible mechanisms for its benefit. In one study, nerve conduction velocity was compared in rats given cisplatin or cisplatin plus ALC and in another group of rats given paclitaxel or paclitaxel plus ALC. The decreases in NCV were significantly less in groups supplemented with ALC. In addition, ALC did not interfere with antitumor effects of the drugs.

Another animal study found ALC prevented paclitaxel-induced neuropathy - an effect that lasted three weeks after discontinuation of ALC. In a separate arm, ALC provided an analgesic effect for rats with already established neuropathy.75 Further animal studies have found acetyl-L-carnitine is protective against the neurotoxicity of oxaliplatin, 76 cisplatin, 77 and vincristine,77 without interfering with their antitumor effects.

Although the pathogenesis of neurotoxicity associated with cancer chemotherapy drugs is largely unknown, cisplatin appears to affect nerve growth factor (NGF). One research group found cisplatin reduced circulating levels of NGF in rats, levels of which seemed to reflect the extent of neurological damage.

In an animal model, ALC modulated cisplatin-induced decreases in NGF,74 and in vitro ALC potentiated the effect of NGF,74 providing a potential mechanism for ALC's benefit for chemotherapy-induced PN. ALC/L-Carnitine for the Treatment of Diabetic Peripheral Neuropathy Clinical studies point to a possible L-carnitine and/or ALC deficiency in diabetic PN. In a clinical investigation, 24 type 2 diabetics with complications were compared to 15 type 2 diabetics without complications. Serum free and total carnitine levels were found to be significantly lower in individuals with diabetic complications, including PN; there were no differences in ALC levels.

Another study compared L-carnitine and ALC levels in peripheral nerves of 11 people with diabetic PN to levels in nerves from 13 people with ischemic non-diabetic neuropathy and 11 normal controls. Although both groups with PN demonstrated decreased L-carnitine and ALC compared to controls, the differences did not reach statistical significance, leading the authors to speculate that carnitine deficiency may be one, but not the primary, factor in diabetic PN.

In a double-blind, placebo-controlled, multicenter trial, 333 subjects with diabetic neuropathy were given ALC or placebo for one year. ALC at a dose of 1,000 mg was administered I.M. for the first 10 days followed by an oral dose of 2,000 mg daily for the remaining 355 days. Nerve conduction velocities, amplitudes, and pain symptoms using a visual analog scale (VAS) were assessed at baseline and at six and 12 months. At 12 months, NCV, amplitude, and VAS pain scores were significantly better in the ALC group compared to placebo; pain scores were reduced from baseline by 39 percent in the ALC group and eight percent in the placebo group.

Another larger study consisted of two multicenter, parallel, double-blind, placebo-controlled trials using the same protocol - 500 mg or 1,000 mg oral ALC or placebo three times daily for one year. One study consisted of centers in the United States and Canada (UCS) while the other study was conducted in centers in the United States, Canada, and Europe (UCES), with a total of 1,346 subjects. Results of the two studies were analyzed individually and as pooled cohorts. Vibrational sensation was significantly improved in the fingers at both 500- and 1,000-mg dosages of ALC three times daily, but in the toes only in the 1,000-mg dosage in the UCS group. In the UCES group, the only improvement in vibrational sense occurred in the toes with the dosage of 1,000 mg ALC three times daily. In the pooled cohorts of UCS and UCES, greater improvement in clinical symptoms was noted in both ALC groups compared to placebo. In the 27 percent of subjects who reported pain at baseline, 1,000 mg ALC three times daily resulted in significant improvements in pain in the UCS and pooled cohorts, but not in the UCES. When analyzed by subgroup it was determined the UCES had more subjects with type 1 diabetes and longer duration of neuropathy compared to the UCS. ALC appeared to work more effectively in patients with type 2 diabetes and a shorter duration of neuropathy.

In a study of 51 children with type 1 diabetes, L-carnitine was supplemented at a dose of 2 g/m2/day for two months. NCV and neurological exams were performed at baseline and at the end of treatment. Children with abnormal NCV but normal neurological exams exhibited improvement in nerve conduction velocity, whereas those with abnormal neurological exams exhibited no such improvement.
Autonomic neuropathy measured by sympathetic skin response was improved in both groups.

Animal studies found acetyl-L-carnitine may benefit cardiac autonomic neuropathy and gastrointestinal autonomic neuropathy. Animal studies have confirmed the clinical affects of ALC for diabetic PN and helped determine potential mechanisms of action. In a study of diabetic rats given either ALC or sorbinil (an aldose reductase inhibitor drug), both were associated with improvements in NCV, decreases in malondialdehyde of sciatic nerve (a sign of reduced lipid peroxidation), and normalized myo-inositol content; sorbinil, but not ALC, reduced nerve sorbitol levels.

Another study found similar results, with ALC increasing nerve myo-inositol and free carnitine levels without affecting sorbitol accumulation.

Another study found deficiencies of ALC in diabetic rats resulted in decreased (Na+/K+)-ATPase activity and myo-inositol levels.

Another esterified form of L-carnitine, propionyl-L-carnitine (esterified with propionic acid instead of acetic acid as in the case of ALC), also improved nerve conduction and sciatic nerve blood flow in streptozotocin-diabetic rats.

Vitamin E
Vitamin E for the Treatment of Diabetic Peripheral Neuropathy Oxidative stress appears to play a significant role in peripheral neuropathy, particularly in the case of PN due to diabetes. In a double-blind, placebo-controlled trial, 21 type 2 diabetics with PN were given either 900 mg vitamin E (n=11) or placebo (n=10) for six months. Electrophysiological parameters of nerve function, examined at baseline and at the end of the study, found significant improvement in two of 12 parameters - median motor NCV and tibial motor nerve distal latency - in the vitamin E group compared to placebo.

In an animal study of streptozotocin-diabetic rats, depletion of vitamin E resulted in a depletion of reduced glutathione in nerves of diabetic and normal rats and an induction or aggravation of abnormalities in nerve conduction, particularly in sensory nerves.

Vitamin E for the Prevention and Treatment of Chemotherapy-induced Peripheral Neuropathy Cisplatin might induce a vitamin E deficiency that may be a cause of the neurotoxicity associated with this chemotherapy drug. Plasma vitamin E levels were found to be low in five patients who had developed severe neuropathy following cisplatin treatment. Two and four cycles of cisplatin also were found to significantly decrease plasma vitamin E levels in another group of five patients in whom vitamin E levels were measured at baseline and after cisplatin treatment.

In a study evaluating the effect of vitamin E on attenuation of cisplatin neurotoxicity, 13 patients received cisplatin plus 300 mg vitamin E daily; 14 received cisplatin alone. Vitamin E was administered orally prior to onset of chemotherapy and continued for three months after cisplatin was concluded. The incidence (30.7% versus 85.7%) and severity of neurotoxicity were significantly less in the group receiving vitamin E. Evaluation of vitamin E in a preclinical animal study found it did not interfere with the tumor inhibition or tumor growth delay of cisplatin.

In two studies by the same researchers, patients on cisplatin or carboplatin, plus other chemotherapy drugs as the type of cancer indicated, were divided into two groups - one receiving chemotherapy plus 300 mg vitamin E twice daily, the other chemotherapy only. Vitamin E was supplemented at commencement of chemotherapy and for three months after chemotherapy was completed. In one trial 30 patients completed the study (14 in the vitamin Eplus-chemotherapy group and 16 in the chemotherapy-only group); while in the second trial 31 patients completed the trial (16 in the vitamin E-plus-chemotherapy group and 15 in the chemotherapy-only group).

The extent of PN was evaluated in both studies by Neurological Symptom Score, Neurological Disability Score, and electrophysiological studies of nerve conduction and amplitudes of action potentials.

Significant differences in incidence of neurotoxicity were seen in both studies when comparing the vitamin E-plus-chemotherapy groups to the chemotherapy-only groups (3/14 versus 11/16 in one study; 4/16 versus 11/15 in the second study). In an identical study by the same researchers, the effect of vitamin E (300 mg twice daily) for prevention of paclitaxel-induced PN was examined. Thirty-two subjects (16 in each group) received either vitamin E-plus-chemotherapy or chemotherapy alone. The incidence of neurotoxicity was three of 16 in the vitamin E group and 10 of 16 in the chemotherapy- only group.

Vitamin E for the Treatment of Other Types of Peripheral Neuropathy
Vitamin E deficiency is associated with significant neurological pathology, including PN. Therefore, a vitamin E deficiency should always be ruled out in cases of PN of unknown origin. In a case report, a 22-year-old man experienced severe demyelinating neuropathy. The only abnormality on laboratory examination was a significant deficiency of vitamin E with fasting serum total tocopherol level on highperformance liquid chromatography (HPLC) measuring 0.3 mg/L (normal 6.0-19.0 mg/L). The patient was started on 1,200 mg vitamin E daily in divided doses and followed for four years. Supplementation resulted in improvement but not complete resolution of nerve conduction abnormalities. Because all other fat-soluble vitamins were normal, broad-spectrum fat malabsorption was ruled out. The authors mentioned an isolated vitamin E deficiency could have been caused by a mutation in the autosomal recessive alpha-tocopherol transfer protein gene.

Gastrectomy can also result in a vitamin E deficiency, which can in turn result in neuropathy. In a study of 11 postgastrectomy patients with vitamin E deficiency (10 with neurological complications), subjects were given 150-300 mg vitamin E daily, resulting in improvement of neurological symptoms in nine of 10 subjects.

Glutathione
Glutathione (GSH) for the Treatment of Oxaliplatin-induced Peripheral Neuropathy Fifty-two patients with advanced colorectal cancer on oxaliplatin chemotherapy were randomized to receive an I.V. infusion of glutathione or saline (26 in each group) before each oxaliplatin cycle; 12 patients dropped out (seven in the placebo arm and five in the GSH arm). After eight cycles, nine patients experienced clinical signs of neuropathy in the GSH group compared to 15 in the placebo group. When severity of neuropathy was assessed by NCI-CTC, 11 of 19 in the placebo arm and two of 21 in the GSH arm had moderate-to-severe PN.

The authors of the above study discussed glutathione's possible mechanism in reducing neurotoxicity of platinum-based drugs. Reactive oxygen species generated by platinum drugs result in neuronal cell death. GSH, as an ROS scavenger, may prevent such damage.

The theory is supported by an in vitro study in which cisplatin induced apoptosis of mouse neurons, which was then prevented by preincubation with N-acetylcysteine, a precursor to GSH.

Glutathione and ALA for the Treatment of Diabetic Peripheral Neuropathy
Because of the connection between oxidative stress and diabetic neuropathy, a preliminary animal study examined the effect of GSH or ALA in the prevention and treatment of diabetic PN. In streptozotocin- diabetic rats, intraperitoneal ALA but not GSH partially reversed the decreased sciatic nerve blood flow initiated by diabetes. Interestingly, ALA but not GSH increased RBC GSH levels. Elevated levels of malondialdehyde (a sign of oxidative stress) were partially reversed by ALA and GSH; nerve conduction velocity was not affected by ALA or GSH.

Thiamine/Benfotiamine
A vitamin B1 (thiamine) deficiency, which can be due to various underlying causes, is known to be a factor in peripheral neuropathy. For example, gastrectomy is associated with thiamine deficiency and resultant PN. A study comparing 17 postgastrectomy PN patients with 11 subjects with thiamine-deficiency neuropathy due to dietary imbalances found the clinical presentation was identical.

Review Peripheral Neuropathy
Benfotiamine is the most extensively studied form of thiamine for treatment of PN. Several clinical trials in healthy adults have demonstrated the superior absorption and bioavailability of this lipid-soluble thiamine analogue compared to several water-soluble thiamine salts.

In addition, because of the lipophilic nature of benfotiamine, it may be more readily transported across cell membranes, including neurons. Benfotiamine/Thiamine for the Treatment of Diabetic Peripheral Neuropathy In a double-blind, randomized, placebo-controlled pilot study, 40 subjects (20 in each group) with diabetic PN were given two 50-mg tablets of benfotiamine four times daily (400 mg total daily dose) or placebo for three weeks. Assessment was via neuropathy symptom and vibration sensation scores from both physician and patient. A statistically significant improvement in the neuropathy score was reported in the treatment group compared to placebo. The most significant improvement reported was decrease in pain, although, there was no significant improvement in vibration perception measured by the tuning fork test.

Several studies have investigated the effect of benfotiamine in combination with other B vitamins in the treatment of diabetic neuropathy. In one study, 30 subjects received Milgamma (50 mg benfotiamine and 250 mcg B12 as cyanocobalamin per tablet) at a dose of two tablets four times daily for three weeks (total daily dose: 400 mg benfotiamine and 2,000 mcg cyanocobalamin), followed by one tablet three times daily for nine weeks. The second group of 15 subjects received a B-complex vitamin supplement at a dose of two tablets three times daily for the entire three months. Changes in pain severity and vibration perception thresholds were measured at baseline and at the end of the study. All Milgamma-treated patients experienced significant relief in neuropathic pain and dramatic improvement in vibration perception thresholds, while subjects receiving a B-complex vitamin experienced only slight, non-statistically significant improvement.

In a second six-week trial, 36 subjects with diabetic PN were divided into three groups of 12 each receiving: (1) Milgamma-N (40 mg benfotiamine, 90 mg pyridoxine, and 250 mcg cyanocobalamin per capsule) at a dose of two capsules four times daily (320 mg benfotiamine, 720 mg pyridoxine, and 2,000 mcg cyanocobalamin daily); (2) Milgamma-N at a lower dose of one capsule three times daily (120 mg benfotiamine, 270 mg pyridoxine, and 750 mcg cyanocobalamin daily); or (3) 50 mg benfotiamine three times daily. Neuropathy was assessed via pain and vibration sensation at baseline and after three and six weeks. Patients in all three groups reported beneficial therapeutic effects, even at three weeks, with the most significant improvement reported by patients receiving the highest-dose benfotiamine.

A double-blind, randomized, placebo-controlled, 12-week study examined the effectiveness of another benfotiamine combination containing both vitamins B6 and B12 in 24 diabetic subjects with PN. A statistically significant improvement in NCV in the peroneal nerve was observed in the treatment group
compared to placebo.

Animal studies also confirm the benefit of benfotiamine for neuropathy in a rat model of diabetic PN.109,110 One study comparing the effect of water- soluble thiamine with lipid-soluble benfotiamine found benfotiamine superior in preventing functional nerve damage and preventing formation of AGEs - a cause of diabetic PN.

At least two in vitro studies confirm the effect of thiamine and benfotiamine on AGEs. Two studies found benfotiamine, and one study found thiamine reduced the formation of AGEs in glucoseincubated
cells. Other in vitro studies have found benfotiamine or thiamine decreased glucose-induced apoptosis of endothelial cells113 and decreased polyol accumulation by inhibition of aldose reductase expression.

Benfotiamine for the Treatment of Alcoholrelated Peripheral Neuropathy Chronic alcoholics commonly develop a thiamine deficiency, resulting in peripheral neuropathy and other health problems. A deficiency of vitamin B1 in this population can be due to inadequate dietary intake, reduced capacity for hepatic storage, inhibition of intestinal transport and absorption, or decreased formation of the active coenzyme form. An animal study found chronic alcohol consumption by rats Peripheral Neuropathy Review.

Supplementation with benfotiamine significantly increased levels of TDP and total thiamine compared to supplementation with thiamine HCl.

An eight-week, randomized, multicenter, placebo- controlled, double-blind study compared the effect of benfotiamine alone to a benfotiamine complex (Milgamma-N) or placebo in 84 alcoholic patients. Benfotiamine was given in a daily oral dose of 320
mg (two 40-mg tablets four times daily) during weeks
1-4, followed by 40 mg three times daily (120 mg total
daily dose) during weeks 5-8. A second group received
Milgamma-N (providing a total daily dose of
320 mg benfotiamine, 720 mg pyridoxine, and 2,000
mcg cyanocobalamin) during weeks 1-4 and a total
daily dose of 120 mg benfotiamine, 270 mg pyridoxine,
and 750 mcg cyanocobalamin during weeks 5-8;
a third group received placebo.116
Parameters measured included vibration
perception in the great toe, ankle, and tibia; neural
pain intensity; motor function and paralysis; sensory
function; and overall neuropathy score and clinical
assessment. Although benfotiamine therapy was
superior to Milgamma-N or placebo for all parameters,
results reached statistical significance only for
motor function, paralysis, and overall neuropathy
score. Why the benfotiamine-alone group had better
results than the Milgamma-N group, despite the fact
that the benfotiamine dosage was equivalent, is not
completely understood. The authors hypothesized vitamins
B6 and B12 might have competed with the
effects of vitamin B1 in the Milgamma-N group. On
the other hand, in the case of diabetic neuropathy, the
positive effects of the combination may be due to the
fact that deficiencies of vitamins B1, B6, and B12 are
all implicated in its possible pathogenesis; whereas,
alcoholic neuropathy is associated with only vitamin
B1 deficiency.
A small Russian study also found benefit
of benfotiamine for alcoholic neuropathy. Fourteen
chronic alcoholic men with polyneuropathy were
given 450 mg benfotiamine daily for two weeks, followed
by 300 mg daily for an additional four weeks;
regression of neuropathy symptoms was observed. A
more in-depth report of the results is not possible because
only the abstract is in English.117
Methylcobalamin for the Treatment of
Peripheral Neuropathy
Vitamin B12 Deficiency Neuropathy
Vitamin B12 deficiency has been associated
with significant neurological pathology, including
peripheral neuropathy. Testing serum metabolites
such as methylmalonic acid and homocysteine can
help clinically identify individuals at risk for a deficiency-
associated neurological syndrome.118 One
of the mechanisms believed to be at play in vitamin
B12 deficiency neuropathy is hypomethylation in
the central nervous system. Inhibition of the B12-
dependent enzyme methionine synthase results in a
fall in the ratio of S-adenosylmethionine (SAM) to
S-adenosylhomocysteine;119 the resultant deficiency
in SAM impairs methylation reactions in the myelin
sheath. The methylation of homocysteine to methionine
requires both methylcobalamin (an active form
of vitamin B12) and the active form of folic acid (5-
methyltetrahydrofolate).120 An animal model of B12
deficiency neuropathy, however, does not support the
hypomethylation theory.121
Animal studies help elucidate some of the
potential mechanisms involved in vitamin B12-associated
neuropathies. Rats rendered B12 deficient by
total gastrectomy were found to have elevated levels
of the neurotoxic cytokine tumor necrosis factor-alpha
(TNF-α) and decreased levels of neurotrophic
epidermal growth factor and the neurotrophic cytokine
interleukin-6. Levels of these cytokines and
growth factors were normalized by the administration
of cobalamin.122
In an experimental animal model of acrylamide-
induced neuropathy, an ultra-high dose of
methylcobalamin was found to stimulate nerve regeneration
by up-regulating gene transcription. In a
comparison of three groups, rats were given intraperitoneal
methylcobalamin at a dose of 500 mcg/kg or
50 mcg/kg body weight, while a third group received
saline. Only the high-dose methylcobalamin group
experienced regeneration of motor neurons.123
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Review Peripheral Neuropathy
Alternative Medicine Review u Volume 11, Number 4 u 2006 Page 307
Methylcobalamin for the Treatment of
Diabetic Peripheral Neuropathy
In a four-month, double-blind, placebo-controlled
trial of type 1 and 2 diabetics with neuropathy,
21 subjects were given oral methylcobalamin at a dose
of 500 mcg three times daily (the authors presumably
erroneously reported this dosage in mgs), while 22
subjects received placebo. Significant improvements
were reported for somatic and autonomic symptoms
in the treatment group compared to placebo.124
A smaller study examined the effect of intrathecal
injections of methylcobalamin in 11 subjects
with type 2 diabetes. The study design was variable in
that several patients had different dosage schedules.
Each subject received 2,500 mcg methylcobalamin
via injection with one or two more injections occurring
at one-month intervals. In addition, five subjects
took 1,500 mcg/day oral methylcobalamin for one
month; one subject got 500 mcg/day I.V. methylcobalamin
for one month; and three subjects received
an additional injection one year after completion of
the initial course. Subjects reportedly began to feel
effects from several hours to several days after the
initial injection - primarily involving a decrease in
heaviness of the lower limbs and improved sensation.
Benefits lasted from several months to four years. No
changes in NCV were noted.125
Another study of 72 patients with diabetic
PN found the combination of methylcobalamin and
prostaglandin E1 was superior to either substance
alone.126 A review of several clinical trials of the use
of methylcobalamin alone or vitamin B12 (form not
specified) combined with other B vitamins found
overall symptomatic relief of neuropathy symptoms
was more pronounced than electrophysiological findings.
127
In a study of 20 type 2 diabetics compared
to 20 age-matched controls, serum vitamin B12 levels
were significantly lower in the diabetic group.
Supplementation of 1,500 mcg/day methylcobalamin
for two months resulted in improved vibratory perception
thresholds and heart rate variability (a sign
of improvement in signs of autonomic neuropathy) in
the diabetic group.128
Supplementation of vitamin B12 may benefit
diabetic PN by correcting a deficiency. While
diabetes itself can result in vitamin B12 deficiency,
metformin, an oral antihyperglycemic agent used to
treat type 2 diabetes, may also cause vitamin B12 deficiency.
129
In streptozotocin-diabetic rats, methylcobalamin
resulted in decreased demyelination and protection
of nerve fiber density and size. The rats were administered
I.M. methylcobalamin at a very high daily
dose of 500 mcg/kg body weight for 16 weeks.130
Methylcobalamin for the Treatment of
Neuropathy Associated with Renal Failure
Uremia is associated with peripheral neuropathy
and is characterized by motor and sensory neuropathy
that begins distally and ascends as the condition
worsens. In a study of nine patients on renal dialysis
due to chronic glomerulonephritis, diabetes, or renal
tuberculosis (six with uremic neuropathy; three with
diabetic/uremic neuropathy), subjects were given 500
mcg methylcobalamin I.V. three times weekly for six
months. Due to poor renal excretion, serum vitamin
B12 reached extremely high levels during the course
of the study (mean, 72,000 pg/mL). Significant decrease
in pain scores was experienced by six of nine
subjects; NCV increased significantly.131
Methylcobalamin has also been found to benefit
uremics with autonomic neuropathy. In a group
of eight dialysis patients with abnormal beat-to-beat
heart rate variability, 1,500 mcg methylcobalamin
daily for six months resulted in improvement of this
sign of autonomic neuropathy - from variability of
3.3 beats/minute at the beginning of the study to 5.8
beats/minute after six months.132
Vitamin B12 deficiency has been reported
in patients with renal failure, providing one potential
cause for neuropathy in this population.132 In
addition, accumulation of neurotoxic compounds is
a likely cause, since dialysis or renal transplant can
ameliorate the condition.133
Cyanide may be one of the neurotoxic metabolites
involved, as researchers have found a relationship
between the severity of neuropathy as measured
by vibrational sensation and tobacco smoking
(a significant source of cyanide).133 Uremic patients
were also found to have high levels of cyanide as
measured by accumulation of thiocyanate, a detoxification
product of cyanide. Another method of detoxifying
cyanide is to utilize the pool of free cyanide to
Copyright © 2005 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 10, Number 4 December 2005
Peripheral Neuropathy Review
Page 308 Alternative Medicine Review u Volume 11, Number 4 u 2006
synthesize cyanocobalamin (a form of vitamin B12).
These researchers found that administration of methylcobalamin
resulted in increased cyanocobalamin
and decreased levels of thiocyanate (a reflection of
free cyanide levels). They theorized methylcobalamin
was providing the cobalamin substrate for utilization
of cyanide in cyanocobalamin synthesis. These
same researchers had previously noted improved vibrational
thresholds in this population of individuals
when supplemented with methylcobalamin.133
Vitamin B12 Status in HIV-associated
Neuropathy
Peripheral neuropathy was diagnosed in 34
of 49 HIV patients (69%) referred to a neurology
clinic for examination of vitamin B12 status. Abnormal
B12 status, defined by a serum level less than
150 pmol/L or a Schilling test reflecting less than
eight-percent absorption, was found in 29 percent of
patients with PN compared to 20 percent in the group
as a whole. Eighty percent of subjects with abnormal
vitamin B12 status had progressed to AIDS. Five of
eight patients who received parenteral vitamin B12
therapy experienced clinical improvement in neuropathy
symptoms within one week of treatment.33
Another study examining 20 subjects with
early-stage HIV infection found a five-percent incidence
of PN, but it was not associated with impaired
vitamin B12 metabolism.34 Neuropathies in this population
are often associated with antiretroviral drugs
(see above).
Folate for the Treatment of Peripheral
Neuropathy
In addition to folic acid's involvement in vitamin
B12 metabolism, a folate deficiency can result in
PN, independent of vitamin B12 status. In a series of 20
subjects with abnormal neurological findings, 10 subjects
fit the diagnostic criteria for peripheral neuropathy.
The only abnormality detected was a low serum,
RBC, or cerebral spinal fluid (CSF) folate level.134
In a Japanese study of 343 patients with various
neurological diseases, primarily axonal neuropathy,
36 subjects (10.5%) demonstrated low serum
folate levels. Supplementation with high-dose folate
(15 mg/day) resulted in improvement in neurological
symptoms in 24 of 36 subjects (67%).135
A folate deficiency may contribute to the
pathogenesis of alcoholic peripheral neuropathy. In
a study of 46 hospitalized alcoholics with PN, eight
percent demonstrated low plasma folate levels two
weeks after alcohol abstention. When functional folate
status was evaluated using the formiminoglutamic
acid (FiGlu) excretion test or the deoxyuridine
suppression (dU) test, 50 percent of this population
was found to be deficient.136
PN can be caused by several medications associated
with folate deficiency, including sulfasalazine,
methotrexate, antituberculosis drugs, anticonvulsants,
and oral contraceptives.137 In a study of 51
epileptic patients newly placed on anticonvulsants
and followed for five years, no clinical signs of neuropathy
were noted, although 18 percent of the group
taking phenytoin (and none in another group on carbamazepine)
showed signs of slowed nerve conduction
or decreased action potentials. Clinical and electrophysiological
signs of neuropathy were noted in
six patients on chronic barbiturate therapy and in 10
patients on chronic phenytoin.138
Patients on longer-term anticonvulsant therapy
appear to be more likely to exhibit signs of neuropathy.
In 29 epileptics on long-term therapy, all but
three showed abnormalities in electrophysiological
measurements of nerve function. Sensory nerve action
potentials were reduced or absent in 76 percent of patients;
all subjects had low serum and CSF folate levels.
These 19 patients were treated with either folinic
acid (n=10) or folic acid (n=9) for one month with significant
reversal of nerve abnormalities; a greater effect
was noted in the folinic acid group. The researchers
theorized that folinic acid was able to raise levels
of folate in the CSF slightly more than folic acid.139
Pyridoxine and Peripheral Neuropathy
Vitamin B6 deficiency may be associated
with the development of peripheral neuropathy. In
addition, in the form of pyridoxine HCl, high doses
of B6 have been implicated as a cause of PN.
Pyridoxine Deficiency Neuropathy
Vitamin B6 deficiency PN has been studied
in an experimental rat model. Morphometric analysis
demonstrated decreased nerve fiber density and increased
axon-to-myelin ratio, indicative of peripheral
neuropathy.140
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Review Peripheral Neuropathy
Alternative Medicine Review u Volume 11, Number 4 u 2006 Page 309
Medications, particularly isoniazid for tuberculosis,
can result in pyridoxine-deficiency neuropathy
that can be prevented by simultaneous supplementation
with vitamin B6.141 Isoniazid appears to
inhibit the activity of vitamin B6.142 PN associated
with isoniazid therapy typically manifests as burning
feet and can be reversed within a few weeks by 250
mg pyridoxine daily.143
A study of patients with carpal tunnel syndrome
(CTS), some with concomitant PN, found
patients with PN (but not CTS without PN) demonstrated
abnormalities of pyridoxine metabolism as
measured by erythrocyte glutamine oxaloacetic acid
transaminase (EGOT) activity.144
PN associated with vitamin B6 deficiency is
seen in patients with uremia. In a study of 66 dialysis
patients, 12 experienced PN with a significant negative
correlation between pyridoxal 5' phosphate (P5P;
the active form of vitamin B6) levels and PN symptoms.
Supplementation of 30 mg vitamin B6 daily
for one month resulted in increased levels of P5P and
improvement in sensory abnormalities in eight of 12
patients.145
Pyridoxine in the Treatment of Diabetic
Peripheral Neuropathy
Pyridoxine may have application for the
treatment of diabetic neuropathy, although studies
have been limited and results equivocal. A study of
50 patients (24 males and 26 females) with significant
diabetic neuropathy found significantly lower levels
of P5P in this population compared to age- and gender-
matched controls with diabetes but without neuropathy.
146 On the other hand, another study examining
various vitamin levels in type 2 diabetics with
or without neuropathy found no correlation between
vitamin B6 levels and neuropathy. In fact, this study
found no correlation between neuropathy and levels
of any vitamins tested - vitamins A or E, beta carotene,
vitamins B1, B2, B6, B12, or folate.147
Despite possible low levels of P5P in individuals
with diabetic neuropathy, intervention studies
have been disappointing. In one double-blind, controlled
study 16 subjects received 25 mg pyridoxine
daily while 14 subjects were given placebo. After three
months, symptoms and neurological signs were assessed.
There were no significant differences between
pyridoxine and placebo groups, with nine patients in
each group demonstrating significant improvements.
However, 16 of 30 subjects were initially low in P5P
and of the 18 patients who experienced improvement,
12 were low in P5P (eight in the pyridoxine group
and four in the placebo group).148
Another double-blind study found no statistically
significant difference between pyridoxine HCl
supplementation or placebo for diabetic PN. Eighteen
diabetic subjects with neuropathy were randomly assigned
to 50 mg pyridoxine HCl three times daily for
four months or placebo. Six of nine in the B6 group
and four of nine in the placebo group experienced
significant relief of symptoms. Only one patient had
low P5P levels at the beginning of the study.149
It is possible that vitamin B6 will provide
therapeutic value for the treatment of PN primarily
in cases where a deficiency is evident. In addition,
magnesium and riboflavin are needed for conversion
of pyridoxine to active P5P in the liver. Diabetics are
frequently deficient in magnesium; thus, supplementing
with active P5P might have resulted in improved
outcomes.
In a study of 200 diabetic patients with peripheral
neuropathy, 100 were randomly assigned to
50 mg pyridoxine and 25 mg thiamine daily, while
100 subjects were assigned to 1 mg of each vitamin
for four weeks. Severity of PN symptoms decreased
in 48.9 percent of subjects on higher-dose pyridoxine/
thiamine, compared to only 11.4 percent of subjects
on 1 mg of each. Only thiamine levels were tested
in this study and low levels were found to correlate
with intensity of neuropathy symptoms. Therefore,
the effect of pyridoxine in this study is difficult to
assess.150
An in vitro study helps to illuminate a possible
mechanism for pyridoxine in the prevention of
diabetic PN. Both pyridoxine and its intermediate
metabolite pyridoxamine were found to inhibit free
radical formation, lipid peroxidation, and protein glycosylation,
and protect (Na+/K+)-ATPase activity - all
mechanisms involved in diabetic PN - in RBCs exposed
to high glucose concentrations.151
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Peripheral Neuropathy Review
Page 310 Alternative Medicine Review u Volume 11, Number 4 u 2006
High-dose Pyridoxine May Cause Peripheral
Neuropathy
During the 1980s and early 1990s a rash of
case reports of peripheral neuropathy associated with
high-dose pyridoxine appeared in the scientific literature.
In most cases the dosages ranged from 1-5
g daily. In one prospective study, 1 or 3 g pyridoxine
was given to five healthy volunteers, resulting in
symptomatic and electrophysiological changes in all
subjects; those receiving the higher dose experienced
earlier symptoms.152
Animal studies continue to examine neurological
abnormalities induced by pyridoxine. For instance,
1,200 or 600 mg/kg/day (a very high dose) to
rats for 6-10 days results in necrosis of sensory neurons,
especially affecting large diameter neurons.153
Why there was a plethora of pyridoxine-toxicity
reports 15-20 years ago, with a dearth of reports
in recent years, remains a mystery. In addition, a
mechanism of pyridoxine's potential toxicity has not
been offered. One study found a mere 25 mg pyridoxine
daily for 10 days resulted in a decrease in folate
levels in eight healthy volunteers, with no change in
vitamin B12 levels.154 Is it possible high-dose vitamin
B6 supplementation causes neuropathies because it
negatively impacts levels of other B vitamins? The
conventional wisdom that suggests the importance
of taking the full range of B-complex vitamins may
have application in this situation.
Biotin for the Treatment of Peripheral
Neuropathy
The B vitamin biotin has application for the
treatment of uremic neuropathy. It is hypothesized
that renal failure and subsequent metabolic imbalances
result in impaired formation by the intestinal
flora and absorption of biotin. In a small study, nine
patients on dialysis suffering from PN were supplemented
with a large dose of biotin - 10 mg daily
in three divided doses - for 1-4 years. Marked improvements
in paresthesia, restless legs, and difficulty
walking were noted in all patients within three
months. One patient who had been unable to walk for
three months improved significantly after six months
of treatment, and at the time the study was submitted
had been walking 2 km/day for two years.155
After using biotin successfully in dialysis patients,
these same researchers began using it for patients
with diabetic PN. In a case series, three subjects
with severe diabetic neuropathy were supplemented
with 10 mg biotin via I.M. injection daily for six
weeks, followed by three times weekly for another
six weeks; oral administration of 5 mg daily continued.
Objective symptom improvement was noted
within 4-8 weeks in all three patients. NCV was only
slightly improved or not at all.156
The Application of Myo-inositol for
Diabetic Peripheral Neuropathy
Myo-inositol is an important constituent
of the phospholipids that make up nerve cell membranes.
Because low nerve myo-inositol levels have
been observed in the pathogenesis of diabetic neuropathy,
the potential for supplementation has been
explored. In an animal model of experimental diabetic
neuropathy, nerve myo-inositol levels were diminished,
with subsequent decreases in (Na+/K+)-ATPase
activity and NCV (by 25-30%), axonal atrophy, and
demyelination; dietary myo-inositol prevented these
signs of nerve degeneration.157 In another animal
model, experimental diabetes induced a decrease in
motor NCV. Supplementation of 500 mg myo-inositol/
rat/day partially prevented this decrease, while
supplementation with an analogue of myo-inositol
- D-myo-inositol-1,2,6-trisphosphate - at a dose of
24 mg/rat/day completely prevented a reduction in
nerve conduction velocity.158
Sural nerve biopsies were conducted on 30
male subjects - 10 with type 1 diabetes (five with
clinical signs of diabetic neuropathy), 10 with impaired
glucose tolerance, and 10 with normal glucose
tolerance. Nerve myo-inositol levels were significantly
lower in diabetics with neuropathy. Also, in
subjects with normal or impaired glucose tolerance,
high nerve myo-inositol levels were associated with
nerve regeneration as illustrated by increased nerve
fiber density.159
Despite myo-inositol's potential to prevent
or reverse the signs and symptoms of diabetic PN,
clinical evidence has been limited. In a small, double-
blind, placebo-controlled, crossover trial, seven
subjects with clinical signs of neuropathy (n=3) or
subclinical neurophysiological signs (n=4) were
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Review Peripheral Neuropathy
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supplemented
with 500 mg myo-inositol or placebo
twice daily for 14 days and crossed over to the other
group. Each group was on placebo for two 14-day
intervals and myo-inositol for one 14-day interval.
Action potentials in the median, sural, and popliteal
nerves increased in amplitude by 76-, 160-, and 40-
percent, respectively, during myo-inositol supplementation.
No significant differences were noted in
NCV during either myo-inositol or placebo supplementation.
160
In a double-blind study, 28 diabetics with
early, subclinical neuropathy were supplemented
with 2 g myo-inositol or placebo three times daily
for two months. No significant changes were noted
in NCV, vibratory perception, or amplitude of action
potentials in either group after two months. Although
blood and muscle tissue levels of myo-inositol were
not found to be low, nerve myo-inositol levels were
not evaluated.161
L-Glutamine for the Treatment of
Chemotherapy-induced Peripheral
Neuropathy
Paclitaxel is a chemotherapeutic agent associated
with PN. Neurological exams were conducted
before and after paclitaxel (average interval between
before-and-after evaluations was 32 days) in 12 patients
supplemented with the amino acid glutamine
and 33 patients who did not receive glutamine. Lglutamine
was supplemented orally at a dose of 10
g three times daily for four days, beginning 24 hours
after a high-dose paclitaxel cycle. Only eight percent
of patients in the glutamine group experienced moderate-
to-severe pain in the fingers and toes compared
to 40 percent in the no-glutamine group. Signs of
PN in the form of decreased vibrational sense, motor
weakness, ataxic gait, and sensory deficits were significantly
less prevalent in the glutamine group.162
Taurine for the Potential Treatment of
Diabetic Peripheral Neuropathy
Several animal studies indicate the amino
acid taurine may provide some benefit for prevention
or treatment of PN due to diabetes. Taurine is deficient
in diabetes, particularly in the Schwann cells
and vascular endothelium of nerves.163 Taurine may
act as an osmolytic agent and inhibitory neurotransmitter,
resulting in modulation of pain perception.
Theoretically, as high glucose results in sorbitol accumulation
within the cell, taurine is depleted in the
peripheral nerves, resulting in excitability and pain.
One study of streptozotocin-diabetic rats found taurine
levels decreased by 31 percent and myo-inositol
levels by 37 percent. When sorbitol accumulation
was decreased by an aldose reductase inhibitor, taurine
levels increased by 22 percent.164 In another animal
study, diabetes resulted in abnormal calcium-ion
signaling. Taurine repletion resulted in normalization
of intracellular calcium concentrations, with resultant
diminution of pain.165 Other animal studies found taurine
decreased diabetes-induced nerve conduction and
nerve blood flow deficits,166,167 and increased nerve
growth factor and nerve ascorbate levels,163 at least in
part via antioxidant mechanisms. Clinical studies are
indicated to determine whether taurine can provide
benefit to individuals with diabetic PN.
The Application of N-acetylcysteine
(NAC) for Peripheral Neuropathy
The amino acid NAC may have application
in the prevention or treatment of neuropathy. NAC is
a potent antioxidant and helps to enhance glutathione
levels.
Application of NAC for Diabetic Peripheral
Neuropathy
Oral administration of NAC to streptozotocin-
diabetic rats resulted in prevention of diabetes-induced
deficits. Motor nerve conduction velocity was
significantly decreased by diabetes; NAC reduced the
decrease in NCV and inhibited atrophy of myelinated
fibers.168 In another study, experimentally-induced
diabetes for two months in rats resulted in 20-percent
reduction in NCV and 48-percent reduction in
endoneurial blood flow; both were largely corrected
by NAC supplementation.169 Clinical studies are warranted
to determine NAC's application for treatment
of diabetic PN.
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NAC for the Treatment of Chemotherapyinduced
Peripheral Neuropathy
A mechanism of cisplatin chemotherapy-induced
PN was elucidated in an in vitro mouse model.
Apoptosis of neurons was induced by cisplatin, but
preincubation with NAC completely blocked apoptosis;
incubation with vitamin E partially blocked
apoptosis.99
A small pilot study was conducted to determine
the effect of NAC on oxaliplatin-induced neuropathy.
Fourteen stage III colon cancer patients were
randomly assigned to 1,200 mg oral NAC or placebo
daily. Neurological evaluations were conducted at
baseline and after four, eight, and 12 cycles of chemotherapy.
After four cycles, two of five in the NAC
group and seven of nine in the placebo group experienced
neuropathy; after eight cycles no one in the
NAC group experienced neuropathy compared to five
of nine in the placebo group. Only one in the NAC
group, but eight of nine in the placebo group, experienced
neuropathy after 12 cycles.170
Table 2 summarizes the potential nutrients
for prevention and treatment of chemotherapy-induced
neuropathy.
Minerals for the Treatment of Diabetic
Peripheral Neuropathy
Magnesium
Plasma magnesium levels have been found to
be significantly lower in diabetic subjects compared
to controls.171,172 Despite the fact magnesium may
be the most common mineral deficiency in diabetes,
its clinical significance for peripheral neuropathy is
unknown. An animal study found oral magnesium
supplementation to diabetic rats resulted in decreased
pain measured by thermal pain thresholds.173
Table 2. Summary of Nutrients for the Treatment of Chemotherapy-induced Peripheral Neuropathy
Acetyl-L-carnitine
Vitamin E or nothing
Glutathione or saline
L-Glutamine or nothing
N-acetylcysteine or
placebo
Cisplatin, paclitaxel,
or both
Cisplatin or paclitaxel
Cisplatin
Cisplatin or
carbaplatin
Oxaliplatin
Paclitaxel
Oxaliplatin
Uncontrolled;
n=26; 10-20
days
Uncontrolled;
n=25; 8 weeks
Controlled;
n=27; 3 months
Two controlled
trials; n=30/31;
3 months
RCT; n=40
completers
Controlled;
n=45 (12
glutamine; 33
no glutamine)
RCT; n=14;
12 cycles of
chemotherapy
I.V.
Oral
Oral
Oral
I.V.
Oral
Oral
Nutrient Intervention Chemotherapy Trial
Route of
Administration
To benefit the clinician, only positive clinical studies have been included in this table.
RCT=randomized, controlled trial
1,000 mg
3,000 mg
300 mg
600 mg
Dosage not
specified
30 g for 4 days
after each chemo
treatment
1,200 mg
Daily Dosage
Range
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Review Peripheral Neuropathy
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Table 3. Summary of Nutrients for the Treatment of Diabetic Peripheral Neuropathy
alpha-Lipoic acid or
placebo
alpha-Lipoic acid
Acetyl-L-carnitine or
placebo
Vitamin E or placebo
Benfotiamine or placebo
Benfotiamine plus
cyanocobalamin
(Milgamma) or B-complex
Benfotiamine, pyridoxine,
and cyanocobalamin
versus benfotiamine alone
Methylcobalamin or
placebo
Methylcobalamin or
nothing
Zinc sulfate or placebo
RCT; n=328; 3 weeks
RCT; n=65; 2 years
RCT; n=509;
7 months
RCT; n=120;
5 days/week for 14
treatments
Small RCT; n=24;
3 weeks
Small uncontrolled;
n=26; 3 months
RCT; n=333; 1 year
2 multicenter RTCs;
n=1,346; 1 year
Small RCT; n=21;
6 months
RCT; n=40; 3 weeks
Comparative trial;
n=30 Milgamma;
n=15 B-complex;
3 months
Open trial; n=36
(12/group); 6 weeks
RCT; n=43; 4 months
Matched controls;
n=40; 2 months
RTC; n=30
I.V.
I.V. for 5 days
followed by oral
I.V. for 3 weeks
followed by oral
I.V.
Oral
Oral
I.M. for 10 days
followed by oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
600-1,200 mg
600-1,200 mg
600 mg (I.V.); 1,800 mg (oral)
600 mg
1,800 mg
600 mg
1,000 mg (I.M.); 2,000 mg
(oral)
1,500-3,000 mg
900 mg
400 mg
400 mg benfotiamine and
2,000 mcg cyanocobalamin
(3 weeks), followed by 150 mg
benfotiamine and 750 mcg
cyanocobalamin (9 weeks)
320 or 120 mg benfotiamine,
720 or 270 mg pyridoxine, and
2,000 or 750 mcg
cyanocobalamin versus 150
mg benfotiamine
1,500 mcg
1,500 mcg
660 mg (267 mg
elemental zinc)
Intervention Clinical Trials
Routes of
Administration Daily Dosage Range
To benefit the clinician, only positive clinical studies have been included in this table.
RCT=randomized, controlled trial
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Zinc
A clinical study examined the effect of zinc
for parameters of blood sugar control and peripheral
neuropathy in 50 subjects. Thirty diabetics with PN
were supplemented with 660 mg zinc sulfate (267
mg elemental zinc) daily or placebo (equal number in
each group) for six weeks and compared to a group
of 20 healthy controls. Serum zinc levels were significantly
lower at the beginning of the study in both
groups with diabetes compared to controls. NCV
in the median and peroneal nerves significantly increased
in the group supplemented with zinc. In addition,
significant improvements in fasting and postprandial
blood sugar were noted in the zinc group
compared to the diabetics taking placebo.174
Chromium
A chromium deficiency, seen in particular in
patients on total parenteral nutrition, can cause a peripheral
neuropathy associated with impaired glucose
tolerance.175,176 Infusion of as little as 250 mcg chromium
daily for three weeks reversed abnormal nerve
conduction.176
Table 3 summarizes the most promising nutrient
treatment options for diabetic PN.
Essential Fatty Acids for Peripheral
Neuropathy
Gamma-linolenic Acid (GLA) for the
Treatment of Diabetic Peripheral
Neuropathy
Diabetics appear to have impaired conversion
of linoleic acid to GLA, apparently due to faulty
desaturase enzyme activity.177 Because metabolites of
GLA are essential for nerve membrane structure and
blood flow, a deficiency could contribute to the development
of neuropathy.
Clinical studies of GLA for PN have been
limited to two, in which evening primrose oil (EPO)
was used. In a preliminary, double-blind study, 22 patients
with diabetic neuropathy were assigned to 360
mg GLA (n=12) or placebo (n=10) for six months.
Subjects on GLA exhibited significantly better neuropathy
scores, NCV, and action potentials compared
to placebo.178
In a subsequent, multicenter, double-blind,
placebo-controlled trial, 84 subjects with mild diabetic
neuropathy were given 480 mg GLA from EPO
(n=44) or placebo (n=40) daily for one year. Thirteen
of 16 parameters of neurological function, including
NCV, improved in the GLA group, while the placebo
group deteriorated.179 While the results of these two
studies appear promising, one of the centers involved
in the multicenter study was determined by the General
Medical Council in Great Britain to have used
fraudulent research techniques by falsifying results.
This center raised suspicions when a clear benefit of
EPO was reported, while the other centers found little
or no difference between EPO and placebo.180,181
Animal studies lend some support for use of
GLA and elucidate its potential mechanisms in diabetic
PN. In a study of streptozotocin-diabetic rats,
diabetes resulted in decreased NCV, abnormal fatty
acid phospholipid composition, and decreased (Na+/
K+)-ATPase activity. Supplementation of diabetic rats
with 260 mg GLA daily, either at onset of diabetes
for 12 weeks (preventive group) or after six weeks
of diabetes for six weeks (reversal group), resulted in
restoration of normal NCV in both the prevention and
reversal groups and partial normalization of (Na+/K+)-
ATPase activity in the prevention group.182
Another animal study found GLA may improve
NCV and neuronal blood flow in diabetic PN.
It compared the effect of GLA from EPO with GLA in
a triglyceride form not found in EPO and found they
were equally effective at improving NCV and blood
flow; sunflower oil with no GLA had no effect.183
GLA and ALA in the Treatment of Diabetic
Peripheral Neuropathy
One study examined the effects of EPO or
ALA on NCV, nerve blood flow, and lipid parameters
in streptozotocin-diabetic rats. While both EPO and
ALA improved neuronal blood flow and NCV, ALA
also improved signs of dyslipidemia, while EPO resulted
in increased dyslipidemia.184 In another animal
study, a conjugate of ALA plus GLA worked better
than either substance alone in improving NCV and
neuronal circulation.185
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Omega-3 Fatty Acids in the Treatment of
Peripheral Neuropathy
Similar to omega-6 fatty acids such as GLA,
omega-3 fatty acids are also essential for healthy nerve
cell membranes and blood flow. A clinical study of
21 type 2 diabetics with symptoms and signs of neuropathy
found 1,800 mg eicosapentaenoic acid (EPA)
daily for 48 weeks significantly decreased symptoms
of coldness and numbness and improved vibrational
perception; improvement in vibratory threshold plateaued
at 12 weeks. Circulation, measured in the dorsal
pedis artery, and lipid profiles also significantly
improved.186
A study in diabetic rats found fish oil, compared
to olive oil, increased NCV, improved (Na+/
K+)-ATPase activity, and prevented histological signs
of nerve degeneration such as demyelination and axonal
degeneration.187
The omega-3 fatty acid, docosahexaenoic
acid (DHA), was isolated in phospholipid liposomes
and fed to diabetic rats at a dose of 60 mg/kg body
weight. Eight weeks of diabetes led to significant
decreases in NCV, nerve blood flow, and (Na+/K+)-
ATPase activity in sciatic nerve and RBCs. DHA
completely prevented the decreases in blood flow and
NCV; it improved (Na+/K+)-ATPase activity in RBCs
but not sciatic nerve. These researchers hypothesized
that DHA might work better than a combination of
DHA and EPA because EPA might interfere with the
beneficial effects of omega-6 fatty acids.188 Since this
study did not compare the two, this is merely conjecture.
A Topical Flavonoid-Vitamin Complex
for the Treatment of Peripheral
Neuropathy
A topical compound called QR-333 was studied
in a double-blind trial of 34 individuals with neuropathy
due to type 1 or 2 diabetes. The compound,
consisting of quercetin, ascorbyl palmitate, and vitamin
D3, was formulated because the flavonoid
quercetin is an aldose reductase inhibitor, vitamin C
in a fat-soluble form could enhance its free radical
scavenging effects in the lipophilic environment of
neural tissue, and a synthetic analogue of vitamin D3
has been shown in vitro to enhance nerve growth factor.
Twenty-three subjects received the active cream
while 11 received placebo three times daily for four
weeks. Reduction in total symptom score was statistically
significant for the treatment group compared to
placebo, with particular improvement in numbness,
irritation from socks or bedding, and jolting pain. It
should be noted, however, there was also a trend toward
improvement in the placebo group. Since the
placebo group was smaller than the treatment group,
statistical significance would have been more difficult
to achieve.189
Herbal Treatments for Peripheral
Neuropathy
St. John's Wort for the Treatment of
Peripheral Neuropathy
Because tricyclic antidepressant medications
are used for PN, a study was conducted to determine
whether St. John's wort (Hypericum perforatum)
would have a similar effect. In a randomized,
double-blind, placebo-controlled, crossover study, 54
patients (49 completed, including 18 diabetics and 29
non-diabetics) were given three tablets of St. John's
wort containing 900 mcg hypericin/tablet (equivalent
to 300 mg of a 0.3-percent hypericin extract per
tablet) or placebo daily for five weeks, then crossed
over to the other treatment. Four pain symptoms were
evaluated - constant pain, lancinating pain events,
touch-evoked pain, and pressure-induced pain. A
trend toward improved overall pain scores was noted,
although no significant differences were achieved
with any individual pain index. Nine individuals in
the treatment group and two in the placebo group
experienced moderate to complete pain relief.190 The
dosage used in this study is the lowest dosage typically
recommended for the treatment of depression.
When using conventional treatments such as gabapentin,
higher-end dosages are typically required for
treatment of neuropathy. Therefore, a study employing
double the dosage used in this study is recommended.
Topical Capsaicin Cream for the
Treatment of Peripheral Neuropathy
Numerous studies have evaluated the effect
of capsaicin cream for the treatment of peripheral
neuropathy. Capsaicin is an active principal of the
herb Capsicum officinalis and is believed to stimulate
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afferent C-fibers (fibers in the mechano-heat class).
The initial stimulation of C-fibers results in burning
and irritation that stimulates release of substance P
(a pain-relieving neuropeptide) and other neuropeptides.
Repeated exposures result in a diminution of
the initial burning and irritation and a long-lasting
analgesic effect.191
Capsaicin for the Treatment of Diabetic
Peripheral Neuropathy
The majority of studies of capsaicin cream
for PN have been conducted in individuals with diabetes.
In a large, multicenter, double-blind, placebocontrolled
trial conducted by The Capsaicin Study
Group, 277 subjects entered the study, 252 continued
for at least two weeks, and 219 completed the eightweek
trial. Subjects applied 0.075-percent capsaicin
cream (n=100 completers) or placebo cream (n=119
completers) four times daily and were evaluated at
two-week intervals for eight weeks. Pain was assessed
via physician assessment as well as patientdriven
VAS. Statistically significant improvements
were noted in physician global assessment (69.5%
versus 53.4%), pain intensity (38.1% versus 27.4%),
and degree of pain relief (58.4% versus 45.3%) in the
capsaicin versus placebo groups, respectively; statistically
significant differences started during the fourth
week.192 Effect on daily activities was also assessed,
and statistically significant improvements in walking,
working, sleep, and participation in recreational activities
were noted in the capsaicin group compared
to placebo.193
In a smaller double-blind study, 54 (49 completers)
subjects with type 1 or 2 diabetes and moderate-
to-severe pain that interfered with sleep or daily
activities applied 0.075-percent capsaicin cream
(n=28; 24 completers) or placebo cream (n=26; 25
completers) to painful areas four times daily for eight
weeks (same protocol as the previous study). Pain
was measured via VAS, physician global assessment,
and effect on interference with daily activities. After
eight weeks, 89.5 percent of the capsaicin group
and 50 percent in the placebo group experienced improvement;
the average decrease in pain intensity was
49.1 percent in the capsaicin group and 16.5 percent
in the placebo group - statistically significant differences.
The differences in pain assessment after two
weeks were similar in both groups, indicating a need
for continued use of capsaicin in order to experience
pain relief.194
Another study using the same protocol as the
above studies was conducted on 22 diabetics with
PN (11 in each group). Decrease in pain intensity via
VAS was 16 percent in the capsaicin group and 4.1
percent in the placebo group. In an open-label continuation
of the study (average follow-up 22 weeks),
50 percent of subjects experienced improvement or
complete amelioration of pain, 25 percent remained
unchanged, and 25 percent worsened.195 Sensory
function was tested in this same group of individuals
and there were no differences between active or
placebo in regard to sensations of vibration, warmth,
or cold.196
Another eight-week, double-blind study compared
the effects of capsaicin cream to amitriptyline
capsules in 235 patients with diabetic neuropathy.
Subjects on capsaicin cream were given placebo capsules
and subjects in the amitriptyline group received
placebo cream. Equal and statistically significant improvements
in pain were noted in both groups. While
no systemic side effects were reported in the capsaicin
group, most on amitriptyline experienced at least
one side effect, most commonly sleepiness, but also
neuromuscular or cardiovascular side effects.197
To determine the mechanism of action of
capsaicin, a study was conducted on 13 subjects with
diabetic PN who used 0.05-percent capsaicin for eight
weeks. Cream was applied to one foot while the other
foot served as a control. In addition to pain scores
and vibrational and thermal thresholds, serum levels
of substance P were measured. Significant improvements
in total pain score and heat thresholds were
noted in the treatment foot compared to the untreated
foot, indicating very localized effects. Substance P
levels increased initially during the first four weeks
of the study, but declined to baseline by the end of
the study, calling into question the long-term effect of
capsaicin on substance P.198
The primary side effect reported by patients
in the various capsaicin studies was burning at the
site of application, sometimes resulting in dropout.
In order to address the issue of topical irritation and
to examine the effect of higher-concentration capsaicin,
a study examined the use of highly concentrated
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capsaicin
(5-10%) in addition to regional anesthesia
in 10 patients with intractable pain (three with neuropathy
- diabetic, HIV-associated, idiopathic). Although
two applications of the cream resulted in pain
relief (significant in nine of 10), I.V. fentanyl had to
be used to counteract the breakthrough burning associated
with such a high concentration of capsaicin.
Analgesic effects lasted from less than a week to more
than 50 weeks. This treatment may provide relief for
chronic, intractable pain and reduce dependence on
opioids.199
Studies on topical treatments for diabetic PN
are summarized in Table 4.
Capsaicin for the Treatment of HIVassociated
Peripheral Neuropathy
In a double-blind study, 26 patients with HIVrelated
PN were given either 0.075-percent capsaicin
cream (n=15) or identical placebo cream (n=11) and
asked to apply the cream and record pain scores four
times daily for four weeks. Dropout rate was high
- 10 in the capsaicin group (five because of localized
burning) and two in the placebo group. No statistically
significant differences were noted between treatment
and placebo groups in regard to any aspect of pain or
quality of life during the course of the study.200 Due to
the depletion of subjects - only five remained in the
capsaicin group - this result is not surprising.
Acupuncture for the Treatment of
Peripheral Neuropathy
Several studies have examined the effect of
acupuncture for the treatment of various types of PN
- diabetic, HIV-associated, chemotherapy-induced,
and mixed etiologies. Some studies have been difficult
to fully analyze as they are in foreign languages
with just the abstract available in English.
One study involved 17 patients with chronic
PN of unspecified etiologies. Subjects were treated
with electroacupuncture twice weekly for four weeks.
Table 4. Summary of Topical Treatments for Diabetic Peripheral Neuropathy
QR-333 (quercetin, ascorbyl
palmitate, and vitamin
D3) or placebo cream
Capsaicin (0.075-percent
capsaicin) or placebo
cream
Capsaicin or placebo
cream versus amitriptyline
or placebo capsules
3 times daily for
4 weeks
4 times daily for
8 weeks
4 times daily for
8 weeks
4 times daily for
8 weeks/22 weeks
8 weeks
RCT
RCT
RCT
RCT (8 weeks);
open label (average
of 22 weeks)
RCT
n=34 (23 active;
11 placebo)
n=219 completers
n=49 completers
n=22
n=235
Intervention
Frequency and
Length of Trial Trial Type Number in Trial
To better support the clinician, only positive clinical studies are included in this table.
RCT=randomized, controlled trial
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VAS was used to assess intensity of continuous and
intermittent pain and duration and number of attacks.
Two weeks after the series of treatments, average
continuous pain score was decreased by 32.9 percent
and pain intensity by 59 percent; average number
of attacks decreased from 4.2 to 2.2 per day. Three
months after treatments were discontinued, pain intensity
was still decreased by 44 percent.201
Acupuncture for the Treatment of HIVassociated
Peripheral Neuropathy
Several studies have examined the effect
of acupuncture for neuropathy associated with HIV
infection. In a large-scale, placebo-controlled, multicenter,
14-week study of 250 patients, standard
acupuncture, amitriptyline, or both were compared
to placebo, control points, or both. Neither acupuncture
nor drug therapy was significantly more effective
than placebo.202
In a very small, uncontrolled trial, seven HIV
patients with antiretroviral-induced neuropathy were
treated with electroacupuncture 20 minutes daily for
30 days. Muscle-stimulated nerve amplitudes and
physical strength increased with general improvement
in functional activity.203
In a case series, 21 subjects with HIV-associated
PN received 30- to 45-minute acupuncture
treatments twice weekly for five weeks. A significant
reduction in pain, assessed by the Pain Rating Scale
and Subjective Peripheral Neuropathy Screen, was
noted post-treatment compared to pre-treatment for
total overall pain score as well as symptoms of numbness,
pins and needles, and pain (aching, burning).204
Table 5 summarizes the most promising treatments
for HIV-associated PN.
Acupuncture for the Treatment of
Chemotherapy-induced Neuropathy
Dose reduction or early termination of treatment
with neurotoxic chemotherapy drugs is often
necessitated due to significant PN. A pilot study of
five cases demonstrated encouraging results with the
use of acupuncture to correct qi, blood, and yang deficiencies
in this population.205
Acupuncture for the Treatment of Diabetic
Peripheral Neuropathy
In a study of 90 subjects with diabetic PN, 30
received wrist-ankle acupuncture, 30 received wholebody
acupuncture, and 30 received conventional
Table 5. Summary of Treatments for HIV-associated Peripheral Neuropathy
Acetyl-L-carnitine
Vitamin B12
Capsaicin or placebo
cream
Acupuncture
Uncontrolled; n=21;
up to 33 months
Uncontrolled; n=16;
3 weeks
Uncontrolled; n=8
RTC; n=26; 4 weeks
Small, uncontrolled;
n=7; 30 days
Case series; n=21;
5 weeks
Oral
I.V. or I.M.
I.V.
Topical
Electroacupuncture
Standard
acupuncture
3,000 mg
500 or 1,000 mg
Dosage not specified
4 times daily
20 minutes daily
30-45 minutes, twice
weekly
Intervention Trial
Routes of
Administration
Daily Dosage
Range
To better support the clinician, only positive clinical studies are included in this table.
RCT=randomized, controlled trial
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medical treatment (control group). Both acupuncture
groups experienced significantly better results than
the conventional medical/control group.206
Forty-four individuals with diabetic PN were
treated with six courses of acupuncture for a 10-week
period. Thirty-four (77%) experienced significant
symptom improvement, with seven subjects reporting
complete elimination of symptoms. Patients were
followed for 18-52 weeks and only eight individuals
required additional treatment. Standard medications
were used by 63 percent of subjects at the beginning
of the trial and 67 percent of these patients were able
to decrease or discontinue medications during the follow-
up period.207
In a series of 68 cases of diabetic PN treated
with acupuncture, 43 individuals experienced marked
improvement, 20 experienced some improvement,
and five exhibited no improvement; overall significant
improvement in NCV was observed. The article,
being in Chinese, was only available in English as
an abstract; therefore, the number and frequency of
treatments and specifically what symptoms were improved
is unknown.208
Magnets for the Treatment of
Peripheral Neuropathy
It is hypothesized that electromagnetic fields
may benefit PN by polarization of neurons that may
be firing ectopically, resulting in neuropathy.209 Pulsed
magnetic field therapy (strength of 20 gauss and frequency
of 30 Hz) was used to treat 24 subjects with
PN of various etiologies - diabetes, chronic inflammatory
demyelinating polyneuropathy, mercury poisoning,
pernicious anemia, paraneoplastic syndrome,
tarsal tunnel syndrome, and idiopathic sensory neuropathy.
The most symptomatic foot in each subject
received treatment, while the contralateral foot served
as a control. Subjects were evaluated after nine onehour
consecutive treatments (weekends off) using
VAS and Patient's Global Assessment of Change.
Average pain scores decreased by 21 percent at the
end of nine treatments and by 49 percent at a 30-day
follow-up assessment; all 24 subjects completed the
study but only 15 were available for follow-up. The
treatment was even more effective for more severe
pain. Of 19 subjects with moderate-to-severe pain, a
28-percent reduction in pain score was experienced
Table 6. Physical Medicine for the Treatment of Diabetic Peripheral Neuropathy
Acupuncture
Magnets or placebo
Yoga or no yoga
Controlled; n=90
Uncontrolled; n=44
Case series; n=68
RTC; n=375;
4 months
Controlled; n=40;
40 days
Wrist-ankle acupuncture (n=30);
whole-body acupuncture (n=30);
conventional medicine/control group
(n=30)
Six courses of acupuncture for a
10-week period
Not specified in abstract (article in
Chinese)
Magnetic insoles or non-magnetized
insoles (placebo)
30-40 minutes of yoga daily
Intervention Trial Description of Therapy
To better support the clinician, only positive clinical studies are included in this table.
RCT=randomized, controlled trial
Copyright © 2005 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 10, Number 4 December 2005
Peripheral Neuropathy Review
Page 320 Alternative Medicine Review u Volume 11, Number 4 u 2006
at the end of treatment compared to baseline; a 39-
percent reduction was observed between baseline and
the end of the 30-day follow-up period.209
A large, multicenter (48 centers), doubleblind,
placebo-controlled trial was conducted on 375
individuals with diabetic PN. Subjects wore either
multipolar, static, 450 G magnetic insoles or placebo
(unmagnetized) insoles in their shoes for four months.
VAS was used to assess numbness and tingling, burning,
and quality of life, with significant decreases in
burning, numbness and tingling, and foot pain on exercise
reported during the third and fourth months of
the study compared to baseline in the magnetic-insole
group compared to placebo.210
Yoga for the Treatment of Diabetic
Neuropathy
In a controlled trial, 20 subjects with type
2 diabetes and mild-to-moderate neuropathy were
treated with 30-40 minutes of yoga daily for 40 days.
A group of 20 subjects matched for age and severity
of disease serving as a control did not engage in yoga
but were prescribed light exercise such as walking.
NCV, assessed in the median nerve for both right and
left hands, improved slightly in the yoga group (from
52.81 to 53.87 in the right hand and 52.46 to 54.75 in
the left hand). NCV in the control group continued to
deteriorate.211
Table 6 summarizes physical medicine treatments
for diabetic PN.
Cutting-Edge Conventional
Treatments for Peripheral Neuropathy
Some cutting-edge conventional approaches
to PN are on the horizon - treatments that potentially
do more than just mask symptoms. Several small,
"dual-action" peptides have been shown to have neurotrophic
activity - C-peptide and islet neogenesisassociated
protein peptide (both from pancreatic proteins),
and derivatives of erythropoietin.212
Recent recognition that C-peptide, originally
thought to be inert and merely a marker for endogenous
insulin production, improves sensory neural
deficits, microvascular blood flow, and renal filtration
in diabetes has stimulated research on its potential for
diabetic neuropathy.212 C-peptide has been found to
stimulate (Na+/K+)-ATPase activity213 and endothelial
nitric oxide synthase for improved circulation.214 In
an animal model of type 1 diabetes, C-peptide for 4-
7 months resulted in a dose-dependent prevention of
signs of neuropathy, including effects on NCV, nerve
fiber number, nerve regeneration, and overall neuropathy
score.215 In a phase II trial of 49 type 1 diabetics
with subclinical PN, subcutaneous administration of
C-peptide or placebo for three months resulted in significant
(80%) improvement in NCV in the C-peptide
group compared to placebo.216
Islet neogenesis-associated protein peptide
(INGAP) is a pancreatic peptide that has been found
to enhance formation of new pancreatic islet cells and
reverse hyperglycemia in type-1 diabetic animals.212
A preliminary study indicates it may hold promise
for treatment of neuropathy associated with diabetes.
Two-week administration of INGAP to streptozotocin-
diabetic rats with neuropathy resulted in improved
thermal detection, enhanced nerve growth in
dorsal root ganglia, and activation of signaling pathways
involved in nerve regeneration.217
In addition to its involvement in hematopoiesis,
erythropoietin receptors have been found in
neurons.212 Erythropoietin appears to directly prevent
axonal degeneration - the gross pathology seen in
peripheral neuropathies of various etiologies, including
diabetes and HIV. Researchers found nitric oxide
signals erythropoietin secretion from Schwann
cells in response to neuronal injury. Administration
of exogenous erythropoietin to animals with axonal
neuropathy prevented axon degeneration and reduced
behavior associated with neuropathic pain.218 Animal
studies of diabetes-induced219 or cisplatin chemotherapy-
induced220 neuropathy found erythropoietin significantly
attenuated nerve degeneration associated
with these two types of neuropathy. An in vitro study
demonstrated erythropoietin's protection of neurons
against the neurotoxic effects of antiretroviral agents;
thus it may have potential for HIV-associated neuropathy.
221
Preliminary research from the University of
Utah and Tufts University has found netrins, a family
of proteins involved in vascular and nerve growth,
may provide promise for the treatment of diabetic PN.
In a phase II trial, netrins injected into diabetic mice
resulted in both blood vessel and nerve growth.222
Copyright © 2005 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 10, Number 4 December 2005
Review Peripheral Neuropathy
Alternative Medicine Review u Volume 11, Number 4 u 2006 Page 321
Conclusion
Peripheral neuropathy presents with considerable
morbidity and can result in significant decreases
in quality of life. While conventional medicine can
offer some relief, the potential side effects or addictive
nature of many of the medications render longterm
use undesirable. Such treatments, furthermore,
merely mask the symptoms and do not address the
underlying pathologies. Alternative therapies, on the
other hand, are typically without side effects and address
nutrient deficiencies, oxidative stress, and other
etiological factors associated with the development
of PN.
Alpha-lipoic acid, acetyl-L-carnitine, benfotiamine,
methylcobalamin, and topical capsaicin are
among the most well-researched alternative options
for the treatment of PN. Other potential nutrient or
botanical therapies include vitamin E, glutathione,
folate, pyridoxine, biotin, myo-inositol, omega-3 and
-6 fatty acids, L-glutamine, taurine, N-acetylcysteine,
zinc, magnesium, chromium, St. John's wort, and
topical capsaicin. In the realm of physical medicine,
acupuncture, magnetic therapy, and yoga have been
found to provide benefit.
A questionnaire-based study examined the
use of alternative treatments for PN in 180 consecutive
outpatients at St. Elizabeth's Medical Center in
Boston, MA. Seventy-seven patients (43%) reported
using alternative therapies; 37 of 77 (48%) employed
more than one type of alternative treatment. Seventeen
(27%) of the respondents reported improvement
in neuropathy symptoms with unconventional approaches.
The treatments most often employed were
"megavitamins" (35%), magnets (30%), acupuncture
(30%), herbal remedies (22%), and chiropractic
manipulation (21%). Those who used alternative
approaches were more likely to be younger, college
educated, and suffering from diabetes compared to
those who did not use unconventional approaches.223
The use of well-researched nutrients, physical
medicine, and the possible addition of new cutting-
edge treatments should decrease the morbidity
associated with peripheral neuropathy and the side
effects associated with the commonly prescribed conventional
pain-relieving treatments in current favor.
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