neuropathy
(Neuropathy by Ana Morales)

Neuropathy – Natural Treatments and Drug Risk Factors

Neuropathy refers to diseases or malfunctions of the nerves that commonly result in symptoms of pain, burning, tingling, and/or numbness. Neuropathy can have many causes including diabetes, spinal cord injuries, liver and renal failure, vitamin B12 deficiency, Guillain-Barre syndrome, hypothyroidism, some cancers, Lyme disease, HIV, several different pharmaceutical drugs, smoking1, and a number of toxic exposures such as acrylamide, arsenic, lead, and thallium. Though there are several pharmaceutical drugs and other approaches that can be used in the treatment of neuropathy, natural medicines have the potential to correct a number of involved metabolic derangements that are not addressed by present clinical guidelines. We discuss these treatments (with a primary focus on diabetic peripheral neuropathy), as well as a handful of other miscellaneous therapies. Some underrecognized drug causes of neuropathy are also discussed.

Treatment-Induced Neuropathy

While there is general awareness that some types of chemotherapy can cause neuropathy, there are several other potential neuropathy-inducing treatments for which there may not be the same level of awareness. Also generally not considered is that some of these drugs are frequently used in combination, which may be resulting in unknown risk of neuropathy for many patients.

Fluoroquinolone Antibiotics and Neuropathy

A case control study found that fluoroquinolone antibiotics are associated with an increased risk of peripheral neuropathy.2 Fluoroquinones are one of the most commonly prescribed classes of antibiotics today.

Insulin, Metformin, and Neuropathy

A retrospective study of over 84,000 patients with type 2 diabetes found that insulin monotherapy is associated with more than double the risk of neuropathy when compared to metformin monotherapy. Not only that, insulin was also found to be associated with more than double the all-cause mortality compared to metformin.3 Keep in mind that this increase in neuropathy risk is relative to metformin, and metformin in itself may already increase risk of neuropathy. Its use has been associated with vitamin B12 deficiency in diabetics, and some evidence suggests vitamin B12 replacement may cause symptomatic improvement among patients with severe diabetic neuropathy.4

Statins and Neuropathy

A 36-month study of 42 patients confirmed that long-term treatment with statins caused a clinically silent but still definite damage to peripheral nerves when the treatment lasts longer than 2 years.5

Other Drugs and Neuropathy

A number of other drugs may also affect the development of neuropathy. These include but are not limited to certain blood pressure drugs, antibiotics, drugs for auto-immune diseases, anticonvulsants, and antivirals.6,7

Unassessed Synergy of Risk Factors and Long-Term Risk

Though some argue the statin study shows that the issue of statins causing neuropathy is not clinically significant, we have to consider what happens after periods much longer than 2 years. Does the damage become relevant at some point? And what happens if other risk factors like insulin use and/or metformin use are simultaneously present? And what if such a person takes a course of fluoroquinolones in addition? It is conceivable that there are many patients who are taking combinations of these drugs who are being set up for intractable neuropathy. This warrants further research.

Natural Medicines and Neuropathy 

A number of natural therapies and their effect on neuropathy are discussed here. We also speculate that there may be some overlap in useful therapeutics between spinal cord injury (irrespective of whether or not the injury involves neuropathic pain) and neuropathy due to other causes. Hence their use in both are discussed. A few miscellaneous therapies are also mentioned. Treatment of diabetic neuropathy is generally based on a combination of glucose control and symptomatic relief. However, several metabolic derangements may be involved in the pathology of diabetic neuropathy that are not comprehensively addressed by this typical approach.8 Using combinations of natural medicines have the potential to move us closer to this goal.

Whole Food, Plant-Based Diet

In 1994 a remarkable study conducted by Crane et al. gave 21 patients with diabetic neuropathy an unrefined vegan diet, along with exercise. Complete relief of pain was reported by 17 of the patients within just 4 to 16 days. Patients also lost weight, greatly reduced their glucose and cholesterol levels, and greatly reduced insulin requirements. Follow-up with 17 of the patients 1 to 4 years later found that 71% almost exactly continued the prescribed treatment, and that symptom relief was either maintained or improved in all but one patient.9 This study has gone largely ignored, despite the remarkably promising results. In 2002 an article argued that improved blood rheology may explain the benefits of an unrefined vegan diet. Nerves have their own system of microcirculation which may be impaired, leading to hypoxia. Improvements in perfusion from a vegan diet may explain the benefits.10

It wasn’t until 2015 that a randomized controlled trial further investigated this treatment. Patients with diabetic neuropathy were randomized to receive either a low-fat, plant-based diet, along with B12 supplementation, or else just B12 supplementation. Patients were followed for 20 weeks. Several neuropathy symptom scores were used as outcomes. In two such scores the plant-based diet reported significant improvements. In other scores improvements were nonsignificant. Electrochemical skin conductance in the foot also improved.11 One issue with this study is that the control intervention of B12 might have had its own benefit, thereby diluting the value of the plant-based diet. The dosage of B12 is also not disclosed. Also note that expectation of benefit may not be equal in both groups, potentially causing overestimation of benefit. Being prescribed a diet and getting weekly counseling is a different experience than just being given a pill. Hence a better control may need to be devised in future studies. This study also did not appear to specify that foods must be unrefined. This is not inline with the protocol used by Crane et al., and would likely diminish the benefits. Reported compliance with the overall diet also seems likely to have been lower.

Given the low risk and potential benefits, a whole food, plant-based diet should be considered in the treatment of diabetic neuropathy.

Gluten Elimination

Gluten sensitivity may be a cause of neuropathy.12,13 One controlled study of 35 patients with idiopathic neuropathy found that a gluten-free diet led to improvements in sural sensory action potentials, whereas the control group experienced deterioration. The difference between the two groups was significant.14 In another study, 17 patients with sensory ganglionopathy were recommended a gluten-free diet. Eleven patients that had good adherence experienced a stabilization of their neuropathy. Four patients that had poor adherence and 2 patients that did not opt for the diet all experienced deterioration.15

Exercise

One small uncontrolled study in 17 patients with diabetic peripheral neuropathy found that 10 weeks of supervised exercise led to significant improvements in pain and neuropathic symptoms, as well as increased intraepidermal nerve fiber branching from a proximal skin biopsy. The authors wrote, “These findings are particularly promising given the short duration of the intervention, but need to be validated by comparison with a control group in future studies.”16 Another follow-up study in 18 patients evaluated the safety of such exercise. There were 57 non-serious adverse events recorded. The authors recommend that physical therapists exercise care in prescribing exercise for patients who have previously been sedentary.17

Gamma-Linolenic Acid (GLA)

A controlled trial in 22 patients with diabetic neuropathy found significant improvements in 6 out of 6 nerve function measurements, wrist and ankle heat threshold values, and overall symptom scores.18 Another controlled trial with 111 diabetic patients of both types 1 and 2 with mild or moderate neuropathy found that 480mg of gamma-linolenic acid caused significant improvements in neuropathy in 13 out of 16 parameters measured at one year.19

Magnesium

A controlled study gave 300mg of magnesium to type 1 diabetes patients with polyneuropathy for five years. By the end of the study, staging of polyneuropathy within the magnesium group showed that 39% had improved, 49% stayed the same, and only 12% worsened. Whereas in the control group only 8% improved, 31% stayed the same, and 61% got worse.20 A study presented at a 1994 AIDS conference reported that 68 AIDS patients who had symptoms consistent with peripheral neuropathy all had low levels of magnesium, and that supplementation with magnesium led to improvement in symptoms.21 In an uncontrolled study 12 cancer patients with neuropathic pain due to malignant infiltration of the brachial or lumbosacral plexus were given a single intravenous dose of either 500mg or 1g of magnesium sulfate. In total, 10 out of 12 patients reported either complete or partial relief of pain for roughly four hours.22

Perhaps topical magnesium chloride as either a saturated solution (“magnesium oil”) or as a lotion might be useful for localized applications.

Capsaicin

A review of topical capsaicin for the treatment of postherpetic neuralgia and HIV-neuropathy concluded, “High-concentration topical capsaicin is therefore similar to other therapies for chronic pain. In this case, the high cost of single and repeated applications suggest that high-concentration topical capsaicin is likely to be used when other available therapies have failed, and that it should probably not be used repeatedly without substantial documented pain relief. Even when efficacy is established, there are unknown risks, especially on epidermal innervation, of repeated application of long periods.”23

Ecklonia Cava Extract

A double-blind placebo-controlled study found that ecklonia cava extract improved neuralgia by the end of 4 weeks. However, this study has not been peer-reviewed. We obtained an unpublished manuscript of the study from the manufacturer.24 It’s a brief 4-page document that is dated September 30, 2005. The study participants were patients of the Mirae Medical Foundation in South Korea, previously diagnosed with neuralgia attributable to a number of conditions, including diabetes.  The cause of the patient’s neuralgia was not consistent across the sample. Dosage was the equivalent of 5 capsules of the brand Fibronol twice a day. Nineteen patients were on active treatment, and 15 were controls. There were no statistically significant differences in age, height, weight, gender ratio, or neuralgic symptoms at baseline. Global Assessment forms measured the active groups’ scores to be an average of 2.74 at baseline, and 1.89 at 4 weeks. The average placebo groups’ scores were 2.87 at baseline and 2.53 at 4 weeks. The difference in symptoms between the two groups was significant (25.3%, p=0.017). Visual Analogue Scales showed the treatment group went from an average score of 46.1 at baseline to 27.1 at 4 weeks. The placebo group went from an average of 51.9 to 43.7. The difference between the two groups was significant (p=0.007). The document states that blinding was not broken during the trial.

Vitamin E

Although a number of trials have suggested that oral administration of vitamin E can prevent chemotherapy-induced peripheral neuropathy25–28, a 2015 trial and a 2016 meta-analysis did not find any such benefit.29,30 One trial in 21 diabetics with mild or moderate peripheral neuropathy found that 6 months of taking 900mg of vitamin E led to significant improvements in 2 out of 12 nerve conduction electrophysiological parameters.31

Glutathione (GSH)

Two trials of intravenous glutathione also showed decreased incidence of chemotherapy-induced polyneuropathy. One trial administered oxilaplatin and the other cisplatin. Neither trial noted reduction in tumor response, indicating that glutathione does not seem to interfere with the efficacy of the applied chemotherapies.32,33 However a larger and more recent study found no such benefit when patients were given the combination of paclitaxel and carboplatin.34

Many supplements mentioned in this article enhance glutathione levels. It may be that part of their benefits are due to this. To the best of our knowledge there has never been a trial testing oral glutathione in the treatment of diabetic neuropathy. While studies have shown that oral glutathione does indeed raise blood levels of glutathione, somewhat poor absorption is a consideration. Liposomal glutathione or acetyl glutathione may overcome issues of absorption and could be sensible candidates for a clinical trial.

Acetyl-L-Carnitine (ALC)

An analysis of two randomized-controlled trials totaling 1,257 patients with established diabetic neuropathy found that acetyl-L-carnitine in doses of either 500mg or 1,000mg twice a day improves a number of measures. These improvements included pain, nerve fiber regeneration, and vibration perception.35 However ALC may actually worsen symptoms scores when used for the prevention of chemotherapy-induced neuropathy.36 A 2016 RCT found that ALC was not inferior to methylcobalamin (vitamin B12), with both groups experiencing improvements in neuropathy symptom score, neuropathy disability score, and nerve conduction velocity.37

B-Complex Vitamins

A 2005 review found that while vitamin B12 may be beneficial, more high-quality, double-blind randomized controlled trials are needed to confirm the effects of vitamin B12 on diabetic neuropathy.38 Vitamin B12 deficiency in diabetics has been linked to metformin use.4 Perhaps this could represent a population most likely to benefit from supplementation? A small study suggested that chronic spinal cord injury patients may be at risk for B12 deficiency, and that B12 supplementation may lead to improvement in symptoms.39 A 2008 Cochrane review found that there is insufficient evidence to determine whether or not B-complex vitamins are beneficial.40 A protocol for an updated Cochrane review was published in 2016 but does not appear to have been conducted yet.41 A 2016 review of B12 found no benefit.42 A mouse model of spinal cord injury found folate administration regulated axonal regeneration. The amount of regeneration followed a biphasic curve, meaning there was an optimal dose where if you go either higher or lower than that, the benefits decline. The authors suggest that folate and possibly other nontoxic dietary methyl donors may be useful in clinical interventions to promote brain and spinal cord healing.43 Of course, there is no clear way to translate this study into an optimal dosing for humans.

We suggest it may be useful to go  back and reanalyze trials looking only at the subgroup of patients who were on metformin. A more obvious benefit from B vitamins might be seen. Also, we are skeptical in general that B-complex vitamins have been fairly tested. For example trials appear to use doses of B12 as small as a few mcg, yet commonly available B-complex supplements contain hundreds of mcg. Some may consider these doses as far greater than is necessary to correct deficiency, but we disagree with this mindset. Firstly, “sufficient” is not necessarily the same thing as “optimal”. Although the body efficiently excretes B12 in excess of it’s binding capacity, large doses can still transiently spike blood levels. Secondly, microcirculation within nerves is likely impaired.10 Are larger doses needed to reach the targeted locations in sufficient quantity? Thirdly, it is not clear if using multiple of four forms of B12 is necessary in order to be most effective.44,45 Since there is little downside to excessive dosing of B12, we suggest the uncertainties of benefit would be best settled by an RCT that tests a liposomal B-complex supplement containing a large dose of B12 (i.e. 500mcg) that is diversified among all four forms. This would put to rest questions of adequate dosage, absorption, and form.

Alpha-Lipoic Acid (ALA)

A 2012 meta-analysis of four trials found alpha-lipoic acid beneficial in the treatment of diabetic peripheral neuropathy. Trials that used TSS scores were analyzed, and the authors found a mean reduction in TSS scores of 2.26 in favor of alpha-lipoic acid administration. A TSS score of 0 means there is no pain, burning, paresthesia, or numbness. A score of 14.64 means all four of these symptoms are severe and more or less continuous. Subgroup analysis found that 3 weeks of 600mg intravenous alpha-lipoic acid resulted in a mean reduction of 2.81 in TSS scores. Oral administration of >=600mg of alpha-lipoic acid for 3 to 5 weeks led to a mean reduction in TSS scores of 1.78. It is unclear if this improvement from oral administration met the definition of being “clinically relevant”.46 Given the short durations of oral administration seen in this analysis, perhaps longer durations may reveal a more obvious cumulative benefit. Another 2012 meta-analysis that had less stringent selection criteria analyzed 15 trials of intravenous ALA. The results suggested both safety and efficacy.47 Though safe when done properly, intravenous administration of ALA may be unsafe if doses are excessive, improperly diluted, or if patients are not properly monitored for hypoglycemia.48

Predictors of improvement with ALA include higher age, lower BMI, male sex, normal blood pressure, history of cardiovascular disease, insulin treatment, longer duration of diabetes and neuropathy, and higher neuropathy stage.49

While it is sometimes claimed that alpha-lipoic acid can cause biotin deficiency, this appears to be unsubstantiated and based off of extrapolation from a flawed animal study. In fact, oral ALA may actually stimulate gut bacteria to synthesize biotin.50

Some individuals claim sensitivity to alpha-lipoic acid. In some rare instances this sensitivity can apparently be severe involving things like extreme fatigue or cognitive impairment. To the best of our knowledge this kind of severe sensitivity has never been reported in any medical journals. It is noted – perhaps exclusively – by individuals who suspect they suffer from mercury poisoning. Since alpha-lipoic acid has mercury-chelating properties, it is possible that mobilization of mercury could be an underlying cause of side effects from alpha-lipoic acid. People with suspected mercury poisoning should exercise caution before taking alpha-lipoic acid. Safe dosing of alpha-lipoic acid for the purposes of mercury detoxification is potentially very different from dosing for other purposes.

CoQ10 (Ubiquinone)

A 2012 randomized controlled trial gave 400mg of CoQ10 or a placebo to patients with diabetic neuropathy for 12 weeks. Significant improvements compared to controls were noted on several different measures. These included improvements in neuropathy symptoms score (from 2.5 ± 0.7 down to 1 ± 0.8, p<0.001) and neuropathy impairment score (from 5.5 ± 4 down to 3.1 ± 2.6, p<0.001). No significant adverse effects were noted.51 However, a 2014 RCT that gave 200mg to patients for 12 weeks did not find a significant improvement in neuropathy measures.52 Perhaps the larger dose is necessary. Also frequently overlooked is that the bioavailability of coQ10 depends on whether or not it is predissolved in fat, and trials don’t always disclose this detail.

Vitamin D

Vitamin D levels have been found to be significantly lower in patients with diabetic neuropathy than in healthy controls.53 Perhaps this could be explained by factors such as decreased physical activity, and hence decreased sun exposure. Though in general, we notice that research is increasingly suggesting that low vitamin D levels are likely to be an effect (rather than a cause) of preexisting disease. A controlled animal study found vitamin D3 improved functional recovery of spinal cord injuries.54 Another study found vitamin D is involved in the regeneration of myelin.55 And a 2015 controlled trial that used sequential assignment (not randomization) gave patients with diabetic peripheral neuropathy 50,000IU of vitamin D3 once a week, for 8 weeks. The results showed significant improvement in neuropathy symptoms score, but not neuropathy disability score or nerve conduction velocities.56 Instead of (or in addition to) taking vitamin D supplements, sunbathing daily would be a sensible thing to try.

Lithium Carbonate

A trial of lithium carbonate failed to improve the functional outcomes and neurological classifications in SCI patients. However it did find improvements in neuropathic pain symptoms, including 2 out of 20 patients having their pain completely eliminated by the end of 6 weeks.57 Another clinical trial focusing on neuropathic pain has been completed, but the results do not yet appear to be published.58

Spinal Decompression Therapy

Some small studies suggest that various spinal decompression therapies may reduce disk-related neuropathic pain, and that an increase in disk height may be associated with a reduction in pain. Larger controlled studies appear to be warranted.59–61

Pulsed Electromagnetic Field Therapy (PEMF)

A number of studies suggest a possible role of pulsed electromagnetic fields (PEMF) in the treatment of neuropathies. In some instances the field is applied to the site of pain, and in other instances it is applied to the brain. In some instances it appears that the analgesic effect is short lived, implying regular treatment may be needed to sustain benefits if this proved to be a viable therapy. Hence long-term safety of PEMF therapy needs investigation.62–69

Epidural Stimulation

The Christopher and Dana Reeve Foundation has discovered that implanting a device that gives epidural stimulation resulted in dramatic improvements in four patients with chronic motor complete spinal cord injury.70 They are currently raising funds to conduct a clinical trial.

Low Level Laser Therapy

In a trial of 60 patients with diabetic peripheral neuropathy low level laser therapy appeared to provide some benefit compared to controls. Further studies are needed to test different types of lasers, as well as different dosage and exposure levels required in different phases of neuropathic care, so as to obtain replicable results.71

Combination Approaches to Neuropathy

Since most of these supplements have little to no side effects, using them in combination to treat neuropathy becomes a feasible and sensible option. In fact, some studies have already started to go this route. This is important because the pathology of diabetic neuropathy is multifaceted8 and therefore is likely to best respond to a multifaceted treatment.

Alpha-Lipoic Acid and Methylcobalamin

A 2013 meta-analysis looked at 17 trials which compared the combination of alpha-lipoic acid plus methylcobalamin (vitamin B12) against just methylcobalamin. Combined data from all studies showed that the combination treatment was significantly superior in measures of both nerve conduction velocity and neuropathic symptoms after just 2 to 4 weeks of treatment.72 A 2015 meta-analysis of 18 trials compared a combination of three treatments (alpha-lipoic acid, methylcobalamin, and prostaglandin E1) against a combination of two treatments (methylcobalamin and prostaglandin E1). These results likewise showed superiority for the larger combination.73

Alpha-Lipoic Acid and Gamma-Linolenic Acid

One study tested a combination of alpha-lipoic acid and gamma-linolenic acid in patients with neuropathic pain from compressive radiculopathy syndrome from disc-nerve root conflict. Patients were either given these two supplements in conjunction with six weeks of a rehabilitation program, or else they were only assigned to the rehabilitation program. Statistically significant decreases in neuropathic symptoms and deficits were found in the supplement group relative to the non-supplement group.74

A Vitamin and Mineral Combination Study

75 type 2 diabetes patients divided into three groups were given a combination of nutritional supplements. The first group received zinc (20 mg), magnesium (250 mg), vitamin C (200 mg) and vitamin E (100 mg). The second received the same nutrients, plus vitamin B1 (10 mg), B2 (10 mg), B6 (10 mg), biotin (200 μg), B12 (10 μg) and folic acid (1 mg). The third group received a placebo. By the end of four months an MNSI questionnaire showed the first group had their neuropathy symptoms decrease from 3.96 to 1.0. The second group from 3.45 to 0.64. And the placebo group from 2.54 to 1.95. There was no significant difference between the three treatment groups in MNSI examinations after 4 months of supplementation. The authors concluded, “These studies suggest that micronutrients supplementation might ameliorate diabetic neuropathy symptoms.”75 It would seem sensible to investigate higher doses for longer periods of time.

A Combination of Glutathione-Enhancing Nutrients

In an open label study 43 patients with peripheral neuropathy were given a combination of alpha-lipoic acid, n-acetyl-cysteine, L-carnitine, selenium, and vitamin C. 26 patients were diabetic, and the rest had neuropathy of unknown origin. By 9 months symptom assessments found reductions in overall pain, burning pain, and numbness ranging from 66% to 70%.76

Topical Quercetin, Vitamin C, and Vitamin D

A small RCT with 34 patients treated diabetic peripheral neuropathy with a topical combination of quercetin, ascorbyl palmitate (fat-soluble vitamin C), and vitamin D. After 4 weeks, there was a reduction in symptoms of numbness, jolting pain, and irritation.77

Open-Label Combination Research

A company that sells a combination formula for neuropathy conducted an email survey of their customers. 450 customers responded. 78% of respondents reported a reduction in symptoms. 93.4% reported no side effects, and 0% reported severe side effects. The ingredients in this product are vitamins B1, B2, B6, B12, R-alpha lipoic acid, vitamin D, feverfew extract, oat straw extract, passionflower extract, and skullcap extract.78 Perhaps people who had positive results were more likely to want to respond to the survey than others, thus producing a favorable bias. This survey is of course not a controlled study, but at least gives some additional confidence about safety.

A 2012 open-label study tested the combination of ALA and superoxide dismutase. After 4 months of treatment, patients significantly improved their electroneurographic parameters and their perception of pain.79

A 2017 open-label study suggested that the combination of ALA, Boswellia Serrata, methylsulfonylmethane (MSM), and bromelain may effectively treat chemotherapy-induced peripheral neuropathy.80

Lyme Disease and Neuropathy

Lyme disease is rarely considered as a cause of neuropathy. In some older studies, there are reports of chronic distal symmetric sensory neuropathy in patients who were properly treated with antibiotics during the acute stage. However, more recent literature expresses skepticism about these reports.81 On the other hand, there are numerous anecdotes from clinicians expressing an association that may not yet be reflected in journals. We recognize that chronic Lyme disease (CLD) following standard antibiotic treatment is a controversial diagnosis, with some believing it is rare or even non-existent, and some believing it is common. Although we will not review this topic until a later date, our opinion is that the evidence does show that CLD can develop following standard antibiotic treatment. Controversial instances aside, a diagnosis of acute Lyme needs to be considered in neuropathy that onsets suddenly.

Summary and Remarks

Natural treatments such as a whole food, plant-based diet, alpha-lipoic acid, coQ10, acetyl-L-carnitine, magnesium, and others have a place in the treatment of neuropathy. Results indicated in some studies might potentially be surpassed after longer treatment durations. Also, using such supplements in combination is a promising avenue that needs to be further researched. The relative lack of side effects of several of these supplements may be favorable when compared to drugs like gabapentin where 66% of patients experience at least one adverse event.82 Also, in some instances the improvements in symptoms are likely due to cumulative and lasting improvements in a disease process. Hence such supplements might be able to gradually reduce the needed dose of concurrent drugs. It may also be sensible to take supplements preventatively, especially if one is taking the previously discussed drugs that put one at increased risk of neuropathy. Every effort should be made to address other modifiable risk factors such as smoking. Lastly, it is worth mentioning that we have seen a combination of neuropathy supplements greatly benefit a chronic spinal cord injury patient who experienced improvements in mobility, coordination, and energy, but no improvements in neuropathic pain.

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