Diabetic neuropathy occurs when prolonged elevation of blood sugar levels damages nerve fibers causing problems with sensation and nerve function. There are several types of diabetic neuropathy, categorized by which nerves are affected. Diabetic neuropathy occurs in both type 1 and type 2 diabetes, and about 40–70% of diabetics will develop the condition.

Fortunately, research shows that lifestyle modification along with natural interventions, such as lipoic acid and B vitamins, can modulate the complex pathways that underlie the development and progression of diabetic neuropathy.

Causes and Risk Factors

Diabetic neuropathy is caused by a combination of the direct effects of high blood sugar on nerve cells as well as damage to the small blood vessels that provide blood to the nerves.

Risk Factors include:

• Long-term poor blood sugar control (primary risk factor)
• Cardiovascular disease
• Age
• Male gender
• Elevated triglycerides
• High body mass index
• Smoking and excess alcohol consumption

Diagnosis and Treatment

Diagnosis

• Presence of characteristic symptoms including lower extremity numbness, pain, sensitivity, dryness, muscle weakness/wasting, difficulty walking, and loss of temperature sensation
• Physical exam
• Fasting blood glucose, hemoglobin A1C, CBC/Chemistry panel, others
• Nerve conduction studies or electromyograms on the foot

Treatment

• Judicious tight blood sugar control is paramount in controlling progression of diabetic neuropathy.
• For painful peripheral neuropathy, pregabalin and/or duloxetine may be prescribed.
• Wound care in limbs affected by peripheral neuropathy is important.

Novel and Emerging Therapies

• Stem cells. Research suggests stem cell transplantation can protect and restore pancreatic cells, improve blood flow to damaged nerves, and may reduce inflammation and thus relieve diabetic neuropathy pain.
• Nabilone. Two studies found nabilone, a synthetic cannabinoid, relieves pain and improves sleep in patients with diabetic neuropathy.
• Botulinum toxin. Studies suggest injection of botulinum toxin, a neurotoxin secreted by the bacterium Clostridium botulinum, to sites of painful diabetic neuropathy may significantly reduce pain and improve sleep quality.

Dietary and Lifestyle Considerations include:

• Diet. Eating a healthy, balanced diet rich in fibrous plant foods and healthy fats can help keep blood glucose levels under control and may reduce risk of diabetes and its complications.
• Exercise. One study found that aerobic exercise, in the form of walking on a treadmill for four hours per week, slowed the progression of diabetic neuropathy.

Targeted Natural Interventions

• Lipoic acid. In clinical trials, doses of 600 – 1,800 mg/day of lipoic acid have led to symptom improvement in people with diabetic neuropathy.
• Acetyl L-carnitine and L-carnitine. One study found that two grams of L-carnitine daily for 10 months improved nerve conduction velocity, which is impaired in diabetic neuropathy. Other studies have found that acetyl-L-carnitine reduced pain, improved vibration sensation in the legs, and increased nerve regeneration in patients with diabetic neuropathy.
• Omega-3 fatty acids. Two studies on animal models found that supplementation with omega-3 fatty acids improved signs of diabetic neuropathy.
• Curcumin. Curcumin may modulate pain associated with diabetic neuropathy.
• Vitamin D. One study on 51 patients with diabetic neuropathy found vitamin D supplementation reduced reported pain levels by 50%. In a case report of a patient with severe pain, vitamin D supplementation provided substantial relief from pain due to diabetic neuropathy.

“Diabetic neuropathy” is the incremental reduction in nerve fiber function as a result of exposure to elevated blood sugar levels (typically, over many years in type 1 diabetes, and sometimes after only a relatively short time in type 2 diabetes). It can be one of the most frustrating complications of diabetes, with symptoms ranging from mild to severe tingling or burning in the extremities. Diabetic neuropathy represents a challenge for both patients and physicians. Not only does this diabetic complication have the potential to severely impact quality of life for people it affects, but it can be very difficult for physicians to treat effectively (National Diabetes Information Clearinghouse 2009; Topiwala 2012).

Although diabetic neuropathy typically causes problems with the peripheral nerves (those in the extremities), it can affect any nerve in the body. It may cause problems with a variety of everyday tasks, such as walking, getting dressed, and eating. Also, it may cause digestive problems. Diabetic neuropathy can also cause loss of sensation in the arms and legs, making patients unaware when they step on something sharp, develop blisters or small cuts, or touch very hot or cold objects (Topiwala 2012; Medline Plus 2012; National Diabetes Information Clearinghouse 2009). Estimates suggest that approximately 40% to 70% of diabetics will develop diabetic neuropathy (Yagihashi 2007; Boulton 2012; Callaghan 2012a; National Diabetes Information Clearinghouse 2009; Feldman 2012a).

Diabetic neuropathy occurs in people with both type 1 and type 2 diabetes, and the risk increases with age and duration of diabetes (Boulton 2012; Edwards 2008). It can be a complex condition, as some people will have significant signs of nerve damage on a physical exam but experience no deficits in everyday life, while others will have only mild deficits on a physical exam but experience severe symptoms, particularly at night (Boulton 2012).

Diabetic neuropathy can be debilitating as the pain and loss of sensation are difficult to treat with conventional therapies (National Diabetes Information Clearinghouse 2009; Topiwala 2012). However, since elevated blood glucose is one of the primary forces driving its development and progression, those affected by diabetic neuropathy have the power to influence the course of this disease through diet and exercise (Callaghan 2012b; Bril 2012; Unger 2007).

In this protocol you will learn how chronically elevated glucose levels damage nerves and give rise to the symptoms of diabetic neuropathy. You will also learn about how this complication of diabetes is diagnosed and treated by conventional medicine; research initiatives that may give rise to new, more effective treatments in the not-to-distant future will also be discussed. In addition, the critical role of dietary and lifestyle modification will be reviewed, and several scientifically studied natural interventions that may benefit those affected by diabetic neuropathy will be outlined.

The development and progression of diabetic neuropathy is complex. There are a number of metabolic, vascular, and hormonal mechanisms involved (Feldman 2012b).

Glycation

One key factor involved in the development and progression of diabetic neuropathy is increased glycation, a process in which glucose and other sugars interact with proteins. Glycation causes proteins throughout the body to become dysfunctional. The dysfunctional molecules created by glycation are termed advanced glycation end products (AGEs) (Sugiyama 1996; Ahmed 2007; Sugimoto 2008).

Because people with diabetes have elevated blood glucose levels, they usually also have higher levels of AGEs. These glycation end products have the capacity to destroy cells or disrupt function in many tissues, including nerves (Brownlee 2001; Feldman 2012b; Morales-Vidal 2012). The damage done to nerves by glycation occurs via two different mechanisms. First, the glycation of nerve proteins inhibits their function, which directly affects nerve activity. Second, AGEs can bind to the surfaces of nerve cells and trigger an inflammatory response, further damaging the neurons (Vincent 2011). Increased levels of reactive oxygen species also contribute to the formation of AGEs (Brownlee 2001).

Inflammation

Inflammation also plays a critical role in diabetic neuropathy, as people with both type 1 and type 2 diabetes have higher levels of C-reactive protein and tumor necrosis factor-alpha (TNF-α), which are two chemicals involved in the inflammatory response. Higher levels of TNF-α are associated with diabetic neuropathy (Edwards 2008; Gonzalez-Clemente 2005). All of these different pro-inflammatory chemicals lead to the presence of an increased number of immune cells, called macrophages, around the nerves. These macrophages contribute to neuropathy by several mechanisms, including the production of reactive oxygen species and enzymes that break down myelin, which is a protein that forms a protective coating around nerves (Edwards 2008).

Vascular Dysfunction

Elevated blood glucose levels also cause vascular dysfunction, leading to circulatory problems. High glucose levels activate a protein called protein kinase C, which triggers the constriction of blood vessels; these constricted blood vessels lead to reduced blood flow to neurons (Evcimen 2007; Brownlee 2001; Feldman 2012b). Blood vessels are also damaged by AGEs, further disrupting blood flow (Ahmed 2005; Halushka 2009). This impaired blood flow to neurons deprives them of oxygen, also known as ischemia. Oxygen deprivation can damage and destroy neurons.

Diabetic neuropathy is caused by a combination of the direct effects of high blood sugar on nerve cells as well as damage to the small blood vessels that provide blood to the nerves (Feldman 2012b; Edwards 2008). Not surprisingly, the main risk factor for diabetic neuropathy is poor control of blood glucose levels (Feldman 2012b; Edwards 2008; Booya 2005; Forrest 1997). Poor blood glucose control allows blood glucose levels to stay high, damaging both nerves and blood vessels. Consequently, many markers of poor blood glucose control, such as fasting blood glucose and hemoglobin A1C (HbA1C; a marker of long term blood glucose levels) are elevated (Fiçicioğlu 1994; Dyck 1999). Supporting this concept are data from two different studies, the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC). The DCCT found that modifying treatment regimens to achieve tighter glycemic control led to a dramatic 60% reduction in diabetic neuropathy after five years (Genuth 2006).

Even in people who are not diabetic, high blood glucose levels caused by prediabetes may contribute to nerve damage. Prediabetes is a precursor to type 2 diabetes and is sometimes called impaired glucose tolerance or insulin resistance. People with prediabetes have blood sugar levels that are elevated, but not high enough to qualify as diabetes. People who have otherwise unexplained neuropathy are more likely to have prediabetes. In addition, people with prediabetes and neuropathy who lower their blood glucose with diet and lifestyle changes can experience improvement in their neuropathy symptoms (Callaghan 2012a). Life Extension recommends an optimal fasting blood glucose range of 80-86 mg/dL.

Other risk factors for diabetic neuropathy have been identified, though not all of them are modifiable. Height is a risk factor for diabetic neuropathy (Edwards 2008; Forrest 1997), suggesting that longer peripheral nerves are more vulnerable to damage from diabetes. Another risk factor is age, as the incidence of diabetic neuropathy increases with age. Similarly, the longer someone has had diabetes, the more likely he or she is to develop diabetic neuropathy. Male gender is also a risk factor for diabetic neuropathy (Edwards 2008; Booya 2005). In addition, males develop diabetic neuropathy earlier than females during the course of the disease (Aaberg 2008).

Many of the other risk factors for diabetic neuropathy are preventable, especially because they pertain to overall cardiovascular health. Due to the role that vascular problems play in diabetic neuropathy, it is not surprising that many of the other risk factors for this complication of diabetes are risk factors for cardiovascular disease. High plasma levels of triglycerides, high body mass index (BMI; a measure of weight relative to height), high blood pressure, diabetic retinopathy, smoking, and excessive alcohol use are all associated with an increased risk of diabetic neuropathy (Booya 2005; Edwards 2008; Feldman 2012b; Forrest 1997; Dyck 1999; Wiggin 2009; Nie 2012). Having clinically diagnosed cardiovascular disease doubles the risk of diabetic neuropathy, regardless of the other risk factors. In addition to the content reviewed here, individuals with diabetic neuropathy are encouraged to read the Life Extension protocol on Atherosclerosis and Cardiovascular Disease, as it contains numerous evidence-based strategies to help promote optimal cardiovascular health.

Symptoms of diabetic neuropathy depend on the type of neuropathy and which nerves are affected. The prominent symptom of peripheral neuropathy is numbness and tingling that begins in the toes and feet and gradually progress up through the legs and to the hands and arms. Diabetic neuropathy may also cause diminished or altered sensation of pain and temperature in affected body parts (Feldman 2012c; Topiwala 2012). Some patients will also develop pain described as a burning, electrical sensation, or stabbing pain (Edwards 2008; American Diabetes Association 2012; Topiwala 2012). The symptoms are often worse at night (National Diabetes Information Clearinghouse 2009; Callaghan 2012a; Topiwala 2012; American Diabetes Association 2012). In severe, long-standing cases, diabetic neuropathy may also cause muscle weakness if motor neurons are affected (National Diabetes Information Clearinghouse 2009; American Diabetes Association 2012; Feldman 2012c).

Other forms of diabetic neuropathy can cause additional symptoms. Diabetics with autonomic neuropathy may experience digestive problems, such as heartburn, abdominal pain, bloating, nausea, constipation, diarrhea, or vomiting a few hours after eating (Morales-Vidal 2012; Vinik 2006; Edwards 2008; National Diabetes Information Clearinghouse 2009; Topiwala 2012). Diabetic neuropathy also may affect the nerves in the heart and those that regulate blood pressure, leading to dizziness or feeling faint after standing up (Giudice 2002; Edwards 2008; Topiwala 2012; Morales-Vidal 2012). Other cardiovascular symptoms include poor heart rate control, leading to either a fast or slow heartbeat, and a lack of increase in heart rate due to exertion (Morales-Vidal 2012; American Diabetes Association 2012). The nerves that serve the bladder are another commonly affected region; this may lead to urinary retention, incontinence, urinating while sleeping, pain upon urination, poor stream, or difficulty initiating urination, sometimes followed by urinary tract infections. Sexual dysfunction, which can manifest as erectile dysfunction or vaginal dryness may also result (Morales-Vidal 2012; Topiwala 2012; American Diabetes Association 2012). Diabetic neuropathy can also affect the nerves that supply the sweat glands, leading to unusually dry skin (American Diabetes Association 2012; Morales-Vidal 2012).

One of the most troubling complications of diabetic neuropathy is foot ulcers. People with diabetic peripheral neuropathy often have diminished sensation in their feet, which means they may not notice foot injuries (Edwards 2008; Callaghan 2012a; Feldman 2012c). When combined with the poor circulation that commonly afflicts people with diabetic neuropathy, these foot ulcers may heal poorly and become infected, which can lead to serious complications and require foot amputation. Diabetes is the leading cause of lower-extremity amputations, accounting for roughly 80 000 cases per year in the United States alone; approximately 15% of people with severe diabetic neuropathy will develop foot ulcers during their disease (Callaghan 2012a). Importantly, people with diabetes have 15 times higher risk of lower limb amputations than people with other diseases (Margolis 2011).

Diagnosis

The diagnosis of diabetic neuropathy is typically based on the presence of characteristic symptoms as well as findings on a physical exam (Feldman 2012c; National Diabetes Information Clearinghouse 2009; Morales-Vidal 2012). A questionnaire called the Michigan Neuropathy Screening Instrument or MNSI that asks “yes” or “no” questions about common symptoms of diabetic neuropathy, such as lower extremity numbness, pain, sensitivity, dryness, weakness, difficulty walking, and loss of temperature sensation is often used to help identify symptoms of diabetic neuropathy (Edwards 2008; Feldman 1994). However, the presence of clinical symptoms alone is not the most reliable indicator of diabetic neuropathy (England 2005). As a result, these symptoms should be correlated with a focused physical exam that looks for signs of a neurological deficit.

Common physical exam findings indicative of diabetic neuropathy include the presence of dry skin, ulcers or infections on the feet, diminished/absent vibration sensation at the big toe, and reduced or absent ankle reflexes (Feldman 1994; England 2005; Feldman 2012c; Tesfaye 2010; Edwards 2008; Meijer 2005). Other signs that may be observed are diminished sensation in the feet to pin pricks, muscle weakness/wasting, and diminished sensitivity to temperature (Feldman 2012c). Further information can be obtained by performing nerve conduction studies or electromyograms on the foot, both of which are techniques that measure the activity of nerves; abnormal results on these tests suggest the presence of diabetic neuropathy (National Diabetes Information Clearinghouse 2009; American Diabetes Association 2012; England 2005).

The signs of autonomic diabetic neuropathy can also be diagnosed on a physical exam. The effects of diabetic neuropathy on the nerves that govern circulation can be measured by checking the variability of the heart rate upon exertion and by checking blood pressure changes due to changes in body position, also known as orthostatic blood pressure (Morales-Vidal 2012; Tesfaye 2010; Edwards 2008).

Treatment

One of the mainstays of treatment of diabetic neuropathy, and the most important strategy to prevent it, is improved blood glucose control (Callaghan 2012a; Edwards 2008; Feldman 2013; National Diabetes Information Clearinghouse 2009; Topiwala 2012). Pharmacologic treatments for diabetic neuropathies can focus on either the underlying mechanism or trying to relieve the symptoms; many conventional therapies fall into the second group (Edwards 2008).

Painful diabetic neuropathy is typically treated using a variety of different medications. Pregabalin (Lyrica®), an anticonvulsant, is often the first treatment tried (Topiwala 2012). Common side effects include dizziness, vertigo, blurred vision, sedation, and problems with coordination (Feldman 2013). Another medication that has been approved by the Food and Drug Administration (FDA) for the treatment of diabetic neuropathic pain is duloxetine (Cymbalta®), a serotonin-norepinephrine reuptake inhibitor (National Diabetes Information Clearinghouse 2009; Ziegler 2009). The mechanism(s) by which duloxetine relieves pain are unclear, but blockade of neuronal sodium channels is thought to be involved (Wang 2010). The most common side effects of duloxetine are nausea, dizziness, somnolence, dry mouth, constipation, and decreased appetite (Ziegler 2009). Other medications that, while not specifically licensed for the treatment of diabetic neuropathy, are commonly used include bupropion (Wellbutrin®), paroxetine (Paxil®), amitriptyline (Elavil®), doxepin (Sinequan®), venlafaxine (Effexor®), and citalopram (Celexa®) (National Diabetes Information Clearinghouse 2009; Ziegler 2009; Topiwala 2012; Feldman 2013). Although these medications are all antidepressants, they may provide relief to those suffering from diabetic neuropathy even in the absence of depression (National Diabetes Information Clearinghouse 2009).

Medications used for treating seizures, such as gabapentin (Neurontin®), a GABA analog, may also help relieve diabetic neuropathic pain in some cases (Ziegler 2009). The mechanism(s) by which gabapentin relieves pain have not been well defined (Tanabe 2008). Opioid medications, such as tramadol and oxycodone, may also provide effective pain relief (National Diabetes Information Clearinghouse 2009; Ziegler 2009; Topiwala 2012; Feldman 2013).

Conventional treatments may also be used to help with the other complications of diabetic neuropathy. For example, people that suffer from delayed gastric emptying can take erythromycin (Eryc®) and metoclopramide (Reglan®) to speed digestion (National Diabetes Information Clearinghouse 2009). Erectile dysfunction can be treated using sildenafil (Viagra®), tadalfil (Cialis®), and vardenafil (Levitra®) (National Diabetes Information Clearinghouse 2009; Topiwala 2012).

Stem Cells

Stem cells have emerged as an intriguing treatment for diabetic neuropathy on multiple fronts. One possible use for stem cells is treating the elevated glucose levels that cause diabetic neuropathy. Research suggests that stem cell transplantation can protect and restore the insulin-secreting cells of the pancreas, lowering blood glucose levels and relieving diabetic neuropathy and other complications (Sino Stem Cells 2013; GSCN 2013). Stem cells may also improve blood flow to damaged nerves, helping reduce pain and heal neurons crippled by diabetic neuropathy (Kim 2012). In addition, researchers found that certain stem cells, termed mesenchymal stem cells, may be able to reduce inflammation and thus relieve diabetic neuropathy pain (Waterman 2012). Stem cells continue to be developed and may become more widely available in the not-too-distant future.

Nabilone

Nabilone (Cesamet®) is a synthetic cannabinoid, which means it has some of the same properties as constituents of marijuana. It is sometimes used to treat nausea due to chemotherapy but may also be effective in treating pain caused by diabetic neuropathy (Toth 2012). Two different studies found that nabilone is effective at relieving diabetic neuropathic pain and also improved the mood and overall quality of life for diabetics. These studies also found that treatment with nabilone improved sleep in patients suffering from diabetic neuropathy (Toth 2012; Bestard 2011). This is important because for many, the pain of diabetic neuropathy is worse at night (Ziegler 2009). Physicians may prescribe nabilone as an off-label treatment option for painful neuropathy.

Botulinum Toxin

Botulinum toxin, a neurotoxin secreted by the bacterium Clostridium botulinum, blocks signaling from the neurotransmitter acetylcholine. Botulinum toxin can be injected in small quantities to temporarily disable nerves and muscles; it is often used for cosmetic reasons or to treat muscle spasticity (Jabbari 2011; Bach-Rojecky 2010). Early studies suggest that injection of botulinum toxin to sites of painful diabetic neuropathy may significantly reduce pain and improve sleep quality, though more studies are needed to determine the effectiveness of this treatment (Yuan 2009; Francisco 2012).

Transcutaneous Electrical Nerve Stimulation

Transcutaneous electrical nerve stimulation (TENS), which is used for the treatment of acute and chronic pain, utilizes small devices that deliver a small electric current through electrodes placed near the painful area (Stein 2013; Vance 2014; Coutaux 2017). One mechanisms of action involves the stimulation of networks of neurons resulting in decreased pain sensation (Vance 2014). TENS was accepted in France for reimbursement by the health insurance system in 2000 (Coutaux 2017).

Many studies have examined TENS for various types of pain, including acute pain, low back pain, osteoarthritis, labor, cancer pain, and postoperative pain (Vance 2014). In a randomized study of 31 peripheral diabetic neuropathy patients that received TENS or sham treatment for 4 weeks, 30 minutes per day, 83% of the TENS group experienced symptomatic improvement compared with 38% in the sham-treated group, pain scores in the TENS group decreased from 3.17 to 1.44, and symptoms reappeared about one month after TENS was terminated (Kumar 1997). In a randomized, single-blind, placebo-controlled study, TENS was examined in combination with amitriptyline for the management of chronic painful peripheral neuropathy in 26 patients with type 2 diabetes. All participants were prescribed amitriptyline, but after four weeks, those who failed to respond or who only partially responded were randomized to the TENS or sham group. Symptomatic improvement was reported in 85% of participants and 36% became asymptomatic. The study revealed that the effect of combining TENS and amitriptyline appears to be superior to TENS alone (Kumar 1998). In a randomized, double-blind, controlled study that enrolled 19 patients with mild-to-moderate diabetic neuropathy, TENS led to significant improvements in total symptom score after 6 weeks (-42%) and 12 weeks (-32%) of treatment (Forst 2004). In another study of 34 peripheral diabetic neuropathy patients treated with TENS, 76% of participants reported a subjective improvement in their neuropathic pain (Julka 1998). A meta-analysis of three randomized controlled trials that enrolled 78 patients showed that after four and six weeks of follow-up, mean pain score was significantly reduced, and at 12 weeks participants reported a subjective improvement in their neuropathic symptoms. No adverse effects were noted (Jin 2010). In another systematic review and meta-analysis of 12 studies, it was shown that TENS improved pain relief in participants with diabetic neuropathy, and the improvement was significantly better than in the placebo group. In addition, electromagnetic stimulation did not show an effect on pain relief (Stein 2013).

The Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology recommended, based on four studies, that TENS is “probably effective” and should be considered in the treatment of painful diabetic neuropathy. It also pointed out that more research is needed into the mechanisms of action, and more rigorous studies are required for examining the efficacy of this approach (Dubinsky 2010). Contraindications and limitations to the use of TENS include: the presence of a pacemaker if TENS is applied to the chest; loss of sensation in the area of the damaged nerve; uncontrolled seizures; certain types of damage to the spinal cord; pregnancy (except when used to treat low back pain during labor); and avoidance in the region over major neck arteries (Coutaux 2017).

Capsaicin

Capsaicin is the constituent in chili peppers responsible for their “spiciness” (Yang 2017). When applied to the skin, capsaicin stimulates some of the sensory nerves involved in pain signaling and produces redness and a mild burning sensation at the application site (Anand 2011). Over time, these nerves become desensitized and no longer transmit pain signals as strongly, resulting in pain reduction. In July 2020, the FDA approved Qutenza, a patch containing 8% synthetic capsaicin for topical treatment of painful diabetic neuropathy (FDA 2020; Blair 2018).

The recommended use of Qutenza is a single 30-minute application of up to four patches applied to the feet. It is approved for use only by healthcare professionals. The skin often must be numbed or cooled before application due to the considerable pain and burning associated with the procedure (AveritasPharma 2020). 

A substantial body of evidence shows 8% capsaicin topical treatment appears effective against multiple types of peripheral neuropathy, including diabetic peripheral neuropathy. Compared with lower-concentration preparations, the 8% form has been found to result in a greater percentage of subjects achieving moderate to substantial pain relief (Derry 2017). For peripheral diabetic neuropathy, a meta-analysis concluded that topical 8% synthetic capsaicin is roughly as effective as oral drugs such as pregabalin, gabapentin, and duloxetine but without systemic side effects such as sleepiness, dizziness, and fatigue (van Nooten 2017). In a double-blind clinical trial, 369 patients with diabetic peripheral neuropathy were randomized to one single capsaicin 8% patch treatment or a placebo patch (Simpson 2017). Over 12 weeks the treatment group achieved improvements in pain relief compared with placebo, as well as markedly more rapid onset of pain relief. Modest improvement in sleep quality in the capsaicin group was noted as well. Results of capsaicin treatment in this trial were comparable to other known treatments, but without systemic side effects. In an open-label randomized trial, 468 subjects with painful diabetic neuropathy were enrolled for the primary objective of assessing safety of capsaicin 8% patches. Patients were separated into groups to receive capsaicin for either 30 or 60 minutes, plus standard of care versus standard of care alone (Drugs.com 2020). After 52 weeks of treatment at eight week or greater intervals, multiple standardized functional measures improved significantly more in the capsaicin groups. The study concluded that this course of capsaicin treatment was well-tolerated, had no negative functional or neurological effects, and did not decrease safety compared with standard of care alone.

In the United States, capsaicin is available over-the-counter in a variety of forms, but in concentrations no greater than 0.25% (Drugs.com 2020). In randomized controlled trials, a 0.025% capsaicin gel and 0.075% capsaicin lotion both failed to provide relief for painful diabetic neuropathy (Kulkantrakorn 2013; Kulkantrakorn 2019). Some evidence suggests capsaicin patches in concentrations of 0.625% and 1.25% can provide short-term relief for peripheral neuropathy and may produce a less-intense burning sensation than the capsaicin 8% patch (Moon 2017).

Dietary and lifestyle modifications are essential for people with diabetic neuropathy because they can help prevent the disease from progressing further. One of the most important ways that diabetics can slow the progression of their neuropathy is to achieve better control of their blood glucose levels (Skyler 1996; Callaghan 2012a). It is in this goal that dietary and lifestyle changes can be most effective. In addition to the strategies outlined in this protocol, readers are encouraged to review the Diabetes and Weight Loss protocols.

Diet

Diet is one of the main ways that people with diabetes can control their blood glucose levels without taking additional medication. Eating well-balanced meals, with a mixture of fruits, vegetables, proteins, and fats will help prevent major swings in blood glucose levels. Eating meals on a regular schedule and coordinating meals with diabetes medications will also minimize blood glucose fluctuations (Mayo Clinic 2011). In addition, specific dietary patterns, such as high-protein, low-carbohydrate diets (Gannon 2004) or diets rich in foods with a low glycemic index (Rizkalla 2004) have been shown to improve blood glucose control. A healthy diet will also help diabetics lose weight, which has been shown to help keep blood glucose levels low (Wing 1987). Notably, a study found that making dietary changes to help keep blood glucose levels under control reduced diabetic neuropathy symptoms in patients with impaired glucose tolerance, which is considered to be a pre-diabetic condition (Smith 2006). Ideally, most people should target a fasting blood glucose level between 70 and 85 mg/dL, although this may be difficult for diabetics to achieve.

Exercise

Regular exercise is also important for people with diabetes. Exercise causes muscle tissue to burn energy, which prevents blood glucose levels from rising too high (Mayo Clinic 2011). Regular physical exercise also helps diabetics lose weight. This improves overall blood glucose levels. In addition, one study found that diabetics who increase their physical activity levels and lose weight have increased numbers of mitochondria in their skeletal muscle fibers (Toledo 2007); this is important because the mitochondria help generate cellular energy. Consequently, this increased mitochondrial density would allow diabetics to burn energy more quickly, helping to keep blood glucose levels lower even when they are not exercising. One study has also found that aerobic exercise, in the form of walking on a treadmill for 4 hours per week, was able to slow the progression of diabetic neuropathy (Balducci 2006).

Cardiovascular Health

Another dietary and lifestyle intervention that diabetics can use to prevent diabetic neuropathy is to improve their overall cardiovascular health. The impact of cardiovascular health on diabetic neuropathy has been established by many studies. Diabetics who have high blood pressure, elevated LDL cholesterol levels, and high triglyceride levels are more likely to develop diabetic neuropathy (Sibal 2006; Tesfaye 2005; Leiter 2005; Davis 2007; Wiggin 2009). Studies have also found that high triglyceride levels may cause nerve damage even in non-diabetics (Kassem 2005). Two different studies found that patients who followed a program of increased physical activity (150-175 minutes of exercise per week), weight loss (sustained loss of 7% of their body weight), and a low-calorie, low-fat diet had lower blood pressure and triglyceride levels, suggesting that these lifestyle changes could help prevent diabetic neuropathy (Diabetes Prevention Program Research Group 2005; Look AHEAD Research Group 2010).

Elevated blood glucose drives complications of diabetes, including neuropathy, via several mechanisms. For example, high glucose promotes inflammation as well as glycation, and perturbs blood flow to neurons, all of which contribute to neuropathy. Unfortunately, most conventional drug treatments aim to provide symptomatic relief without targeting these underlying mechanisms (McIlduff 2011). However, several natural interventions have been shown in studies to modulate biological pathways that underlie the development and progression of neuropathy. Thus, by taking steps to keep fasting glucose levels within the optimal range of 70 – 85 mg/dL and supplementing with natural compounds that mitigate the negative effects of excess glucose, one can ensure a robust defense against diabetic complications.

Life Extension has identified several novel strategies that can help optimize glucose control. These strategies are outlined in the Weight Loss protocol and the Diabetes protocol. Individuals with diabetic neuropathy are encouraged to review these protocols in addition to the suggestions outlined here.

Honokiol

Honokiol is a polyphenolic compound from the bark of the magnolia tree (Magnolia grandifolia). Magnolia bark extracts have been used traditionally as sedatives to improve sleep and relieve anxiety, and honokiol is being investigated for its potential usefulness in treating inflammatory pain (Alexeev 2012; Woodbury 2013).

Like other polyphenols, honokiol has oxidative stress-reducing and anti-inflammatory activities. In addition, it appears to cross the blood-brain barrier and interact with certain neurotransmitter receptors in the brain (Woodbury 2013; Alexeev 2012). Laboratory research shows honokiol and some of its derivatives activate certain GABA receptors (Bernaskova 2015), and may also interact with receptors for glutamate, dopamine, and serotonin, and influence acetylcholine signaling (Alexeev 2012). One form of honokiol has even been shown to stimulate cannabinoid receptors that may be involved in decreasing pain perception (Gertsch 2012).

In one study, treatment with honokiol reduced pain-related behaviors in mice in experimental models of inflammation (Lin 2009). Findings from other animal studies indicate honokiol may decrease acute inflammatory pain without causing motor or cognitive side effects, and may prevent and decrease some of the chronic pain-related changes in the brain (Woodbury 2015; Lin 2007).

Palmitoylethanolamide

Palmitoylethanolamide (PEA) is a lipid compound that occurs naturally in tissues throughout the body, including the central nervous system. It can also be found in foods such as soy lecithin, egg yolk, and peanuts (Mattace Raso 2014; LoVerme 2005). A growing body of research suggests PEA supplementation may be effective for relieving pain from a variety of causes without triggering adverse side effects (Artukoglu 2017; Paladini 2016; Gabrielsson 2016). Most of the existing preclinical research indicates that PEA works by changing the expression of certain genes and reducing inflammatory signaling, but other possible mechanisms for its analgesic effect have also been proposed, including its ability to stimulate signaling through cannabinoid receptors in the nervous system (Gabrielsson 2016; Di Cesare Mannelli 2013; Skaper 2012; Khasabova 2012).

Several clinical trials have shown that PEA can reduce pain from a broad array of causes, including diabetic neuropathy, chemotherapy-induced peripheral neuropathy, sciatic nerve compression, carpal tunnel syndrome, osteoarthritis, low back pain, failed back surgery, stroke-related nerve pain, multiple sclerosis, dental pain, chronic pelvic pain, post-herpetic neuralgia, and vaginal pain (Hesselink 2012). In an observational study of individuals with chronic pain due to a variety of conditions who were unable to control their pain with usual therapies, adding 600 mg PEA twice daily for three weeks followed by once daily for another four weeks decreased average pain intensity scores in all participants who completed the study (Gatti 2012).

In a randomized controlled trial, 636 participants with pain due to compression of the sciatic nerve received either 300 mg PEA daily, 600 mg PEA daily, or placebo in conjunction with their usual pain medications for three weeks. Both doses of PEA resulted in greater pain reduction than placebo, and the higher dose was more effective than the lower dose. In fact, those in the 600 mg group experienced more than a 50% reduction in pain scores (Keppel Hesselink 2015). In 118 patients with nerve pain, 30 days of standard treatment plus 600 mg PEA daily was more effective than standard treatment alone (Dominguez, Martin 2012). A randomized clinical trial found that 900 mg PEA daily for one week followed by 600 mg daily for one week was more effective than ibuprofen, at a dose of 600 mg three times daily for two weeks, for relieving temporomandibular joint (TMJ) pain (Marini 2012).  

Micronized preparations of PEA have also been studied. Micronization results in smaller particles that may be absorbed more readily. Micronized PEA, at doses of 600–1,200 mg/day, reduced pain in subjects with diabetes- or trauma-related nerve pain, chronic pain after failed back surgery, and acute pain from tooth extraction (Cocito 2014; Paladini 2017; Bacci 2011). In a report of 100 cases of nerve pain related to spinal disorders, the inclusion of an ultra-micronized PEA supplement in pain management therapy showed promising results (Chirchiglia 2017). A meta-analysis found that women with chronic pelvic pain due to endometriosis appear to benefit from the combination of 800 mg micronized PEA daily plus 80 mg per day of polydatin, a natural free radical-reducing agent found in grapes and red wine (NIH 2017; Indraccolo 2017). In a randomized controlled trial, the combination of PEA and polydatin was more effective than placebo for reducing abdominal pain in irritable bowel syndrome patients (Cremon 2017).

Lipoic acid

Lipoic acid is a compound produced within the body that exerts a variety of beneficial effects within the body, especially in the context of glucose metabolism (McIlduff 2011). In fact, lipoic acid is an approved treatment for diabetic neuropathy in Germany (McIlduff 2011; Head 2006). In addition, it appears lipoic acid may positively influence glucose metabolism in people with diabetes (Korotchkina 2004). Important mechanisms by which lipoic acid helps combat diabetic neuropathy include inhibition of glycation and inflammation (Thirunavukkarasu 2005; Kunt 1999; Bierhaus 1997). It has also been reported that lipoic acid can protect against oxidative damage in neuronal cell culture (Bharat 2002). It also improves blood flow to nerves and allows them to use energy more efficiently (Bertolotto 2012; McIlduff 2011). In animal studies, lipoic acid has been found to prevent and even reverse nerve dysfunction caused by high blood sugar levels.

Results of clinical trials have been promising. One trial showed that 3 daily doses of 600 mg of alpha-lipoic acid over 3 weeks led to significant symptomatic improvement in 12 patients with diabetic neuropathy. In another trial, 181 patients were divided into groups receiving placebo or 600, 1200, or 1800 mg of alpha-lipoic acid daily. Significant symptomatic improvement was noted in the 1800 mg/day group in as little as one week, with the 600 and 1200 mg groups experiencing improvement by week 2 (McIlduff 2011). In both of these trials, sensations of pain and burning were alleviated. A separate study found that oral administration of 600 mg of lipoic acid daily over the course of 4 years improved neuropathic symptoms and slowed the progression of mild to moderate diabetic neuropathy (Ziegler 2011).

Other trials show that intravenous lipoic acid is also beneficial for diabetic neuropathy. One study revealed that daily intravenous administration of alpha-lipoic acid for 3 weeks is an effective treatment for diabetic neuropathy, and another trial reported that intravenous administration for 2-4 weeks was efficacious (McIlduff 2011; Han 2012).

Lipoic acid is available as a supplement in 2 forms: alpha-lipoic acid and R-lipoic acid. Evidence suggests that the sodium salt of R-lipoic acid may be more bioavailable than alpha-lipoic acid (Carlson 2007).

N-acetylcysteine

N-acetylcysteine (NAC) is a small molecule able to pass through cell membranes and serves as a precursor for the amino acid cysteine, which itself functions directly as an antioxidant and helps increase the levels of another naturally occurring antioxidant, glutathione. NAC also functions as an antioxidant on its own, and it was shown to protect neurons from oxidative damage (Kamboj 2010; Sakai 2001). In addition, NAC has been shown to suppress the formation of AGEs (Nakayama 1999). Multiple studies on animal models of diabetic neuropathy found that NAC prevents neuron death and protects against nerve damage (Kamboj 2010; Love 1996; Sagara 1996; Head 2006).

Acetyl L-Carnitine (ALC) and L-Carnitine

Carnitine is an amino acid-like compound important for mitochondrial energy production (Evans 2008). Some of the interest in carnitine’s role in diabetic neuropathy stems from evidence that diabetics with complications, including diabetic neuropathy, have lower blood levels of free and total carnitine than diabetics without complications; this finding supports previous findings from animal studies (Tamamoguillari 1999). As a result, ALC and L-carnitine have been studied as potential treatments for diabetic neuropathy. Carnitine supplementation may help combat carnitine deficiency, improve insulin resistance, allow cells to use glucose more efficiently, help regenerate damaged nerve fibers, or help damaged neurons transport intracellular components more effectively (Evans 2008).

Multiple human trials have been conducted on the effects of carnitine supplementation on diabetic neuropathy. One study found that L-carnitine (2 g daily for 10 months) improves nerve conduction velocity, which is impaired in diabetic neuropathy (Ulvi 2010). Studies done on ALC found that it reduced pain, improved vibration sensation in the legs, and increased nerve regeneration in patients suffering from diabetic neuropathy (Bansal 2006; Sima 2005; Adriaensen 2005; Evans 2008; De Grandis 2002). Carnitine supplements may also aid in treating the autonomic neuropathy caused by diabetes; a study done on an animal model found that ALC reduced the cardiovascular signs of diabetic autonomic neuropathy (Giudice 2002).

B-Vitamins

B-vitamins are a family of vitamins that play many roles in the human body, especially in cellular energy generation and nervous system function (Selhub 2000).

Thiamine (B1) and benfotiamine. A lack of thiamine can directly cause neuropathy (Head 2006). Early research found that thiamine could be used to treat painful diabetic neuropathy. Benfotiamine is a fat-soluble derivative of thiamine that is more readily absorbed by the digestive tract (Sanchez-Ramirez 2006).

Benfotiamine may modulate several pathways that contribute to diabetic neuropathy: the formation of AGEs, the protein kinase C pathway, and damaging changes that can occur within cells due to high glucose levels (Varkonyi 2008; Balakumar 2010). It may also help prevent vascular problems that contribute to neuropathy (Stracke 2008). Multiple clinical trials have examined the effects of benfotiamine on diabetic neuropathy (Stracke 2008; Haupt 2005; Winkler 1999; Head 2006) and have found that, particularly at doses ranging from 300 to 600 mg daily, it was able to relieve diabetic neuropathy symptoms, especially pain.

Vitamin B12. Vitamin B12 is critical for the function of the nervous system, and a lack of it can cause significant peripheral neuropathy (Head 2006). In addition, people with diabetic neuropathy often have high levels of the blood vessel-damaging compound homocysteine, which can be elevated in the presence of low vitamin B12 levels (Fahmy 2010). Researchers have also examined the potential benefits of vitamin B12 supplementation in treating diabetic neuropathy; the form of vitamin B12 known as methylcobalamin, which has an affinity for nerve tissue, has been studied extensively in this regard (Mizukami 2011). Studies in animal models of diabetic neuropathy have found that methylcobalamin may mitigate the damage caused by diabetic neuropathy, possibly by modulating the protein kinase C signaling pathway or activating chemical signals that help nerves survive and regenerate (Mizukami 2011; Okada 2010; Jian-Bo 2010).

Clinical studies have also yielded promising results. A combination of 2 mg of methylcobalamin, 3 mg of L-methylfolate (a form of folic acid), and 35 mg of pyridoxal 5’-phosphate (a form of vitamin B6) was found in multiple clinical trials to improve symptoms of neuropathy and help maintain the health of small nerves in the lower extremities (Jacobs 2011; Walker 2010; Fonseca 2013). Combinations of these three nutrients have also been found to help reduce hospitalization and medical care costs in people with diabetic neuropathy (Wade 2012). Studies looking at methylcobalamin alone have also been encouraging. Both oral methylcobalamin (1500 mcg daily) and injected methylcobalamin (2000 mcg daily) were found to improve numbness, reflexes, sensitivity to vibration, pin-prick stimulation, gait, and pain (Talaei 2009; Dominguez 2012). One study even found that methylcobalmin was more effective than nortriptyline, an antidepressant commonly used to treat diabetic neuropathic pain (Talaei 2009).

Folate and vitamin B6. Much like methylcobalamin, vitamin B6 is important for nerve function, while folate may help improve the function of blood vessels that supply the nerves (Fonseca 2013). As discussed previously, derivatives of folate and vitamin B6 have been tested in clinical trials, along with methylcobalamin, and showed positive results (Jacobs 2011; Walker 2010; Fonseca 2013).

Vitamins C and E

Research has found that diabetics have low levels of vitamin C; and this appears to be a result of the disease itself, not of decreased dietary intake of vitamin C (Sinclair 1994). Another piece of evidence pointing to the importance of vitamin C is that people with diabetic neuropathy have elevated levels of “reduced” vitamin C, which is vitamin C that has already been used by the body. This suggests that diabetic neuropathy places an extra strain on the body’s stores of vitamin C. Reduced levels of vitamin E are also seen in people with diabetic neuropathy and animals with diabetes (Ziegler 2004). Vitamin E supplementation alone has been found to improve signs of peripheral neuropathy (Martinello 1998) and may also improve nerve conduction in people with type 2 diabetes (Tutuncu 1998). In addition, treatment with vitamins C and E has been found to be beneficial in both animal models of diabetic neuropathy (Sharma 2009) and one clinical trial (Farvid 2011).

Minerals

One study found that diabetics have lower levels of zinc, chromium, and manganese in their hair and blood, suggesting that deficiencies of these nutrients may be associated with diabetic neuropathy (Gul Kazi 2008). Moreover, diabetes is the most common disease that causes secondary magnesium deficiency, with 25-30% of type 1 diabetics and 13.5-47.7% of type 2 diabetics having magnesium deficiency (Rondon 2010). In rat models of diabetes, administration of oral magnesium or a magnesium-releasing compound helped protect nerves from diabetic neuropathy (Hosseini 2010; Rondon 2010). A clinical trial also found that 500 mg of oral magnesium supplementation daily for 5 years slowed the progression of diabetic neuropathy in humans (De Leeuw 2004). Zinc has also shown promise as a treatment for diabetic neuropathy. Clinical studies have found that zinc supplementation helps improve glycemic control and also reduces the severity of diabetic neuropathy (Jayawardena 2012; Gupta 1998; Hayee 2005). Finally, a clinical study found that supplementation with micronutrients, including zinc and magnesium, together with vitamins C and E, with or without vitamins from the B group, for 4 months improved signs of diabetic neuropathy (Farvid 2011).

Omega-3 fatty acids

Omega-3 fatty acids have historically been studied for their effects on vascular disease, as diets high in omega-3 fatty acids are associated with a lower risk of heart disease. While data from clinical trials on the benefits of omega-3 fatty acids specifically in the context of diabetic neuropathy is lacking, several animal models of diabetic neuropathy have suggested a potential role for these important fats (De Caterina 2007). One theory is that diabetic neuropathy is associated with lower levels of omega-3 fatty acids in the membranes of affected nerves. Two different studies on animal models of diabetic neuropathy found that supplementation with omega-3 fatty acids improved signs of diabetic neuropathy (Gerbi 1999; Coste 2003).

Curcumin

Curcumin, a yellow pigment found in the plant Curcuma longa, is a major component of turmeric (Sharma 2006). Curcumin possesses anti-inflammatory properties (Joshi 2013). Evidence suggests that curcumin may modulate pain sensations via decreasing levels of a free radical called nitric oxide and suppressing the inflammatory mediator TNF-α (Sharma 2006). As a result, it may interfere with pain signaling from nerves damaged by diabetic neuropathy as well as prevent oxidative damage to nerves (Lakshmanan 2011).

The main evidence for the use of curcumin in diabetic neuropathy stems from preclinical studies. In an animal model of diabetic neuropathy, curcumin has been found to reduce oxidative damage in the nerves from the central and peripheral nervous systems (Acar 2012; Lakshmanan 2011). Curcumin administration also reduced cell death in animal models of diabetic neuropathy (Cao 2010; Lakshmanan 2011). Additional studies have found that curcumin reduced inflammation and sensitivity to pain in animal models of this disease (Sharma 2007; Sharma 2006; Kulkarni 2010; Attia 2012; Li 2013).

Vitamin D

Vitamin D deficiency was reported to be an independent risk factor for the development of diabetic neuropathy in peripheral nerves (Shehab 2012), and supplementation may be helpful for some diabetics with neuropathy. Vitamin D deficiency is present in people with both type 1 and type 2 diabetes, and it is more common in diabetics who have significant symptoms of neuropathy and reduced pain threshold (Bell 2012). A study that enrolled adults with diabetes reported that vitamin D insufficiency, defined as levels below 30 ng/mL, is associated with worse self-reported diabetic neuropathy symptoms, and this association persisted even after adjustments were made for several variables, such as obesity or diabetes duration and control (Soderstrom 2012). Two different papers have been published on the effects of vitamin D supplementation in people with diabetic neuropathy and vitamin D deficiency. One study on 51 patients with type 2 diabetes found that vitamin D supplementation reduced reported pain levels by almost 50% and suggested that vitamin D could be used as an “analgesic” in patients with pain caused by diabetic neuropathy (Lee 2008). The second is a case report of a patient with vitamin D deficiency and diabetic neuropathy that was severe enough to require use of narcotic pain medications to control his symptoms. This individual gained significant pain relief from vitamin D supplementation, suggesting that taking vitamin D may provide substantial relief from diabetic neuropathy symptoms (Bell 2012). Life Extension suggests that most people strive to maintain 25-hydroxyvitamin D levels of 50 – 80 ng/mL.

Resveratrol and Grape Seed Extract

Resveratrol is a natural phytochemical found in grapes, red wine, and Japanese knotweed. In an animal model of diabetes, resveratrol was shown to protect against neuropathy as a result of its ability to inhibit inflammation as well as reduce oxidative stress and DNA damage (Kumar 2007; Kumar 2010). In another preclinical study, resveratrol was found to decrease sensitivity to pain when combined with insulin (Sharma 2007).

Compounds derived from grape seed called proanthocyanidins were shown, in an animal model of diabetes, to improve the speed of conduction in motor nerves and modulate pain sensation; they also decreased the loss of the protective sheath known as myelin, which surrounds nerves. In addition, they decreased the production of AGEs, which suggests they also decreased the oxidative damage to the nerves that occurs as part of diabetic neuropathy (Cui 2008).