peripheral neuropathy: pathogenic mechanisms and ... neuropathy-- pathogenic...peripheral neuropathy...

Peripheral Neuropathy Review

Peripheral Neuropathy: Pathogenic Mechanismsand Alternative Therapies

Kathleen A. Head, ND

AbstractPeripheral neuropathy (PN), associated withdiabetes, neurotoxic chemotherapy, humanimmunodeficiency virus (HIV)/antiretroviral drugs,alcoholism, nutrient deficiencies, heavy metaltoxicity, and other etiologies, results in significantmorbidity. Conventional pain medicationsprimarily mask symptoms and have significantside effects and addiction profiles. However, awidening body of research indicates alternativemedicine may offer significant benefit to thispatient population. Alpha-lipoic acid, acetyl-L-carnitine, benfotiamine, methylcobalamin,and topical capsaicin are among the most well-researched alternative options for the treatmentof PN. Other potential nutrient or botanicaltherapies 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 physicalmedicine, acupuncture, magnetic therapy, andyoga have been found to provide benefit. Newcutting-edge conventional therapies, includingdual-action peptides, may also hold promise.(Altern Med Rev 2006;11 (4):294-329)

IntroductionPrevalence

Peripheral neuropathy (PN) - characterizedby pain, numbness, and tingling in the extremitiesand slow nerve conduction - affects a significant per-centage of the U. S. population and can be extremelydebilitating. A J 999-2000 report, National Health andNutrition Examination Survey (NHANES), of 2,873men and women ages 40 or older (419 with diabetes),found a PN prevalence of 14.8 percent.' PN was de-fined as at least one insensitive area on the foot with

monofilament testing; it was also assessed by self-re-ported symptoms. The incidence of PN was signifi-cantly higher (62%) in the subset with diabetes. Theincidence of PN also increased significantly with age.NHANES found 8.1 percent of the 40-49 year agegroup had PN, compared to 34.7 percent of individu-als over age 80.

Etiological FactorsPeripheral neuropathy manifests as axonal

degeneration. Diagnosis of PN involves a completeevaluation to determine the extent of the neurologicaldeficit as well as a complete history and physical ex-amination to determine the possible etiology. Despitethorough history and physical exam, etiology remainsa mystery in approximately 50 percent of cases.^

Peripheral neuropathy can be the result ofgenetics, chronic disease, environmental toxins, al-coholism, nutritional deficiencies, or side effects ofcertain medications.

Among chronic diseases, diabetes mellitus isthe most common cause of PN. Mechanisms involvedin diabetes-associated PN are discussed in depth ina later section. Other endocrinological abnormalitiesthat can result in neuropathy include hypothyroidismand acromegaly.^ The neuropathy associated with hy-pothyroidism commonly manifests as carpal tunnelsyndrome. Other manifestations resemble diabeticneuropathy, with tingling paresthesias in a stock-ing-glove distribution. PN of acromegaly (excessgrowth hormone) includes carpal tunnel syndromeand sensorimotor polyneuropathy. Human immu-

Kattileen A. Head, ND - Technical Advisor, Thome Research, inc.; Editor-in-Chief,Alternative Medicine Review.Correspondence address: Thome Research, PO Box 25, Dover, iD 83825.E-maii; i<[email protected]

Page 294 Alternative Medicine Review • Volume 11, Number 4 • 2006

Review Peripheral Neuropathy

I^Oxidative Stress

I^Sorbitol

sUNitric Oxide^Homocysteine

nodeficiency virus (HIV)also results in PN, usuallyinvolving distal, nonpain-ful paresthesias, decreasedankle reflexes, and abnor-mal pain and temperatureperception."* Amyloidosisis another chronic diseaseresulting in PN.

Envi ronmenta lneurotoxins that can causeperipheral neuropathy in-clude exposure to mold inwater-damaged buildings,^solvents such as n-hexaneand methyl n-butyl ketone,*and heavy metals, including thallium,' arsenic,'' lead,**mercury,^ and germanium.'"

Peripheral neuropathy is common amongchronic alcohol abusers, with prevalence as low asnine percent and as high as 50 percent. Alcohol-as-sociated PN is related to a combination of factors, in-cluding malnutrition, nutrient deficiencies (thiaminein particular), and direct neurotoxicity of alcohol."

Medications that commonly result in PNinclude the chemotherapy drugs cisplatin, suramin,paclitaxel, and docetaxel,'^ as well as cholesterol-lowering statin drugs,'' HIV antiretroviral drugs, andthalidomide.'^

Pathogenesis of PeripheralNeuropathyDiabetic Peripheral Neuropathy

PN affects 30 percent of hospitalized and 20percent of non-hospitalized individuals with diabe-tes.'"* The mechanisms underlying PN depend on eti-ology. Diabetes, being the most common etiologicalfactor, is also the most studied in terms of pathogen-esis. While conventional theory holds that prolongedhyperglycemia results in the complications associ-ated with diabetes, including neuropathy, a recentstudy found PN can manifest even in individuals withabnormal glucose tolerance, a pre-diabetic condition.The study found that in a group with chronic idio-pathic polyneuropathy, subjects were twice as likelyto have abnormal glucose tolerance than age-matchedcontrols from the general population.'^

Figure 1. Pathophysiological Factors in Diabetic Peripheral Neuropathy

I'Advanced GlycosylatedEnd Products (AGEs)

vU(Na+/K+)-ATPase ActivityvUFree Carnitine and Myo-inositol

Impaired Endothelial Function

The pathophysiology of diabetic neuropathy(summarized in Figure 1) includes increased oxida-tive stress yielding advanced glycosylated end prod-ucts (AGEs), polyol accumulation, decreased nitricoxide/impaired endothelial function,'* impaired (NaVK+)-ATPase activity,''' and homocysteinemia.'^ Notonly are nerve cells more likely to be destroyed in ahyperglycemic environment, but repair mechanismsare also defective. Reduced levels of neurotrophicagents, including nerve growth factor and insulin-like growth factor, have been noted in experimentaldiabetes.'^

Oxidative Stress/Protein GlycosylationDiabetes results in increased products of

oxidation. In hyperglycemia, glucose combines withprotein, yielding glycosylated proteins, which canbecome damaged by free radicals and combine withfats, yielding AGEs that damage sensitive tissues. Inaddition, glycosylation of antioxidant enzymes canrender the defense system less efficient.

Significant evidence points to increasedoxidative stress in diabetic PN, either because of en-hanced production of reactive oxygen species (ROS)or defective scavenging of free radicals. A study com-pared markers of oxidative stress in 189 people withdiabetes (105 with PN, 22 with PN plus cardiac au-tonomic neuropathy [CAN], and 22 with no PN orCAN) with 85 controls.'"* Markers of oxidative stressincluded plasma 8-iso-prostaglandin F , superox-ide anion generation, and lag time to peroxidation

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Figure 2. The Sorbitol Pathway

Aldose ReductaseD-Glucose D-Sorbitol

NADPH NADP+

SorbitolDehydrogenase

NADPH

D-Fructose

by peroxynitrite. Subjects with PN or PN plus CANdemonstrated significant elevations of all three mark-ers, as well as significant decreases in the protectiveantioxidant vitamins C and E.

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

Sytze van Dam provides a review of thepathophysiology of oxidative sti ess in PN, includ-ing a summary of additional in Utro and animal re-search.^' I

Poiyol AccumulationGlucose is able to passively diffuse without

insulin into certain types of cells, including nervecells. Once inside the cell, glucose is converted tosorbitol and other polyols by the enzyme aldose re-ductase (Eigure 2). Beeause polyols do not passivelydiffuse out of cells, they concentrate within cells suchas neurons, creating an osmotic gradient that allowsexcess sodium and water to follow. ^

It is now believed that, in addition to osmoticeffects, polyol-pathway linked metabolic changes areinvolved. Eructose is also a byproduct of polyol-path-way activation via the sorbitol clehydrogenase-driv-en conversion of sorbitol to fructose. High fructoselevels result in increased AGE precursors,^^ anothersource of oxidative stress.

Accumulation of sorbitoland fructose in nerve cells hasbeen shown to decrease (Na+/K+)-ATPase activity. ^ i i addi-tion, free carnitinej and myo-ino-sitol content in the| caudal nervesof diabetic rats were significantlydecreased with poiyol accumu-lation. '* Providing the rats withan aldose reductase inhibitordecreased the depletion of bothmyo-inositol and carnitine in cau-dal nerves "* and preserved (NaVK' )-ATPase activity in the sciaticnerve, ^ adding further evidencethat metabolic derangements are

associated with polyol-pathway hyperactivity.

Nitric Oxide Deficiency/Impaired EndothelialFunction: The Arginine Connection

Vascular factors have also been implicated inthe pathogenesis of diabetic PN. Nerve blood flow isdiminished in experimental diabetic neuropathy, andnumerous studies indicate it may be rhediated by al-terations in nitric oxide metabolism. One such studyexamined nerve blood flow and nitric oxide synthase(NOS) activity in the mierovasculature serving pe-ripheral nerves in diabetic rats. ^ Hyperglycemia re-sulted in a significant diminution of nerve blood fiowcompared to controls. N-nitro-L-arginine, an inhibi-tor of NOS, also resulted in decreased nerve bloodfiow. L-arginine reversed the effects of NOS inhibi-tion and restored blood fiow to the nerves.

An animal study also foundi disruptions inneuronal nitric oxide synthase (nNOS) in experimen-tal diabetes. Decreased nNOS expression was associ-ated with increased neuropathic pain. i*

Nitric oxide plays an important role in con-trolling (Na+/K+)-ATPase activity,^'' ^ diminution ofwhich has been implicated in the pathogenesis ofPN.'^ Experimental analysis revealed hyperglyce-mia results in an excess of endothelial superoxideradicals that result in reduced stimulation of NO on(NaVK+)-ATPase activity; this effectlis inhibited byL-arginine.^^ Another animal study, however, did notfind a relationship between altered NO activity andthe development of sensory PN. ** !



Erectile dysfunction (ED) in diabetic mencorrelates with reduced NO activity and resultant en-dothelial dysfunction. A study of 60 men with dia-betes (30 with ED) found a further correlation withperipheral neuropathy. Heat/pain perception was ab-normal in 40 percent of diabetics with ED but in only10 percent of diabetics without ED, while warmthperception was abnormal in 50 percent of those withED compared to 30 percent without ED.^' These re-sults indicate a probable connection between abnor-mal NO activity and neuropathy in a clinical setting.

A Coimection Between Increased PolyolActivity and Decreased NO Activity?

The interrelationships between the variouspathogenetic aspects of diabetic PN are poorly un-derstood. An animal study attempted to elucidate apossible connection between aldose reductase activ-ity (enhanced polyol pathway activity) and decreasedNO activity. The researchers found NO to be an im-portant mediator of nerve (Na+/K*)-ATPase and al-dose reductase activity on NCV. NADPH is a cofac-tor for both NOS and aldose reductase. Therefore, theauthors theorize that hyperglycemia increases activ-ity of aldose reductase, subsequently decreasing NOSactivity via cofactor competition.'''

tememiaDiabetes and its complications are associated

with elevated homocysteine levels. A group of 65subjects with type 2 diabetes were divided into twogroups, those with neuropathy (n=43) and those with-out neuropathy (n=22). The frequency of hyperhomo-cysteinemia (>15 fitnol/L) was significantly higher inthe group with neuropathy (13/43) compared to thosewithout neuropathy (1/22). Of the three vitamin co-factors for homocysteine metabolism (vitamins B6and B12 and folate), plasma vitamin B12 levels dem-onstrated a downward trend in the neuropathy group,whereas there were no differences in vitamin B6 orfolate levels between the two groups."*

Hyperhomocysteinemia is associated withimpairment of endothelial function, providing amechanism for its possible involvement in diabeticcomplications, including neuropathy. Researcherspropose a synergistic effect between AGEs and ho-mocysteine, resulting in endothelial damage. In a

group of 75 type 1 diabetics, those with hyperhomo-cysteinemia had significantly higher plasma throm-bomodulin levels (a sign of endothelial damage; 62.2ng/mL versus 38.2 ng/mL) and higher prevalence ofneuropathy (57% versus 41%).'°

Not all studies have found a correlation be-tween high homocysteine levels and diabetic neu-ropathy. In a study of 629 people (266 with normalglucose tolerance, 167 with impaired glucose toler-ance, and 162 with type 2 diabetes) no definitive cor-relation was found between hyperhomocysteinemiaand PN.- '

Alcohol-related NeuropathyNeuropathy associated with chronic liver

disease/alcoholism appears to be associated with di-rect toxic effects of alcohol, malnutrition, thiaminedeficiency, and genetics. Ammendola et al found thestrongest correlation was between incidence of axo-nal neuropathy (most commonly of the sural nerve)and total lifetime dose of ethanol, compared to otherparameters examined (malnutrition and family his-tory of alcoholism)." Other B-vitamin deficiencies,including folate deficiency, have also been associatedwith cases of alcohol-related neuropathy.'^

Thyroid/Pituitary NeuropathiesMucinous deposits in soft tissue resulting in

nerve compression and carpal tunnel-like symptomshave been implicated in neuropathy associated withhyperthyroidism.' Neuropathy associated with excessgrowth hormone or acromegaly has been associatedwith subperineurial-tissue proliferation and dimin-ished myelinated and unmyelinated fibers.'

AIDS-associated NeuropathyPeripheral neuropathy affects as many as

one-third of individuals with acquired immunodefi-ciency syndrome (AIDS), most commonly manifest-ed as distal, symmetrical polyneuropathy. A study of251 HIV-positive individuals found the incidence ofneuropathy was significantly correlated with extentof immune deficiency (reflected in low CD4 counts)and malnutrition (decreased weight, hemoglobin, andserum albumin).''

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Table 1. Cancer Chemotherapeutic AgentsAssociated with Peripheral Neuropathy

Cisplatin and its analogs5-Fluorouracil5-AzacytedineVinca alkaloids (vincristine, vinblastine, etc.)Taxoids (paclitaxel, docetaxel)CytarabineEtoposideGemcitabineHexamethylmelamineIfosphamideMisonidazoleSuraminVM-26

PN associated with AIDS resembles PNcaused by vitamin B12 deficiency. Kieburtz et al re-port a prevalence of vitamin B12 deficiency (20%) inHIV-infected patients with PN. ^ Others have report-ed no association between vitamin B12 deficiencyand AIDS-related PN." :"*

Other proposed mechanisms (aside fromantiretroviral drugs, addressed below) for the highincidence of PN in AIDS includestress and infiammatory cytokine

increased oxidativeproduction, and im-

paired repair mechanisms caused by decreased S-ad-enosylmethionine.^^

Drug-induced NeuropatliyFactors that render peripheral nerves suscep-

tible to drug toxicity include a leaky blood-peripheralnerve barrier (compared to the blood-brain barrier)and genetics.'^

Antiretroviral AgentsAntiretroviral drugs used to treat individu-

als with HIV are implicated in PN. One study of 147HIV-positive adults found exposure to didanosine(ddl) or stavudine (d4T) significantly increased therisk of developing PN (odds ratio of 3.21 and 7.66,respectively);^*" zalcitabine (ddC) can also cause neu-ropathies.'- It is believed the neuropathies occur inpart because of drug-induced mitochondrial defects.In a rabbit model, ddC resulted in demyelination via

Schwann cell mitochondrial toxicity.^^ High lacticacid levels are associated with the use of antiretro-viral drugs and may be used to differentiate drug-induced versus AIDS-related neuropathy in peoplewith HIV.3^ !

iCancer Chemotherapeutic Agents

Numerous cancer chemotherapy drugs areassociated with neurotoxicity and PN (Table 1).

High cumulative doses of cisplatin resultin incidence of PN as high as 70-100 percent, withmore conventional lower doses resulting in a PN rateof 12 percent. Impaired DNA repair riiechanisms arebelieved to be the cause of PN in this population.'^

Taxoids such as paclitaxel; and docetaxelresult in peripheral neuropathy, particularly at highdoses. The mechanism is unknown but large arraysof disordered microtubules, a major effect on tumorcells, may be a cause of neurotoxicity.'^ Vinca alka-

loids may exert neurotoxic effects by inhibiting mi-crotubular assembly.'^ I

Lipid-lowering Drugs iPN is one of the less commori 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-controlstudy using automated databases found a significantincrease in neuropathy in people taking lipid-lower-ing drugs as a whole (odds ratio: 1.2^); statins (oddsratio: 1.22), and fibrates (another class of lipid-lower-ing drugs; odds ratio: 1.54).' '

Potential mechanisms include interruptionof cholesterol synthesis, resulting in disruption ofcholesterol-rich neuronal membranes, or inhibitionof coenzyme QIO synthesis (also inhibited by HMGCoA reductase), resulting in neuron| mitochondrialdamage. ** ;

A suspected case of diabetic, neuropathy ina patient with type 1 diabetes on a statin drug com-pletely resolved when the statin drug jwas withdrawn- indicating the neuropathy was froni statin use, notdiabetes.^^ On the other hand, statin drugs may actu-ally restore normal nerve function in jdiabetic neuro-pathy. In a study of mice with type|2 diabetes andneuropathy, the statin drug rosuvastatiii restored nervefunction and vascularity, at least in piart by restoringnNOS, which improved microcirculation."*"



Conventional Treatment of PNTreatment of peripheral neuropathy depends,

in part at least, on the cause of the neuropathy. Inthe case of drug-induced neuropathy, removing theoffending agent or decreasing the dose can result inresolution of the symptoms. In other cases, such asin the case of alcohol-related neuropathy, correct-ing a deficiency (in this case B vitamins, particularlythiamine) is essential. Initially, it is often necessary toprovide thiamine intravenously.

Because of the prevalence of PN in diabetes,much of the research has focused on diabetic neuropa-thy. Conventional treatments include antidepressants(tricyclics - TCAs and serotonin selective reuptakeinhibitors - SSRIs), anticonvulsants, antiarrhythmics(sodium-channel blockers; mexiletine), N-methyl-D-aspartate (NMDA) receptor antagonists, five-percentlidocaine patches, opioid and non-opioid analgesics,*'and aldose reductase inhibitors (such as sorbinil'*^ orzenarestat*^).

A review of placebo-controlled and compara-tive studies examined the efficacy and safety of sev-eral classes of drugs for neuropathy, including SSRIs,TCAs, NMDA-receptor antagonists, sodium-channelblockers, narcotic analgesics (tramadol, oxycodone),and first- and second-generation anticonvulsants (e.g.,carbamazepine, sodium valproate, and gabapentin).'"*The authors concluded that gabapentin showed thegreatest efficacy with the fewest side effects and po-tential drug interactions. Other anticonvulsants inearly stages of testing forPN include pregabalin (bet-ter absorbed than gabapentin)'*' and lacosamide.'"'

Alternative Treatments for PeripheralNeuropathyalpha-Lipoic AcidClinical Effects of Alpha-lipoic Acid (ALA)for Diabetic Peripheral Neuropathy

ALA, among the most well-researched nu-trients for peripheral neuropathy, has been used as atreatment for PN in Europe for decades. Three large-scale, double-blind, placebo-controlled trials - the Al-pha-Lipoic Acid in Diabetic Neuropathy (ALADIN)studies - have examined various routes of administra-tion, dosages, and neurological effects of ALA. Thefirst ALADIN study (n=328 type 2 diabetics) found

three weeks of intravenous (I. V.) ALA at 600 or 1,200mg daily was superior to placebo for reducing symp-toms of neuropathy measured by several pain-scorequestionnaires; the 600-mg dose yielded slightly bet-ter results with fewer side effects."*'

ALADIN II examined nerve conductionparameters as well as Neuropathic Disability Score(NDS) in a two-year trial of 65 patients with type 1or 2 diabetes. Patients were assigned to one of threetreatment groups: 600 mg ALA twice daily, 600 mgALA once daily plus placebo once daily, or doubleplacebo. After receiving the treatments I.V. for fivedays, subjects were placed on oral administration ofthe respective treatments. ALA resulted in significantimprovement in some nerve conduction parametersbut not in NDS compared to placebo."***

In the seven-month ALADIN III trial, 509PN subjects with type 2 diabetes received 600 mgI.V. ALA daily for three weeks, followed by 600 mgorally three times daily for six months; 600 mg I.V.ALA daily for three weeks, followed by placebo threetimes daily for six months; or double placebo. Whileno significant differences were noted in subjectivesymptom evaluation among the groups, treatmentwith ALA was associated with improvement in nervefunction."*

In the randomized, double-blind, placebo-controlled Symptomatic Diabetic Neuropathy (SYD-NEY) trial, 120 type 2 diabetic patients with PN wereadministered 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 sig-nificant improvement in overall symptoms, includinglancinating and burning pain, numbness, and tinglingcompared to the placebo group; improvement in onenerve conduction parameter was also reported.*

A meta-analysis of four placebo-controlledtrials (n=l,258) -ALADIN I and III, SYDNEY, and afourth unpublished trial (Neurological Assessment ofThioctic Acid; NATHAN II), all with the same proto-col of 600 mg ALA administered I.V. for three weeks- found a continuous daily improvement in symptomscores beginning on the eighth day of treatment.^'

Several smaller studies confirm the potentialbenefit of ALA for diabetic peripheral neuropathy.Like the first ALADIN study, one small study lastedonly three weeks. Type 2 diabetics with symptomatic



PN were given 600 mg ALA (n=l2) or placebo(n=12) orally three times daily. Even with the study'sshort duration, burning pain and NDS improved sig-nificantly in the ALA group compared to placebo.^^A smaller oral dose was also found effective in anuncontrolled study of 26 type 2 diabetics with PN. Anoral daily dose of 600 mg ALA for three months re-sulted in reversal from symptomatic to asymptomaticneuropathy; five patients had no signs of neuropathybased on symptom evaluation or NCV."

A small study of 10 subjects with diabetic PNfound 600 mg I.V ALA for three weeks resulted inimproved nerve function as well as decreased symp-tom scores. In this study, nerve microcirculation wasexamined by measuring capillary blood cell velocity(CBV). In normal healthy volunteers, cooling of onehand results in a decrease in CBV in the contralateralhand. In this small sample of 10 subjects no such re-action occurred. However, after three weeks of ALAtreatment, response to cooling was observed with sig-nificant reduction in CBV. In addition, there was asignificant reduction in neuropathy symptom scores.'"*In another small study of diabetics with PN, some ofthese same researchers further confirmed that one ofthe mechanisms of action of ALA involves improvedmicrocirculation to the nerves, and that this effect oc-curs acutely, even after one I.V infusion of ALA.''

A Russian study found ALA was most effec-tive in patients with mild neurological symptoms anda short history of diabetes.'* ALA has also been foundto be effective for diabetics with cardiac autonomicneuropathy" at an oral dose of 800 mg daily for fourmonths, and for diabetic mononeuropathy of the cra-nial nerves'* at a dose of 600 mg I.V. for 10 days fol-lowed by 600 mg/day orally for 60 days.

Mechanisms of Action of ALA for theTreatment of Diabetic PN

A clinical study was conducted to determinethe effect of ALA on nitric oxide production in 16individuals with diabetic neuropathy. Prior to ALAsupplementation total plasma concentrations of ni-trates and nitrites - a reflection of NO production- were two-fold lower in diabetic subjects than inhealthy volunteers. ALA supplementation - 600 mgI.V. five days/week and 600 mg orally on weekendsfor three weeks, followed by 600 mg ALA orally for

the remaining 20 days - resulted in normalizationof NO metabolite levels as well as improvement inclinical symptoms and electrophysiological signs ofneuropathy."* Theoretically, increased NO productionwould result in increased circulation to the neurons.

Several in vitro and animal studies havehelped elucidate the mechanisms of action of ALAfor diabetic PN. In an in vitro study, sciatic nerve wasincubated in glucose, resulting in a four-fold increasein lipid peroxidation. Addition of ALA as the R(+)form, the S(-) form, or the racemic mixture resultedin significant reductions in lipid peroxidation as mea-sured by TBARS. There were no differences in ef-fectiveness of the various forms of ALA.*' Anotherin vitro study confirmed ALA's effect on decreasinglipid peroxidation in a high-glucose environment. Inaddition, ALA was found to decrease protein glyco-sylation (measured by glycosylated hemoglobin) andincrease (NaVK+)-ATPase activity.''' The effect ofALA on lipid peroxidation was confirmed in a studyof people with diabetic PN. A daily dose of 600 mgALA for 70 days resulted in significant reductions inserum lipid peroxides that had been elevated com-pared to non-diabetic controls.*^^

Several studies examining the mechanism ofALA have been conducted on streptozotocin-diabeticrats with neuropathy. ALA was found to increase glu-cose uptake by nerve cells,*" nerve myo-inositol,''^'^glutathione levels,'^'*' (NaVK-')-ATPase activity,'^and nerve blood fiow,''' and normalize NAD:NADHratios.''"'

A cetyl-L-Carnitine (ALC)IL-CarnitineALC for Treatment of PeripheralNeuropathy Associated with HIV

Infection with HIV has been associated witha secondary deficiency of the amino acid L-carnitine.This deficiency may be due to malabsorption andother gastrointestinal disturbances, renal loss, shiftsin metabolism,*' and use of antiretroviral drugs.'''

Antiretroviral drugs are a major cause ofperipheral neuropathy in HIV-positive individu-als, potentially due to a drug-induced deficiency ofL-carnitine or ALC. As mentioned previously, se-vere axonal peripheral neuropathy can occur in sub-jects treated with the nucleoside analogues ddl, ddCand d4T (d-drugs), probably due to their action of



reducing mitochondrial DNA content. In a non-ran-domized study, serum L-carnitine and ALC levels in12 HIV-positive individuals, with axonal peripheralneuropathy on various combinations of ddl, ddC, andd4T, were compared to 21 subjects on ddl or zidovu-dine (AZT) without neuropathy, 10 HIV-negativesubjects with axonal or demyelinating autoimmuneneuropathies, and 13 healthy individuals, the latterthree groups serving as controls. Subjects with PNon antiretroviral d-drugs had significantly lower ALClevels compared to the control groups; there were nosignificant differences in L-carnitine levels amongthe groups.**

Another larger study did not support thesefindings. Free carnitine, ALC, and total carnitine weremeasured in a group of 232 HIV-positive individualswith PN. Although there were a significant numberin the study group with lower total and free carni-tine levels compared to healthy controls, there wereno significant differences in ALC levels. There werealso no significant differences between exposure toantiretrovirals or extent of neuropathy and carnitinelevels.' ^

Although ALC deficiency in HIV-positive in-dividuals with PN associated with d-drug antiretrovi-rals remains an open question, preliminary evidencepoints to a potential therapeutic effect of ALC in thispopulation. In a study of 21 HIV-positive subjectswith PN, 1,500 mg oral ALC twice daily for up to33 months resulted in improved symptoms of neu-ropathy in 76 percent of subjects. In addition, peri-odic skin biopsies examining histological innervationfound improvements beginning after six months oftreatment.™

Another small, short-term study examinedthe effect of 500 mg or 1 g ALC administered I.V orintramuscularly (LM.) daily for three weeks to HIV-positive individuals. Pain intensity was measuredbefore and after treatment, and 10 subjects reportedsymptom improvement, five reported no change, andone reported a worsening of symptoms.'" Larger,long-term, placebo-controlled studies are indicated todetermine the possible benefit of ALC for PN associ-ated with HIV

Potential mechanisms of action of ALC mayinclude counteracting the drug-induced mitochon-drial damage by direct antioxidant effects, promotion

of free fatty acid transport across the mitochondrialmembrane improving cellular energy metabolism,correcting a deficiency, or enhancing the response tonerve growth factor™

ALC for the Treatment of CairncerChemotherapy-induced Neuropathy

As mentioned previously, cancer chemother-apy drugs, including the taxanes (paclitaxel, docetax-el), platinum drugs (cisplatin, oxaliplatin, carbopla-tin), and vinca alkaloids (vincristine, vinblastine) areassociated with significant neurotoxicity, particularlyif prescribed in high doses. The associated peripheralneuropathy can be disabling and can persist for yearsafter discontinuation of the drug. Other cancer che-motherapeutic agents with potential neurotoxicity arelisted above in Table 1.

Acetyl-L-carnitine has been tested in clini-cal and animal studies for the treatment of chemo-therapy-induced peripheral neuropathy. In one study,26 patients with cisplatin- or paclitaxel-induced PNwere given I.V. infusions of 1 g ALC daily for 10-20days. The severity of PN was assessed by the WorldHealth Organization (WHO) Toxicity Grading List atbaseline and at the end of treatment. All five cispla-tin-treated patients experienced at least one grade im-provement in neuropathy symptoms, while eight of 12patients in the paclitaxel group and eight of 10 in thecombination paclitaxel/cisplatin group experiencedat least one grade improvement in symptoms.''^

Oral doses of ALC have also been found ef-fective for chemotherapy-induced PN, although im-provement may take longer than with I.V. or I.M.routes of administration. Twenty-five patients with pa-clitaxel- or cisplatin-induced PN of grade 3 or greaterduring chemotherapy or grade 2 or greater persistingfor at least three months post-chemotherapy, based onNational Cancer Institute Common Toxicity Criteria(NCI-CTC), were given 1 g ALC three times dailyfor eight weeks. Sensory symptoms improved in 15of 25 patients (1 grade in nine; 2 grades in six); mo-tor symptoms improved in 11 of 14 reporting motorneuron dysfunction. Symptomatic relief persistedlong after discontinuation of ALC - for an averageof 13 months in 12 of 13 surviving patients. In addi-tion, significant improvement was noted in sensorynerve action potentials and sensory NCV in 21 and



22 subjects, respectively. The one patient in the studywho experienced a worsening of symptoms was alsoreceiving the drug vinorelbine."

Several animal studies support the use ofALC for chemotherapy-induced PN and help elu-cidate possible mechanisms for its benefit. In onestudy, nerve conduction velocity was comparedin rats given cisplatin or cisplatin plus ALC and inanother group of rats given paclitaxel or paclitaxelplus ALC. The decreases in NCV were significantlyless in groups supplemented with ALC. In addition,ALC did not interfere with antitumor effects of thedrugs.'" Another animal study found ALC preventedpaclitaxel-induced neuropathy - an effect that lastedthree weeks after discontinuation of ALC. In a sepa-rate arm, ALC provided an analgesic effect for ratswith already established neuropathy.'' Further animalstudies have found acetyl-L-earnitine is protectiveagainst the neurotoxicity of oxaliplatin,'*' cisplatin,"and vincristine," without interfering with their anti-tumor effects.'"^"

Although the pathogenesis of neurotoxicityassociated with cancer chemotherapy drugs is largelyunknown, cisplatin appears to affect nerve growthfactor (NGF). One research group found cisplatinreduced circulating levels of NGF in rats, levels ofwhich seemed to reflect the extent of neurologicaldamage.^" In an animal model, ALC modulated cis-platin-induced decreases in NGF,''" and in vitro ALCpotentiated the effect of NGF,''" providing a potentialmechanism for ALC's benefit for chemotherapy-in-duced PN.

ALC/L-Carnitine for the Treatment ofDiabetic Peripheral Neuropathy

Clinical studies point to a possible L-carni-tine and/or ALC deficiency in diabetic PN. In a clini-cal investigation, 24 type 2 diabetics with complica-tions were compared to 15 type 2 diabetics withoutcomplications. Serum free and total carnitine levelswere found to be significantly lower in individualswith diabetic complications, including PN; therewere no differences in ALC levels.™

Another study compared L-carnitine andALC levels in peripheral nerves of 11 people withdiabetic PN to levels in nerves from 13 people withischemic non-diabetic neuropathy and 11 normal

controls. Although both groups with PN demonstra-ted decreased L-carnitine and ALC compared to con-trols, the differences did not reach statistical signifi-cance, leading the authors to speculate that carnitinedeficiency may be one, but not the primary, factor indiabetic PN. "

In a double-blind, placebo-controlled, mul-ticenter trial, 333 subjects with diabetic neuropathywere given ALC or placebo for one year. ALC at adose of 1,000 mg was administered I.M. for the first10 days followed by an oral dose of 2,000 mg dailyfor the remaining 355 days. Nerve conduction veloci-ties, amplitudes, and pain symptoms using a visualanalog scale (VAS) were assessed at baseline and atsix and 12 months. At 12 months, NCV, amplitude,and VAS pain scores were significantly better in theALC group compared to placebo; pain scores were re-duced from baseline by 39 percent in the ALC groupand eight percent in the placebo group.*'

Another larger study consisted of two multi-center, parallel, double-blind, placebo-controlled tri-als using the same protocol - 500 mg or 1,000 mg oralALC or placebo three times daily for one year. Onestudy consisted of centers in the United States andCanada (UCS) while the other study was conductedin centers in the United States, Canada, and Europe(UCES), with a total of 1,346 subjects. Results of thetwo studies were analyzed individually and as pooledcohorts. Vibrational sensation was significantly im-proved in the fingers at both 500- and 1,000-mg dos-ages of ALC three times daily, but in the toes only inthe 1,000-mg dosage in the UCS group. In the UCESgroup, the only improvement in vibrational sense oc-curred in the toes with the dosage of 1,000 mg ALCthree times daily. In the pooled cohorts of UCS andUCES, greater improvement in clinical symptomswas noted in both ALC groups compared to place-bo. In the 27 percent of subjects who reported painat baseline, 1,000 mg ALC three times daily resultedin significant improvements in pain in the UCS andpooled cohorts, but not in the UCES. When analyzedby subgroup it was determined the UCES had moresubjects with type 1 diabetes and longer duration ofneuropathy compared to the UCS. ALC appeared towork more effectively in patients with type 2 diabetesand a shorter duration of neuropathy.*^



In a study of 51 children with type 1 dia-betes, L-carnitine was supplemented at a dose of 2g/m^/day for two months. NCV and neurologicalexams were performed at baseline and at the end oftreatment. Children with abnormal NCV but normalneurological exams exhibited improvement in nerveconduction velocity, whereas those with abnormalneurological exams exhibited no such improvement.Autonomic neuropathy measured by sympatheticskin response was improved in both groups.*-' Animalstudies found acetyl-L-carnitine may benefit cardiacautonomic neuropathy*" and gastrointestinal auto-nomic neuropathy.*'

Animal studies have confirmed the clinicalaffects of ALC for diabetic PN and helped determinepotential mechanisms of action. In a study of diabeticrats given either ALC or sorbinil (an aldose reductaseinhibitor drug), both were associated with improve-ments in NCV, decreases in malondialdehyde of sci-atic nerve (a sign of reduced lipid peroxidation), andnormalized myo-inositol content; sorbinil, but notALC, reduced nerve sorbitol levels.**" Another studyfound similar results, with ALC increasing nervemyo-inositol and free carnitine levels without affect-ing sorbitol accumulation.^" Another study found defi-ciencies of ALC in diabetic rats resulted in decreased(Na+/K+)-ATPase activity and myo-inositol levels."

Another esterified form of L-carnitine, pro-pionyl-L-carnitine (esterified with propionic acid in-stead of acetic acid as in the case of ALC), also im-proved nerve conduction and sciatic nerve blood fiowin streptozotocin-diabetic rats.**

Vitamin EVitamin E for the Treatment of DiabeticPeripheral Neuropathy

Oxidative stress appears to play a significantrole in peripheral neuropathy, particularly in the caseof PN due to diabetes. In a double-blind, placebo-con-trolled trial, 21 type 2 diabetics with PN were giveneither 900 mg vitamin E (n=l 1) or placebo (n=10) forsix months. Electrophysiological parameters of nervefunction, examined at baseline and at the end of thestudy, found significant improvement in two of 12 pa-rameters - median motor NCV and tibial motor nervedistal latency - in the vitamin E group compared toplacebo.*'

In an animal study of streptozotocin-diabeticrats, depletion of vitamin E resulted in a depletion ofreduced glutathione in nerves of diabetic and normalrats and an induction or aggravation of abnormalitiesin nerve conduction, particularly in sensory nerves.'-"'

Vitamin E for the Prevention and Treatment

Cisplatin might induce a vitamin E deficien-cy that may be a cause of the neurotoxicity associ-ated with this chemotherapy drug. Plasma vitaminE levels were found to be low in five patients whohad developed severe neuropathy following cisplatintreatment. Two and four cycles of cisplatin also werefound to significantly decrease plasma vitamin E lev-els in another group of five patients in whom vitaminE levels were measured at baseline and after cisplatintreatment.*'

In a study evaluating the effect of vitamin Eon attenuation of cisplatin neurotoxicity, 13 patientsreceived cisplatin plus 300 mg vitamin E daily; 14received cisplatin alone. Vitamin E was administeredorally prior to onset of chemotherapy and continuedfor three months after cisplatin was concluded. Theincidence (30.7% versus 85.7%) and severity of neu-rotoxicity were significantly less in the group receiv-ing vitamin E. Evaluation of vitamin E in a preclinicalanimal study found it did not interfere with the tumorinhibition or tumor growth delay of cisplatin.^^

In two studies by the same researchers, pa-tients on cisplatin or carboplatin, plus other chemo-therapy drugs as the type of cancer indicated, were di-vided into two groups - one receiving chemotherapyplus 300 mg vitamin E twice daily, the other chemo-therapy only. Vitamin E was supplemented at com-mencement of chemotherapy and for three monthsafter chemotherapy was completed. In one trial 30patients completed the study (14 in the vitamin E-plus-chemotherapy group and 16 in the chemothera-py-only group);'-^ while in the second trial 31 patientscompleted the trial (16 in the vitamin E-plus-che-motherapy group and 15 in the chemotherapy-onlygroup).**" The extent of PN was evaluated in both stud-ies by Neurological Symptom Score, NeurologicalDisability Score, and electrophysiological studies ofnerve conduction and amplitudes of action potentials.



Significant differences in incidence of neurotoxicitywere seen in both studies when comparing the vita-min E-plus-chemotherapy groups to the chemother-apy-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 research-ers, the effect of vitamin E (300 hig twice daily) forprevention of paclitaxel-induced PN was examined.Thirty-two subjects (16 in each group) received ei-ther vitamin E-plus-chemotherapy or chemotherapyalone. The incidence of neurotoxicity was three of 16in the vitamin E group and 10 of 16 in the chemo-therapy-only group.'^

Vitamin E for the Treatment of Other Typesof Peripheral Neuropathy

Vitamin E deficiency is associated with sig-nificant neurological pathology, including PN. There-fore, a vitamin E deficiency should always be ruledout in cases of PN of unknown origin. In a case report,a 22-year-old man experienced severe demyelinat-ing neuropathy. The only abnormality on laboratoryexamination was a significant deficiency of vitaminE with fasting serum total tocopherol level on high-performance liquid chromatography (HPLC) mea-suring 0.3 mg/L (normal 6.0-19.0 mg/L). The patientwas started on 1,200 mg vitamin E daily in divideddoses and followed for four years. Supplementationresulted in improvement but not complete resolutionof nerve conduction abnormalities. Because all otherfat-soluble vitamins were nornial, broad-spectrumfat malabsorption was ruled out. The authors men-tioned an isolated vitamin E deficiency could havebeen caused by a mutation in the autosomal recessivealpha-tocopherol transfer protein gene.'^

Gastrectomy can also result in a vitamin Edeficiency, which can in turn result in neuropathy. Ina study of 11 postgastrectomy patients with vitaminE deficiency (10 with neurological complications),subjects were given 150-300 mg vitamin E daily, re-sulting in improvement of neurological symptoms innine of 10 subjects.'^

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GlutathioneGlutathione (GSH) for the Treatment ofOxaliplatin-induced Peripheral Neuropathy

Fifty-two patients with advanced colorectalcancer on oxaliplatin chemotherapy were .random-ized to receive an I.V. infusion of glutathione or sa-line (26 in each group) before each oxaliplatin cycle;12 patients dropped out (seven in the placebo arm andfive in the GSH arm). After eight cycles, nine patientsexperienced clinical signs of neuropathy in the GSHgroup compared to 15 in the placebo group. Whenseverity of neuropathy was assessed by NCI-CTC, 11of 19 in the placebo arm and two of 21 in the GSHarm had moderate-to-severe PN.'*

The authors of the above study discussed glu-tathione's possible mechanism in reducing neurotox-icity of platinum-based drugs. Reactive oxygen spe-cies generated by platinum drugs result in neuronalcell death. GSH, as an ROS scavenger, may preventsuch damage.'* The theory is supported by an in vitrostudy in which cisplatin induced apoptosis of rhouseneurons, which was then prevented by preineubationwith N-acetylcysteine, a precursor to GSH."

Glutathione and ALA for the Treatment ofDiabetic Peripheral Neuropathy

Because of the connection between oxidativestress and diabetic neuropathy, a preliminary animalstudy examined the effect of GSH or ALA in the pre-vention and treatment of diabetic PN. In streptozoto-cin-diabetic rats, intraperitoneal ALA but not GSHpartially reversed the decreased sciatic nerve bloodfiow initiated by diabetes. Interestingly, ALA but notGSH increased RBC GSH levels. Elevated levels ofmalondialdehyde (a sign of oxidative stress) werepartially reversed by ALA and GSH; nerve conducetion velocity was not affected by ALA or GSH.'™

ThiaminetBenfotiamineA vitamin Bl (thiamine) deficiency, which

can be due to various underlying causes, is knownto be a factor in peripheral neuropathy. For example,gastrectomy is associated with thiamine deficiencyand resultant PN. A study comparing 17 postgastrec-tomy PN patients with 11 subjects with thiamine-de-ficiency neuropathy due to dietary imbalances foundthe clinical presentation was identical.""

Alternative Medicine Review • Volume 11, Number 4 • 2006


Benfotiamine is the most extensively studiedform of thiamine for treatment of PN. Several clinicaltrials in healthy adults have demonstrated the superi-or absorption and bioavailabihty of this lipid-solublethiamine analogue compared to several water-solublethiamine salts.'°^'°" In addition, because of the lipo-philic nature of benfotiamine, it may be more readilytransported across cell membranes, including neu-rons.

Benfotiamine/Thiamine for the Treatment ofDiabetic Peripheral Neuropathy

In a double-blind, randomized, placebo-con-trolled pilot study, 40 subjects (20 in each group) withdiabetic PN were given two 50-mg tablets of benfo-tiamine four times daily (400 mg total daily dose) orplacebo for three weeks. Assessment was via neuro-pathy symptom and vibration sensation scores fromboth physician and patient. A statistically significantimprovement in the neuropathy score was reported inthe treatment group compared to placebo. The mostsignificant improvement reported was decrease inpain, although, there was no significant improvementin vibration perception measured by the tuning forktest.'05

Several studies have investigated the effect ofbenfotiamine in combination with other B vitamins inthe treatment of diabetic neuropathy. In one study, 30subjects received Milgamma® (50 mg benfotiamineand 250 meg B12 as cyanocobalamin per tablet) at adose of two tablets four times daily for three weeks(total daily dose: 400 mg benfotiamine and 2,000meg cyanocobalamin), followed by one tablet threetimes daily for nine weeks. The second group of 15subjects received a B-complex vitamin supplement ata dose of two tablets three times daily for the entirethree months. Changes in pain severity and vibrationperception thresholds were measured at baseline andat the end of the study. All Milgamma-treated patientsexperienced significant relief in neuropathic pain anddramatic improvement in vibration perception thresh-olds, while subjects receiving a B-complex vitaminexperienced only slight, non-statistically significantimprovement.""'

In a second six-week trial, 36 subjects withdiabetic PN were divided into three groups of 12 eachreceiving: (1) Milgamma-N® (40 mg benfotiamine.

90 mg pyridoxine, and 250 meg cyanocobalamin percapsule) at a dose of two capsules four times daily(320 mg benfotiamine, 720 mg pyridoxine, and 2,000meg cyanocobalamin daily); (2) Milgamma-N at alower dose of one capsule three times daily (120 mgbenfotiamine, 270 mg pyridoxine, and 750 meg cya-nocobalamin daily); or (3) 50 mg benfotiamine threetimes daily. Neuropathy was assessed via pain andvibration sensation at baseline and after three and sixweeks. Patients in all three groups reported benefi-cial therapeutic effects, even at three weeks, with themost significant improvement reported by patientsreceiving the highest-dose benfotiamine."'''

A double-blind, randomized, placebo-con-trolled, 12-week study examined the effectiveness ofanother benfotiamine combination containing bothvitamins B6 and B12 in 24 diabetic subjects with PN.A statistically significant improvement in NCV in theperoneal nerve was observed in the treatment groupcompared to placebo.'"*

Animal studies also confirm the benefit ofbenfotiamine for neuropathy in a rat model of dia-betic PN."""° One study comparing the effect of wa-ter-soluble thiamine with lipid-soluble benfotiaminefound benfotiamine superior in preventing functionalnerve damage and preventing formation of AGEs - acause of diabetic PN."°

At least two in vitro studies confirm the effectof thiamine and benfotiamine on AGEs. Two studiesfound benfotiamine"'"^ and one study found thia-mine"^ reduced the formation of AGEs in glucose-incubated cells. Other in vitro studies have foundbenfotiamine or thiamine decreased glucose-inducedapoptosis of endothelial cells"-' and decreased polyolaccumulation by inhibition of aldose reductase ex-pression.""

Benfotiamine for the Treatment of Akohol-related Peripheral Neuropathy

Chronic alcoholics commonly develop a thi-amine deficiency, resulting in peripheral neuropathyand other health problems. A deficiency of vitamin B1in this population can be due to inadequate dietary in-take, reduced capacity for hepatic storage, inhibitionof intestinal transport and absorption, or decreasedformation of the active coenzyme form. An animalstudy found chronic alcohol consumption by rats



resulted in a significant depletion in thiamine diphos-phate (TDP) - the active coenzyrhe form of thiamine.Supplementation with benfotiamine significantly in-creased levels of TDP and total thiamine compared tosupplementation with thiamine HCI."^

An eight-week, randomized, multicenter, pla-cebo-controlled, double-blind study compared the ef-fect of benfotiamine alone to a benfotiamine complex(Milgamma-N) or placebo in 84 alcoholic patients.Benfotiamine was given in a daily oral dose of 320mg (two 40-mg tablets four times daily) during weeks1 -4, followed by 40 mg three times daily (120 mg to-tal daily dose) during weeks 5-8. A second group re-ceived Milgamma-N (providing a total daily dose of320 mg benfotiamine, 720 mg pyridoxine, and 2,000meg cyanocobalamin) during weeks 1-4 and a totaldaily dose of 120 mg benfotiamine, 270 mg pyridox-ine, and 750 meg cyanocobalamin during weeks 5-8;a third group received placebo."^

Parameters measured included vibrationperception in the great toe, ankle, and tibia; neuralpain intensity; motor function and paralysis; sensoryfunction; and overall neuropathy score and clini-cal assessment. Although benfotiamine therapy wassuperior to Milgamma-N or placebo for all param-eters, results reached statistical significance only formotor function, paralysis, and overall neuropathyscore. Why the benfotiamine-alone group had betterresults than the Milgamma-N group, despite the factthat the benfotiamine dosage was equivalent, is notcompletely understood. The authors hypothesized vi-tamins B6 and B12 might have competed with theeffects of vitamin Bl in the Milgamma-N group. Onthe other hand, in the case of diabetic neuropathy, thepositive effects of the combination may be due to thefact that deficiencies of vitamins Bl, B6, and B12 areall implicated in its possible pathogenesis; whereas,alcoholic neuropathy is associated with only vitaminBl deficiency.

A small Russian study also found benefitof benfotiamine for alcoholic neuropathy. Fourteenchronic alcoholic men with polyneuropathy weregiven 450 mg benfotiamine daily for two weeks, fol-lowed by 300 mg daily for an additional four weeks;regression of neuropathy symptoms was observed. Amore in-depth report of the results is not possible be-cause only the abstract is in English."''

Methylcobalamin for the Treatment ofPeripheral NeuropathyVitamin B12 Deficiency Neuropathy

Vitamin B12 deficiency has been associatedwith significant neurological pathology, includingperipheral neuropathy. Testing serum metabolitessuch as methylmalonic acid and homocysteine canhelp clinically identify individuals at risk for a de-ficiency-associated neurological syndrome."* Oneof the mechanisms believed to be at play in vitaminB12 deficiency neuropathy is hypomethylation inthe central nervous system. Inhibition of the B12-dependent enzyme methionine synthase results in afall in the ratio of S-adenosylmethionine (SAM) toS-adenosylhomocysteine;"' the resultant deficiencyin SAM impairs methylation reactions in the myelinsheath. The methylation of homocysteine to methio-nine requires both methylcobalamin (an active formof vitamin B12) and the active form of folic acid (5-methyltetrahydrofolate).'^" An animal model of B12deficiency neuropathy, however, does not support thehypomethylation theory.'^'

Animal studies help elucidate some of thepotential mechanisms involved in vitamin B]2-asso-ciated neuropathies. Rats rendered B12 deficient bytotal gastrectomy were found to have elevated levelsof the neurotoxic cytokine tumor necrosis factor-al-pha (TNF-a) and decreased levels of neurotrophicepidermal growth factor and the neurotrophic cy-tokine interleukin-6. Levels of these cytokines andgrowth factors were normalized by the administrationof cobalamin.'^^

In an experimental animal model of acryl-amide-induced neuropathy, an ultra-high dose ofmethylcobalamin was found to stimulate nerve re-generation by up-regulating gene transcription. In acomparison of three groups, rats were given intraperi-toneal methylcobalamin at a dose of 500 mcg/kg or50 mcg/kg body weight, while a third group receivedsaline. Only the high-dose methylcobalamin groupexperienced regeneration of motor neurons.'^^



Methylcobalamin for the Treatment ofDiabetic Peripheral Neuropathy

In a four-month, double-blind, placebo-con-trolled trial of type 1 and 2 diabetics with neuropathy,21 subjects were given oral methylcobalamin at a doseof 500 meg three times daily (the authors presumablyerroneously reported this dosage in mgs), while 22subjects received placebo. Significant improvementswere reported for somatic and autonomic symptomsin the treatment group compared to placebo.'^"

A smaller study examined the effect of intra-thecal injections of methylcobalamin in 11 subjectswith type 2 diabetes. The study design was variable inthat several patients had different dosage schedules.Each subject received 2,500 meg methylcobalaminvia injection with one or two more injections occur-ring at one-month intervals. In addition, five subjectstook 1,500 meg/day oral methylcobalamin for onemonth; one subject got 500 meg/day I.V methylco-balamin for one month; and three subjects receivedan additional injection one year after completion ofthe initial course. Subjects reportedly began to feeleffects from several hours to several days after theinitial injection - primarily involving a decrease inheaviness of the lower limbs and improved sensation.Benefits lasted from several months to four years. Nochanges in NCV were noted.' ^

Another study of 72 patients with diabeticPN found the combination of methylcobalamin andprostaglandin El was superior to either substancealone.'^'' A review of several clinical trials of the useof methylcobalamin alone or vitamin B12 (form notspecified) combined with other B vitamins foundoverall symptomatic relief of neuropathy symptomswas more pronounced than electrophysiological find-ings.'"

In a study of 20 type 2 diabetics comparedto 20 age-matched controls, serum vitamin B12 lev-els were significantly lower in the diabetic group.Supplementation of 1,500 meg/day methylcobalaminfor two months resulted in improved vibratory per-ception thresholds and heart rate variability (a signof improvement in signs of autonomic neuropathy) inthe diabetic group.'^*

Supplementation of vitamin B12 may ben-efit diabetic PN by correcting a deficiency. Whilediabetes itself can result in vitamin B12 deficiency.

metformin, an oral antihyperglycemic agent used totreat type 2 diabetes, may also cause vitamin Bl2 de-ficiency.'^'

In streptozotocin-diabetic rats, methylcobal-amin resulted in decreased demyelination and protec-tion of nerve fiber density and size. The rats were ad-ministered I.M. methylcobalamin at a very high dailydose of 500 meg/kg body weight for 16 weeks.'-"'

Methylcobalamin for the Treatment ofNeuropathy Associated with Renal Failure

Uremia is associated with peripheral neuro-pathy and is characterized by motor and sensory neuro-pathy that begins distally and ascends as the conditionworsens. In a study of nine patients on renal dialysisdue to chronic glomerulonephritis, diabetes, or renaltuberculosis (six with uremic neuropathy; three withdiabetic/uremic neuropathy), subjects were given 500meg methylcobalamin I.V. three times weekly for sixmonths. Due to poor renal excretion, serum vitaminB12 reached extremely high levels during the courseof the study (mean, 72,000 pg/mL). Significant de-crease in pain scores was experienced by six of ninesubjects; NCV increased significantly.'-"

Methylcobalamin has also been found to ben-efit uremics with autonomic neuropathy. In a groupof eight dialysis patients with abnormal beat-to-beatheart rate variability, 1,500 meg methylcobalamindaily for six months resulted in improvement of thissign of autonomic neuropathy - from variability of3.3 beats/minute at the beginning of the study to 5.8beats/minute after six months.'^^

Vitamin B12 deficiency has been reportedin patients with renal failure, providing one poten-tial cause for neuropathy in this population.'^^ Inaddition, accumulation of neurotoxic compounds isa likely cause, since dialysis or renal transplant canameliorate the condition.'^^

Cyanide may be one of the neurotoxic me-tabolites involved, as researchers have found a rela-tionship between the severity of neuropathy as mea-sured by vibrational sensation and tobacco smoking(a significant source of cyanide).'" Uremic patientswere also found to have high levels of cyanide asmeasured by accumulation of thiocyanate, a detoxifi-cation product of cyanide. Another method of detoxi-fying cyanide is to utilize the pool of free cyanide to



synthesize cyanocobalamin (a form of vitamin B12).These researchers found that administration of meth-ylcobalamin resulted in increased cyanocobalaminand decreased levels of thiocyariate (a reflection offree cyanide levels). They theorized methylcobala-min was providing the cobalamin substrate for utili-zation of cyanide in cyanocobalarnin synthesis. Thesesame researchers had previously noted improved vi-brational thresholds in this population of individualswhen supplemented with methylcobalamin.'^^

Vitamin B12 Status in HIV-associatedNeuropathy

Peripheral neuropathy was diagnosed in 34of 49 HIV patients (69%) referred to a neurologyclinic for examination of vitamin B12 status. Abnor-mal B12 status, defined by a serum level less than150 pmol/L or a Schilling test reflecting less thaneight-percent absorption, was found in 29 percent ofpatients with PN compared to 20 percent in the groupas a whole. Eighty percent of subjects with abnormalvitamin B12 status had progressed to AIDS. Five ofeight patients who received parenteral vitamin B12therapy experienced clinical improvement in neuro-pathy symptoms within one week of treatment.^^

Another study examining 20 subjects withearly-stage HIV infection found a five-percent inci-dence of PN, but it was not associated with impairedvitamin B12 metabolism.^" Neurdpathies in this pop-ulation are often associated with antiretroviral drugs(see above).

Folate for the Treatment of PeripheralNeuropathy

In addition to folic acid's involvement in vita-min B12 metabolism, a folate deficiency can result inPN, independent of vitamin B12 status. In a series of 20subjects with abnormal neurological findings, 10 sub-jects fit the diagnostic criteria for peripheral neuropa-thy. The only abnormality detected was a low serum,RBC, or cerebral spinal fluid (CSF) folate level.'3"

In a Japanese study of 343 patients with vari-ous neurological diseases, primarily axonal neuropa-thy, 36 subjects (10.5%) demonstrated low serumfolate levels. Supplementation with high-dose folate(15 mg/day) resulted in improvement in neurologicalsymptoms in 24 of 36 subjects

A folate deficiency may contribute to thepathogenesis of alcoholic peripheral neuropathy. Ina study of 46 hospitalized alcoholics with PN, eightpercent demonstrated low plasma folate levels twoweeks after alcohol abstention. When functional fo-late status was evaluated using the formiminoglu-tamic acid (FiGlu) excretion test or the deoxyuridinesuppression (dU) test, 50 percent of this populationwas found to be deficient.'^''

PN can be caused by several medications as-sociated with folate deficiency, including sulfasala-zine, methotrexate, antituberculosis drugs, anticon-vulsants, and oral contraceptives.'^^ In a study of 51epileptic patients newly placed on anticonvulsantsand followed for five years, no clinical signs of neu-ropathy were noted, although 18 perceht of the grouptaking phenytoin (and none in another group on car-bamazepine) showed signs of slowed nerve conduc-tion or decreased action potentials. Clinical and elec-trophysiological signs of neuropathy were noted insix patients on chronic barbiturate therapy and in 10patients on chronic phenytoin.'^*

Patients on longer-term anticonvulsant thera-py appear to be more likely to exhibit signs of neu-ropathy. In 29 epileptics on long-term therapy, all butthree showed abnormalities in electrophysiologicalmeasurements of nerve function. Sensory nerve actionpotentials were reduced or absent in 76 percent of pa-tients; all subjects had low serum and CSF folate lev-els. These 19 patients were treated with either folinicacid (n=10) or folic acid (n=9) for one month with sig-nificant reversal of nerve abnormalities; a greater ef-fect was noted in the folinic acid group. The research-ers theorized that folinic acid was able to raise levelsof folate in the CSF slightly more than folic acid.'-"

Pyridoxine and Peripheral NeuropathyVitamin B6 deficiency may be associated

with the development of peripheral neuropathy. Inaddition, in the form of pyridoxine HCl, high dosesof B6 have been implicated as a cause of PN.

Pyridoxine Deficiency NeuropathyVitamin B6 deficiency PN has been studied

in an experimental rat model. Morphornetric analysisdemonstrated decreased nerve fiber density and in-creased axon-to-myelin ratio, indicative of peripheralneuropathy.'""



Medications, particularly isoniazid for tuber-culosis, can result in pyridoxine-deficiency neuropa-thy that can be prevented by simultaneous supple-mentation with vitamin B6.'"' Isoniazid appears toinhibit the activity of vitamin B6.'"^ PN associatedwith isoniazid therapy typically manifests as burningfeet and can be reversed within a few weeks by 250mg pyridoxine daily.'"-

A study of patients with carpal tunnel syn-drome (CTS), some with concomitant PN, foundpatients with PN (but not CTS without PN) demon-strated abnormalities of pyridoxine metabolism asmeasured by erythrocyte glutamine oxaloacetic acidtransaminase (EGOT) activity.'""

PN associated with vitamin B6 deficiency isseen in patients with uremia. In a study of 66 dialysispatients, 12 experienced PN with a significant nega-tive correlation between pyridoxal 5' phosphate (P5P;the active form of vitamin B6) levels and PN symp-toms. Supplementation of 30 mg vitamin B6 dailyfor one month resulted in increased levels of P5P andimprovement in sensory abnormalities in eight of 12patients.'"^

Pyridoxine in the Treatment of DiabeticPeripheral Neuropathy

Pyridoxine may have application for thetreatment of diabetic neuropathy, although studieshave been limited and results equivocal. A study of50 patients (24 males and 26 females) with significantdiabetic neuropathy found significantly lower levelsof P5P in this population compared to age- and gen-der-matched controls with diabetes but without neu-ropathy.'"' On the other hand, another study exam-ining various vitamin levels in type 2 diabetics withor without neuropathy found no correlation betweenvitamin B6 levels and neuropathy. In fact, this studyfound no correlation between neuropathy and levelsof any vitamins tested - vitamins A or E, beta caro-tene, vitamins Bl, B2, B6, B12, or folate.'"'

Despite possible low levels of P5P in indi-viduals with diabetic neuropathy, intervention studieshave been disappointing. In one double-blind, con-trolled study 16 subjects received 25 mg pyridoxinedaily while 14 subjects were given placebo. After threemonths, symptoms and neurological signs were as-sessed. There were no significant differences between

pyridoxine and placebo groups, with nine patients ineach group demonstrating significant improvements.However, 16 of 30 subjects were initially low in P5Pand of the 18 patients who experienced improvement,12 were low in P5P (eight in the pyridoxine groupand four in the placebo group).'"*

Another double-blind study found no statisti-cally significant difference between pyridoxine HClsupplementation or placebo for diabetic PN. Eighteendiabetic subjects with neuropathy were randomly as-signed to 50 mg pyridoxine HCl three times daily forfour months or placebo. Six of nine in the B6 groupand four of nine in the placebo group experiencedsignificant relief of symptoms. Only one patient hadlow P5P levels at the beginning of the study.'"'

It is possible that vitamin B6 will providetherapeutic value for the treatment of PN primarilyin cases where a deficiency is evident. In addition,magnesium and riboflavin are needed for conversionof pyridoxine to active P5P in the liver. Diabetics arefrequently deficient in magnesium; thus, supplement-ing with active P5P might have resulted in improvedoutcomes.

In a study of 200 diabetic patients with pe-ripheral neuropathy, 100 were randomly assigned to50 mg pyridoxine and 25 mg thiamine daily, while100 subjects were assigned to 1 mg of each vitaminfor four weeks. Severity of PN symptoms decreasedin 48.9 percent of subjects on higher-dose pyridoxine/thiamine, compared to only 11.4 percent of subjectson 1 mg of each. Only thiamine levels were testedin this study and low levels were found to correlatewith intensity of neuropathy symptoms. Therefore,the effect of pyridoxine in this study is difficult toassess.'^"

An in vitro study helps to illuminate a pos-sible mechanism for pyridoxine in the prevention ofdiabetic PN. Both pyridoxine and its intermediatemetabolite pyridoxamine were found to inhibit freeradical formation, lipid peroxidation, and protein gly-cosylation, and protect (NaVK' )-ATPase activity - allmechanisms involved in diabetic PN - in RBCs ex-posed to high glucose concentrations.'^'



High-dose Pyridoxine May Cause PeripheralNeuropathy

During the 1980s and early 1990s a rash ofcase reports of peripheral neuropathy associated withhigh-dose pyridoxine appeared in the scientific lit-erature. In most cases the dosages ranged from 1-5g daily. In one prospective study, 1 or 3 g pyridox-ine was given to five healthy volunteers, resulting insymptomatic and electrophysiological changes in allsubjects; those receiving the higher dose experiencedearlier symptoms.'^^

Animal studies continue to examine neuro-logical abnormalities induced by pyridoxine. For in-stance, 1,200 or 600 mg/kg/day (a very high dose) torats for 6-10 days results in necrosis of sensory neu-rons, especially affecting large diameter neurons.'"

Why there was a plethora of pyridoxine-tox-icity reports 15-20 years ago, with a dearth of reportsin recent years, remains a mystery. In addition, amechanism of pyridoxine's potential toxicity has notbeen offered. One study found a triere 25 mg pyridox-ine daily for 10 days resulted in a decrease in folatelevels in eight healthy volunteers, with no change invitamin Bl2 levels.'^" Is it possible high-dose vitaminB6 supplementation causes neuropathies because itnegatively impacts levels of other B vitamins? Theconventional wisdom that suggests the importanceof taking the full range of B-complex vitamins mayhave application in this situation.

Biotin for the Treatment of PeripheralNeuropathy

The B vitamin biotin has application for thetreatment of uremic neuropathy. It is hypothesizedthat renal failure and subsequent metabolic imbal-ances result in impaired formation by the intestinalfiora and absorption of biotin. In a small study, ninepatients on dialysis suffering from PN were supple-mented with a large dose of biotin - 10 mg dailyin three divided doses - for 1-4 years. Marked im-provements in paresthesia, restless legs, and diffi-culty walking were noted in all patients within threemonths. One patient who had been unable to walk forthree months improved significantly after six monthsof treatment, and at the time the study was submittedhad been walking 2 km/day for two years.'^'

After using biotin successfully in dialysis pa-tients, these same researchers began using it for pa-tients with diabetic PN. In a case series, three subjectswith severe diabetic neuropathy were supplementedwith 10 mg biotin via I.M. injectioii daily for sixweeks, followed by three times weekly for anothersix weeks; oral administration of 5 mg daily con-tinued. Objective symptom improvement was notedwithin 4-8 weeks in all three patients. NCV was onlyslightly improved or not at all.''''

The Application of Myo-inositol forDiabetic Peripheral Neuropathy

Myo-inositol is an important constituentof the phospholipids that make up nerve cell mem-branes. Because low nerve myo-inositol levels havebeen observed in the pathogenesis of diabetic neu-ropathy, the potential for supplementation has beenexplored. In an animal model of experimental diabet-ic neuropathy, nerve myo-inositol levels were dimin-ished, with subsequent decreases in (NaVK+)-ATPaseactivity and NCV (by 25-30%), axonal atrophy, anddemyelination; dietary myo-inositol prevented thesesigns of nerve degeneration.'" In another animalmodel, experimental diabetes induced a decrease inmotor NCV. Supplementation of 500 mg myo-ino-sitol/rat/day partially prevented this decrease, whilesupplementation with an analogue of myo-inositol- D-myo-inositol-l,2,6-trisphosphate - at a dose of24 mg/rat/day completely prevented a reduction innerve conduction velocity.'^*

Sural nerve biopsies were conducted on 30male subjects - 10 with type 1 diabetes (five withclinical signs of diabetic neuropathy), 10 with im-paired glucose tolerance, and 10 with normal glu-cose tolerance. Nerve myo-inositol levels were sig-nificantly lower in diabetics with neuropathy. Also, insubjects with normal or impaired glucose tolerance,high nerve myo-inositol levels were associated withnerve regeneration as illustrated by increased nervefiber density."'

Despite myo-inositol's potential to preventor reverse the signs and symptoms of diabetic PN,clinical evidence has been limited. In a small, dou-ble-blind, placebo-controlled, crossover trial, sevensubjects with clinical signs of neuropathy (n=3) orsubclinical neurophysiological signs (n=4) were



supplemented with 500 mg myo-inositol or placebotwice daily for 14 days and crossed over to the othergroup. Each group was on placebo for two 14-dayintervals and myo-inositol for one 14-day interval.Action potentials in the median, sural, and poplitealnerves increased in amplitude by 76-, 160-, and 40-percent, respectively, during myo-inositol supple-mentation. No significant differences were noted inNCV during either myo-inositol or placebo supple-mentation."'°

In a double-blind study, 28 diabetics withearly, subclinical neuropathy were supplementedwith 2 g myo-inositol or placebo three times dailyfor two months. No significant changes were notedin NCV, vibratory perception, or amplitude of actionpotentials in either group after two months. Althoughblood and muscle tissue levels of myo-inositol werenot found to be low, nerve myo-inositol levels werenot evaluated.'^'

L-Glutamine for the Treatment ofChemotherapy-induced PeripheralNeuropathy

Paclitaxel is a chemotherapeutic agent asso-ciated with PN. Neurological exams were conductedbefore and after paclitaxel (average interval betweenbefore-and-after evaluations was 32 days) in 12 pa-tients supplemented with the amino acid glutamineand 33 patients who did not receive glutamine. L-glutamine was supplemented orally at a dose of 10g three times daily for four days, beginning 24 hoursafter a high-dose paclitaxel cycle. Only eight percentof patients in the glutamine group experienced mod-erate-to-severe pain in the fingers and toes comparedto 40 percent in the no-glutamine group. Signs ofPN in the form of decreased vibrational sense, motorweakness, ataxic gait, and sensory deficits were sig-nificantly less prevalent in the glutamine group. "'

Taurine for the Potential Treatment ofDiabetic Peripheral Neuropathy

Several animal studies indicate the aminoacid taurine may provide some benefit for preventionor treatment of PN due to diabetes. Taurine is defi-cient in diabetes, particularly in the Schwann cellsand vascular endothelium of nerves.'^^ Taurine may

act as an osmolytic agent and inhibitory neurotrans-mitter, resulting in modulation of pain perception.Theoretically, as high glucose results in sorbitol ac-cumulation within the cell, taurine is depleted in theperipheral nerves, resulting in excitability and pain.One study of streptozotocin-diabetic rats found tau-rine levels decreased by 31 percent and myo-inosi-tol levels by 37 percent. When sorbitol accumulationwas decreased by an aldose reductase inhibitor, tau-rine levels increased by 22 percent.""" In another ani-mal study, diabetes resulted in abnormal calcium-ionsignaling. Taurine repletion resulted in normalizationof intracellular calcium concentrations, with resultantdiminution of pain. ""'Other animal studies found tau-rine decreased diabetes-induced nerve conduction andnerve blood flow deficits,' ^-" ' and increased nervegrowth factor and nerve ascorbate levels,"^^ at least inpart via antioxidant mechanisms. Clinical studies areindicated to determine whether taurine can providebenefit to individuals with diabetic PN.

The Application of N-acetylcysteine(NAC) for Peripheral Neuropathy

The amino acid NAC may have applicationin the prevention or treatment of neuropathy. NAC isa potent antioxidant and helps to enhance glutathionelevels.

Application of NAC for Diabetic PeripheralNeuropathy

Oral administration of NAC to streptozoto-cin-diabetic rats resulted in prevention of diabetes-in-duced deficits. Motor nerve conduction velocity wassignificantly decreased by diabetes; NAC reduced thedecrease in NCV and inhibited atrophy of myelinatedfibers.'^* In another study, experimentally-induceddiabetes for two months in rats resulted in 20-per-cent reduction in NCV and 48-percent reduction inendoneurial blood flow; both were largely correctedby NAC supplementation."^' Clinical studies are war-ranted to determine NAC's application for treatmentof diabetic PN.



Table 2. Summary of Nutrients for the Treatment of Chemotherapy-induced Peripheral Neuropathy

Nutrient Intervention ChemotherapyRoute ofAdministration

Acetyl-L-carnitine

Vitamin E or nothing

Cisplatin, paclitaxel,or both

Cisplatin or paclitaxel

Cisplatin

Cisplatin orcarbaplatin

Uncontrolled;n=26; 10-20days

Uncontrolled;n=25; 8 weeks

Controlled;n=27; 3 months

Daily DosageRange

1,000 mg

3,000 mg

300 mg

Glutathione or saline Oxaliplatin

L-Glutamine or nothing Paclitaxel

N-acetylcysteine orplacebo

Oxaliplatin

Two controlledtrials; n=30/31;3 months

RCT; n=40completers

Controlled;n=45(12glutamine; 33no glutamine)

RCT; n=14;12 cycles ofchemotherapy

600 mg

Dosage notspecified

30 g for 4 daysafter each chemotreatment

1,200 mg

To benefit the clinician, only positive clinical studies have been included in this table.RCT=randomized, controlled trial

NAC for the Treatment of Chemotherapy-induced Peripheral Neuropathy

A mechanism of cisplatin chemotherapy-in-duced PN was elucidated in an in vitro mouse model.Apoptosis of neurons was induced by cisplatin, butpreineubation with NAC completely blocked apop-tosis; incubation with vitamin E partially blockedapoptosis."

A small pilot study was conducted to deter-mine the effect of NAC on oxaliplatin-induced neu-ropathy. Fourteen stage III colon cancer patients wererandomly assigned to 1,200 mg oral NAC or placebodaily. Neurological evaluations were conducted atbaseline and after four, eight, and 12 cycles of che-motherapy. After four cycles, two of five in the NACgroup and seven of nine in the placebo group expe-rienced neuropathy; after eight cycles no one in theNAC group experienced neuropathy compared to fiveof nine in the placebo group. Only one in the NAC

group, but eight of nine in the placebci group, experi-enced neuropathy after 12 cycles.'™ i

Table 2 summarizes the potential nutrientsfor prevention and treatment of chemotherapy-in-duced neuropathy. ;

Minerals for the Treatment of DiabeticPeripheral Neuropathy 1Magnesium j

Plasma magnesium levels have been found tobe significantly lower in diabetic subjects comparedto controls.''"'''^ Despite the fact m^agnesium maybe the most common mineral deficiericy in diabetes,its clinical significance for peripheral neuropathy isunknown. An animal study found oral magnesiumsupplementation to diabetic rats resulted in decreasedpain measured by thermal pain thresholds.'"

Page 312 Alternative Medicine Review • Volume 11, Nurnber 4 • 2006


Table 3. Summary of Nutrients for the Treatment of Diabetic Peripheral Neuropathy

Intervention Clinical TrialsRoutes ofAdministration Daily Dosage Range

RCT; n=328; 3 weeks I.V. 600-1,200 mg

alpha-Lipoic acid orplacebo

RCT; n=65; 2 years

RCT; n=509;7 months

RCT; n=120;5 days/week for 14treatments

I.V. for 5 daysfollowed by oral

600-1,200 mg

I.V. for 3 weeksfollowed by oral

600mg(I.V.); 1,800 mg (oral)

600 mg

alpha-Lipoic acid

Acetyl-L-carnitine orplacebo

Vitamin E or placebo

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

1,800 mg

I.M. for 10 daysfollowed by oral

600 mg

1,000 mg (I.M.); 2,000 mg(oral)

1,500-3,000 mg

900 mg

Benfotiamine or placebo RCT; n=::40; 3 weeks 400 mg

Benfotiamine pluscyanocobalamin(Milgamma) or B-complex

Comparative frial;n=30 Milgamma;n=15 B-complex;3 months

Benfotiamine, pyridoxine. Open trial; n=36and cyanocobalamin (12/group); 6 weeksversus benfotiamine alone

Methylcobalamin orplacebo

Methylcobalamin ornothing

Zinc sulfate or placebo

RCT; n=43; 4 months I Oral

Matched controls; Oraln=40; 2 months

RTC; n=30 I Oral

400 mg benfotiamine and2,000 meg cyanocobalamin(3 weeks), followed by 150 mgbenfotiamine and 750 megcyanocobalamin (9 weeks)

320 or 120 mg benfotiamine,720 or 270 mg pyridoxine, and2,000 or 750 megcyanocobalamin versus 150mg benfotiamine

1,500 meg

1,500 meg

660 mg (267 mgelemental zine)

To benefit the clinician, only positive clinical studies have been included in this table.RCT=randomized, controlled trial


ZincA clinical study examined the effect of zinc

for parameters of blood sugar control and peripheralneuropathy in 50 subjects. Thirty diabetics with PNwere supplemented with 660 mg zinc sulfate (267mg elemental zinc) daily or placebo (equal number ineach group) for six weeks and compared to a groupof 20 healthy controls. Serum zinc levels were sig-nificantly lower at the beginning of the study in bothgroups with diabetes compared to controls. NCVin the median and peroneal nerves significantly in-creased in the group supplemented with zinc. In ad-dition, significant improvements in fasting and post-prandial blood sugar were noted in the zinc groupcompared to the diabetics taking placebo.' '*

ChromiumA chromium deficiency, seen in particular in

patients on total parenteral nutrition, can cause a pe-ripheral neuropathy associated with impaired glucosetolerance.'^^'^ Infusion of as little as 250 meg chro-mium daily for three weeks reversed abnormal nerveconduction.''''

Table 3 summarizes the most promising nu-trient treatment options for diabetic PN.

Essential Fatty Acids for PeripheralNeuropathyGamma-linolenic Acid (GLA) for theTreatment of Diabetic PeripheralNeuropathy

Diabetics appear to have impaired conver-sion of linoleic acid to GLA, apparently due to faultydesaturase enzyme activity.'^' Because metabolites ofGLA are essential for nerve membrane structure andblood flow, a deficiency could contribute to the devel-opment of neuropathy.

Clinical studies of GLA for PN have beenlimited to two, in which evening primrose oil (EPO)was used. In a preliminary, double-blind study, 22 pa-tients with diabetic neuropathy were assigned to 360mg GLA (n=12) or placebo (n=10) for six months.Subjects on GLA exhibited significantly better neu-ropathy scores, NCV, and action potentials comparedto placebo.'™

In a subsequent, multicenter, double-blind,placebo-controlled trial, 84 subjects with mild dia-betic neuropathy were given 480 mg GLA from EPO(n=44) or placebo (n=40) daily for one year. Thirteenof 16 parameters of neurological function, includingNCV, improved in the GLA group, while the placebogroup deteriorated,'™ While the results of these twostudies appear promising, one of the centers involvedin the multicenter study was determined by the Gen-eral Medical Council in Great Britain to have usedfraudulent research techniques by falsifying results.This center raised suspicions when a clear benefit ofEPO was reported, while the other centers found littleor no difference between EPO and placebo. "*"•"*'

Animal studies lend some support for use ofGLA and elucidate its potential mechanisms in dia-betic PN. In a study of streptozotocin-diabetic rats,diabetes resulted in decreased NCV, abnormal fattyacid phospholipid composition, and decreased (NaVK"')-ATPase activity. Supplementation of diabetic ratswith 260 mg GLA daily, either at onset of diabetesfor 12 weeks (preventive group) or after six weeksof diabetes for six weeks (reversal group), resulted inrestoration of normal NCV in both the prevention andreversal groups and partial normalization of (NaVK*)-ATPase activity in the prevention group. "*

Another animal study found GLA may im-prove NCV and neuronal blood fiow in diabetic PN.It compared the effect of GLA from EPO with GLA ina triglyceride form not found in EPO and found theywere equally effective at improving NCV and bloodfiow; sunflower oil with no GLA had no effect."*-

GLA and ALA in the Treatment of DiabeticPeripheral Neuropathy

One study examined the effects of EPO orALA on NCV, nerve blood fiow, and Hpid parametersin streptozotocin-diabetic rats. While both EPO andALA improved neuronal blood flow and NCV, ALAalso improved signs of dyslipidemia, while EPO re-sulted in increased dyslipidemia.'*'' In another animalstudy, a conjugate of ALA plus GLA worked betterthan either substance alone in improving NCV andneuronal circulation,'^^



Omega-3 Fatty Acids in the Treatment ofPeripheral Neuropathy

Similar to omega-6 fatty acids such as GLA,omega-3 fatty acids are also essential for healthy nervecell membranes and blood flow. A clinical study of21 type 2 diabetics with symptoms and signs of neu-ropathy found 1,800 mg eicosapentaenoic acid (EPA)daily for 48 weeks significantly decreased symptomsof coldness and numbness and improved vibrationalperception; improvement in vibratory threshold pla-teaued at 12 weeks. Circulation, measured in the dor-sal pedis artery, and lipid profiles also significantlyimproved.'^^

A study in diabetic rats found fish oil, com-pared to olive oil, increased NCV, improved (NaVK+)-ATPase activity, and prevented histological signsof nerve degeneration such as demyelination and ax-onal degeneration.'^^

The omega-3 fatty acid, docosahexaenoicacid (DHA), was isolated in phospholipid liposomesand fed to diabetic rats at a dose of 60 mg/kg bodyweight. Eight weeks of diabetes led to significantdecreases in NCV, nerve blood flow, and (Na /K"")-ATPase activity in sciatic nerve and RBCs. DHAcompletely prevented the decreases in blood flow andNCV; it improved (Na+/K+)-ATPase activity in RBCsbut not sciatic nerve. These researchers hypothesizedthat DHA might work better than a combination ofDHA and EPA because EPA might interfere with thebeneficial effects of omega-6 fatty acids."*** Since thisstudy did not compare the two, this is merely conjec-ture.

A Topical Flavonoid-Vitamin Complexfor the Treatment of PeripheralNeuropathy

A topical compound called QR-333 was stud-ied in a double-blind trial of 34 individuals with neu-ropathy due to type 1 or 2 diabetes. The compound,consisting of quercetin, ascorbyl palmitate, and vi-tamin D3, was formulated because the flavonoidquercetin is an aldose reductase inhibitor, vitamin Cin a fat-soluble form could enhance its free radicalscavenging effects in the lipophilic environment ofneural tissue, and a synthetic analogue of vitamin D3has been shown in vitro to enhance nerve growth fac-tor. Twenty-three subjects received the active cream

while 11 received placebo three times daily for fourweeks. Reduction in total symptom score was statisti-cally significant for the treatment group compared toplacebo, with particular improvement in numbness,irritation from socks or bedding, and jolting pain. Itshould be noted, however, there was also a trend to-ward improvement in the placebo group. Since theplacebo group was smaller than the treatment group,statistical significance would have been more diffi-cult to achieve.'*'

Herbal Treatments for PeripheralNeuropathySt. John's Wort for the Treatment ofPeripheral Neuropathy

Because tricyclic antidepressant medicationsare used for PN, a study was conducted to deter-mine whether St. John's wort {Hypericum perfora-tum) would have a similar effect. In a randomized,double-blind, placebo-controlled, crossover study, 54patients (49 completed, including 18 diabetics and 29non-diabetics) were given three tablets of St. John'swort containing 900 meg hypericin/tablet (equiva-lent to 300 mg of a 0.3-percent hypericin extract pertablet) or placebo daily for five weeks, then crossedover to the other treatment. Eour pain symptoms wereevaluated - constant pain, lancinating pain events,touch-evoked pain, and pressure-induced pain. Atrend toward improved overall pain scores was noted,although no significant differences were achievedwith any individual pain index. Nine individuals inthe treatment group and two in the placebo groupexperienced moderate to complete pain relief.'*" Thedosage used in this study is the lowest dosage typi-cally recommended for the treatment of depression.When using conventional treatments such as gaba-pentin, higher-end dosages are typically required fortreatment of neuropathy. Therefore, a study employ-ing double the dosage used in this study is recom-mended.

Topical Capsaicin Cream for theTreatment of Peripheral Neuropathy

Numerous studies have evaluated the effectof capsaicin cream for the treatment of peripheralneuropathy. Capsaicin is an active principal of theherb Capsicum officinalis and is believed to stimulate



afferent C-fibers (fibers in the mechano-heat class).The initial stimulation of C-fibers results in burningand irritation that stimulates release of substance P(a pain-relieving neuropeptide) and other neuropep-tides. Repeated exposures result in a diminution ofthe initial burning and irritation and a long-lastinganalgesic effect.'^'

Capsaicin for the Treatment of DiabeticPeripheral Neuropathy

The majority of studies of capsaicin creamfor PN have been conducted in individuals with dia-betes. In a large, multicenter, double-blind, placebo-controlled trial conducted by The Capsaicin StudyGroup, 277 subjects entered the study, 252 continuedfor at least two weeks, and 219 completed the eight-week trial. Subjects applied 0.075-percent capsaicincream (n=100 completers) or placebo cream (n=119completers) four times daily and were evaluated attwo-week intervals for eight weeks. Pain was as-sessed via physician assessment as well as patient-driven VAS. Statistically significant improvementswere 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 thecapsaicin versus placebo groups, respectively; statis-tically significant differences started during the fourthweek.' ^ Effect on daily activities was also assessed,and statistically significant improvements in walking,working, sleep, and participation in recreational ac-tivities were noted in the capsaicin group comparedto placebo.'''^

In a smaller double-blind study, 54 (49 com-pleters) subjects with type 1 or 2 diabetes and moder-ate-to-severe pain that interfered with sleep or dailyactivities applied 0.075-percent capsaicin cream(n=28; 24 completers) or placebo cream (n=26; 25completers) to painful areas four times daily for eightweeks (same protocol as the previous study). Painwas measured via VAS, physician global assessment,and effect on interference with daily activities. Af-ter eight weeks, 89.5 percent of the capsaicin groupand 50 percent in the placebo group experienced im-provement; the average decrease in pain intensity was49.1 percent in the capsaicin group and 16.5 percentin the placebo group - statistically significant differ-ences. The differences in pain assessment after two

weeks were similar in both groups, indicating a needfor continued use of capsaicin in order to experiencepain relief.' ''

Another study using the same protocol as theabove studies was conducted on 22 diabetics withPN (11 in each group). Decrease in pain intensity viaVAS was 16 percent in the capsaicin group and 4.1percent in the placebo group. In an open-label con-tinuation of the study (average follow-up 22 weeks),50 percent of subjects experienced improvement orcomplete amelioration of pain, 25 percent remainedunchanged, and 25 percent worsened.'^' Sensoryfunction was tested in this same group of individu-als and there were no differences between active orplacebo in regard to sensations of vibi'ation, warmth,or cold."""

Another eight-week, double-blind study com-pared the effects of capsaicin cream to amitriptylinecapsules in 235 patients with diabetic neuropathy.Subjects on capsaicin cream were given placebo cap-sules and subjects in the amitriptyline group receivedplacebo cream. Equal and statistically significant im-provements in pain were noted in both groups. Whileno systemic side effects were reported in the capsai-cin group, most on amitriptyline experienced at leastone side effect, most commonly sleepiness, but alsoneuromuscular or cardiovascular side effects.''''

To determine the mechanism of action ofcapsaicin, a study was conducted on 13 subjects withdiabetic PN who used 0.05-percent capsaicin for eightweeks. Cream was applied to one foot while the otherfoot served as a control. In addition to pain scoresand vibrational and thermal thresholds, serum levelsof substance P were measured. Significant improve-ments in total pain score and heat thresholds werenoted in the treatment foot compared to the untreatedfoot, indicating very localized effects. Substance Plevels increased initially during the first four weeksof the study, but declined to baseline by the end ofthe study, calling into question the long-term effect ofcapsaicin on substance P.'***

The primary side effect reported by patientsin the various capsaicin studies was burning at thesite of application, sometimes resulting in dropout.In order to address the issue of topical irritation andto examine the effect of higher-concentration capsai-cin, a study examined the use of highly concentrated



Table 4. Summary of Topical Treatments for Diabetic Peripheral Neuropathy

Intervention

QR-333 (quercetin, ascor-byl palmitate, and vitaminD3) or placebo cream

Frequency andLength of Trial

3 times daily for4 weeks

Trial Type Number in Trial

n=34 (23 active;11 placebo)

4 times daily for8 weeks

Capsaicin (0.075-percent 4 times daily forcapsaicin) or placebo

n=219 completers

n=49 completers

cream

Capsaicin or placebocream versus amitriptylineor placebo capsules

8 weeks

4 times daily for8 weeks/22 weeks

8 weeks

ROT (8 weeks);open label (averageof 22 weeks)

n=235

To better support the clinician, only positive clinical studies are included in this table,RCT=randomized, controlled trial

capsaicin (5-10%) in addition to regional anesthesiain 10 patients with intractable pain (three with neu-ropathy - diabetic, HIV-associated, idiopathic). Al-though two applications of the cream resulted in painrelief (significant in nine of 10), I.V. fentanyl had tobe used to counteract the breakthrough burning as-sociated with such a high concentration of capsaicin.Analgesic effects lasted from less than a week to morethan 50 weeks. This treatment may provide relief forchronic, intractable pain and reduce dependence onopioids.'^^

Studies on topical treatments for diabetic PNare summarized in Table 4.

Capsaicin for the Treatment of HIV-associated Peripheral Neuropathy

In a double-blind study, 26 patients with HIV-related PN were given either 0.075-percent capsaicincream (n=15) or identical placebo cream (n=ll) andasked 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 localizedburning) and two in the placebo group. No statisticallysignificant differences were noted between treatmentand placebo groups in regard to any aspect of pain orquality of life during the course of the study,^" Due tothe depletion of subjects - only five remained in thecapsaicin group - this result is not surprising.

Acupuncture for the Treatment ofPeripheral Neuropathy

Several studies have examined the effect ofacupuncture for the treatment of various types of PN- diabetic, HIV-associated, chemotherapy-induced,and mixed etiologies. Some studies have been diffi-cult to fully analyze as they are in foreign languageswith just the abstract available in English.

One study involved 17 patients with chronicPN of unspecified etiologies. Subjects were treatedwith electroacupuncture twice weekly for four weeks.



Table 5. Summary of Treatments for HIV-associated Peripheral Neuropathy

InterventionRoutes ofAdministration

Acetyl-L-carnitine

Vitamin B12

Capsaicin or placebocream

Acupuncture

I.V. or I.M.

Uncontrolled; n=21;up to 33 months

Uncontrolled; n=16;3 weeks

Uncontrolled; n=8

RTC; n=26; 4 weeks Topical

Daily DosageRange

3,000 mg

500 or 1,000 mg

Dosage not specified

4 times daily

Small, uncontrolled;n=7; 30 days

Case series; n=21;5 weeks

Electroacupuncture 20 minutes daily

Standardacupuncture

30-45 minutes, twiceweekly

To better support the clinician, only positive clinical studies are included in this table,RCT=randomi2ed, controlled trial

VAS was used to assess intensity of continuous andintermittent pain and duration and number of attacks.Two weeks after the series of treatments, averagecontinuous pain score was decreased by 32.9 percentand pain intensity by 59 percent; average numberof attacks decreased from 4.2 to 2.2 per day. Threemonths after treatments were discontinued, pain in-tensity was still decreased by 44 percent.^"'

Acupuncture for the Treatment of HIV-associated Peripheral Neuropathy

Several studies have examined the effectof acupuncture for neuropathy associated with HIVinfection. In a large-scale, placebo-controlled, mul-ticenter, 14-week study of 250 patients, standardacupuncture, amitriptyline, or both were comparedto placebo, control points, or both. Neither acupunc-ture nor drug therapy was significantly more effectivethan placebo. °^

In a very small, uncontrolled trial, seven HIVpatients with antiretroviral-induced neuropathy weretreated with electroacupuncture 20 minutes daily for30 days. Muscle-stimulated nerve amplitudes andphysical strength increased with general improve-ment in functional activity.^"'

In a case series, 21 subjects with HIV-as-sociated PN received 30- to 45-minute acupuncturetreatments twice weekly for five weeks. A significantreduction in pain, assessed by the Pain Rating Scaleand Subjective Peripheral Neuropathy Screen, wasnoted post-treatment compared to pre-treatment fortotal overall pain score as well as symptoms of numb-ness, pins and needles, and pain (achiiig, burning). '"*

Table 5 summarizes the most promising treat-ments for HIV-associated PN.

Acupuncture for the Treatment ofChemotherapy-induced Neuropathy

Dose reduction or early termination of treat-ment with neurotoxic chemotherapy drugs is oftennecessitated due to significant PN. A pilot study offive cases demonstrated encouraging results with theuse of acupuncture to correct qi, blood, and yang de-ficiencies in this population.^°^

Acupuncture for the Treatment of DiabeticPeripheral Neuropathy

In a study of 90 subjects with diabetic PN, 30received wrist-ankle acupuncture, 30 received whole-body acupuncture, and 30 received conventional

Page 318 Alternative Medicine Review • Volume 11, Nutnber 4 • 2006


Table 6. Physical Medicine for the Treatment of Diabetic Peripheral Neuropathy

Intervention

Controlled; n=90

Description of Therapy

Wrist-ankle acupuncture (n=30);whole-body acupuncture (n=30);conventional medicine/control group(n=30)

Acupuncture

Magnets or placebo

Yoga or no yoga

Uncontrolled; n=44

Case series; n=68

RTC; n=375;4 months

Controlled; n=40;40 days

Six courses of acupuncture for a10-week period

Not specified in abstract (article inChinese)

Magnetic insoles or non-magnetizedinsoles (placebo)

30-40 minutes of yoga daily

To better support the clinician, only positive clinical studies are included in this table.RCT=randomized, controlled trial

medical treatment (control group). Both acupuncturegroups experienced significantly better results thanthe conventional medical/control group. °*

Forty-four individuals with diabetic PN weretreated with six courses of acupuncture for a 10-weekperiod. Thirty-four (77%) experienced significantsymptom improvement, with seven subjects report-ing complete elimination of symptoms. Patients werefollowed for 18-52 weeks and only eight individualsrequired additional treatment. Standard medicationswere used by 63 percent of subjects at the beginningof the trial and 67 percent of these patients were ableto decrease or discontinue medications during the fol-low-up period. °^

In a series of 68 cases of diabetic PN treatedwith acupuncture, 43 individuals experienced markedimprovement, 20 experienced some improvement,and five exhibited no improvement; overall signifi-cant improvement in NCV was observed. The article,being in Chinese, was only available in English asan abstract; therefore, the number and frequency oftreatments and specifically what symptoms were im-proved is unknown. "*

Magnets for the Treatment ofPeripheral Neuropathy

It is hypothesized that electromagnetic fieldsmay benefit PN by polarization of neurons that maybe firing ectopically, resulting in neuropathy. "^ Pulsedmagnetic field therapy (strength of 20 gauss and fre-quency of 30 Hz) was used to treat 24 subjects withPN of various etiologies - diabetes, chronic inflam-matory demyelinating polyneuropathy, mercury poi-soning, pernicious anemia, paraneoplastic syndrome,tarsal tunnel syndrome, and idiopathic sensory neu-ropathy. The most symptomatic foot in each subjectreceived treatment, while the contralateral foot servedas a control. Subjects were evaluated after nine one-hour consecutive treatments (weekends off) usingVAS and Patient's Global Assessment of Change.Average pain scores decreased by 21 percent at theend of nine treatments and by 49 percent at a 30-dayfollow-up assessment; all 24 subjects completed thestudy but only 15 were available for follow-up. Thetreatment was even more effective for more severepain. Of 19 subjects with moderate-to-severe pain, a28-percent reduction in pain score was experienced



at the end of treatment compared to baseline; a 39-percent reduction was observed between baseline andthe end of the 30-day follow-up period. °^

A large, multieenter (48 centers), double-blind, placebo-controlled trial was conducted on 375individuals with diabetic PN. Subjects wore eithermultipolar, static, 450 G magnetic insoles or placebo(unmagnetized) insoles in their shoes for four months.VAS was used to assess numbness and tingling, burn-ing, and quality of life, with significant decreases inburning, numbness and tingling, and foot pain on ex-ercise reported during the third and fourth months ofthe study compared to baseline in the magnetic-insolegroup compared to placebo.^'"

Yoga for the Treatment of DiabeticNeuropathy

In a controlled trial, 20 subjects with type2 diabetes and mild-to-moderate neuropathy weretreated with 30-40 minutes of yoga daily for 40 days.A group of 20 subjects matched for age and severityof disease serving as a control did not engage in yogabut were prescribed light exercise such as walking.NCV, assessed in the median nerve for both right andleft hands, improved slightly in the yoga group (from52.81 to 53.87 in the right hand and 52.46 to 54.75 inthe left hand). NCV in the control group continued todeteriorate.^"

Table 6 summarizes physical medicine treat-ments for diabetic PN.

Cutting-Edge ConventionalTreatments for Peripheral Neuropathy

Some cutting-edge conventional approachesto PN are on the horizon - treatments that potentiallydo more than just mask symptoms. Several small,"dual-action" peptides have been shown to have neu-rotrophie activity - C-peptide and islet neogenesis-associated protein peptide (both from pancreatic pro-teins), and derivatives of erythropoietin.^'^

Recent recognition that G-peptide, originallythought to be inert and merely a marker for endog-enous insulin production, improves sensory neuraldeficits, microvascular blood fiow, and renal filtrationin diabetes has stimulated research on its potential fordiabetic neuropathy.^'^ G-peptide has been found tostimulate (NaVK*)-ATPase activity^'^ and endothelial

nitric oxide synthase for improved circulation.^''' Inan animal model of type 1 diabetes, C-peptide for 4-7 months resulted in a dose-dependent prevention ofsigns of neuropathy, including effects on NCV, nervefiber number, nerve regeneration, and overall neuro-pathy score. ' In a phase II trial of 49 type 1 diabeticswith subclinical PN, subcutaneous administration ofC-peptide or placebo for three months resulted in sig-nificant (80%) improvement in NCV in the C-peptidegroup compared to placebo.^""

Islet neogenesis-associated protein peptide(INGAP) is a pancreatic peptide that has been foundto enhance formation of new pancreatic islet cells andreverse hyperglyeemia in type-l diabetic animals.^'^A preliminary study indicates it may hold promisefor treatment of neuropathy associated with diabe-tes. Two-week administration of I N G A P to strepto-zotocin-diabetic rats with neuropathy resulted in im-proved thermal detection, enhanced nerve growth indorsal root ganglia, and activation of signaling path-ways involved in nerve regeneration.^!^

In addition to its involvement in hemato-poiesis, erythropoietin receptors have been found inneurons.^'^ Erythropoietin appears to directly preventaxonal degeneration - the gross pathology seen inperipheral neuropathies of various etiologies, includ-ing diabetes and HIV. Researchers found nitric ox-ide signals erythropoietin secretion from Schwanncells in response to neuronal injury. Administrationof exogenous erythropoietin to animals with axonalneuropathy prevented axon degeneration and reducedbehavior associated with neuropathic pain. '* Animalstudies of diabetes-induced^" or cisplatin chemother-apy-induced^^" neuropathy found erythropoietin sig-nificantly attenuated nerve degeneration associatedwith these two types of neuropathy. An in vitro studydemonstrated erythropoietin's protection of neuronsagainst the neurotoxic effects of antiretroviral agents;thus it may have potential for HIV-associated neu-ropathy.^ '

Preliminary research from the University ofUtah and Tufts University has found netrins, a familyof 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 miceresulted in both blood vessel and nerve



ConclusionPeripheral neuropathy presents with consid-

erable morbidity and can result in significant decreas-es in quality of life. While conventional medicine canoffer some relief, the potential side effects or addic-tive nature of many of the medications render long-term use undesirable. Such treatments, furthermore,merely mask the symptoms and do not address theunderlying pathologies. Alternative therapies, on theother hand, are typically without side effects and ad-dress nutrient deficiencies, oxidative stress, and otheretiologieal factors associated with the developmentofPN.

Alpha-lipoic acid, acetyl-L-carnitine, benfo-tiamine, methyleobalamin, and topical capsaicin areamong the most well-researched alternative optionsfor the treatment of PN. Other potential nutrient orbotanical 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, andtopical capsaicin. In the realm of physical medicine,acupuncture, magnetic therapy, and yoga have beenfound to provide benefit.

A questionnaire-based study examined theuse of alternative treatments for PN in 180 consecu-tive outpatients at St. Elizabeth's Medical Genter inBoston, MA. Seventy-seven patients (43%) reportedusing alternative therapies; 37 of 77 (48%) employedmore than one type of alternative treatment. Seven-teen (27%) ofthe respondents reported improvementin neuropathy symptoms with unconventional ap-proaches. The treatments most often employed were"megavitamins" (35%), magnets (30%), acupunc-ture (30%), herbal remedies (22%), and chiroprac-tic manipulation (21%). Those who used alternativeapproaches were more likely to be younger, collegeeducated, and suffering from diabetes compared tothose who did not use unconventional approaches. ^^

The use of well-researched nutrients, physi-cal medicine, and the possible addition of new cut-ting-edge treatments should decrease the morbidityassociated with peripheral neuropathy and the sideeffects associated with the commonly prescribed con-ventional pain-relieving treatments in current favor.

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