“Every nerve that can thrill with pleasure, can also agonize with pain.”
– Horace Mann

Diabetic Peripheral Neuropathy (DPN)

Peripheral neuropathy is characterized by diffuse damage to the peripheral nerve fibers. The most common cause of peripheral neuropathy is diabetes, and 30–90% of patients with diabetes have peripheral neuropathy. DPN can be associated with significant impairment of quality of life, causing sleep disturbances, anxiety and interference with physical functioning. It is important to understand means to prevent and treat DPN.

 

It is recommended to first read the following sections to become familiarized with some of the terms and concepts related here:

 

Education – Pain

Neuropathic (Nerve) Pain

Neurobiology of Pain

 

see also:

Central Sensitization

Opioids

Neurobiology of Opioids

Opioid Tolerance

Opioid Induced Hyperalgesia

Post-Mastectomy Pain

 

Medications for Nerve Pain:

Gabapentin (Neurontin) & Pregabalin (Lyrica)

Palmitoylethanolamide (PEA)

Dextromethorphan (DXM)

 

For specific agents used in the treatment of neuropathic pain, see below.

 

 

Definitions and Terms Related to Pain


Key to Links:

Grey text – handout

Red text – another page on this website

Blue text – Journal publication

 

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Diabetic Peripheral Neuropathy (DPN)

Diabetic sensorimotor polyneuropathy (DSPN) is the most common type of diabetic neuropathy and is characterized by symmetric numbness and tingling in the hands and feet. Additionally, 16–34% of patients with diabetes report painful symptoms in this distribution, called painful diabetic neuropathy (PDN).  The most recent (2011) National Diabetes Fact Sheet estimates the total of diagnosed and undiagnosed diabetes cases in the United States is approaching 25 million, and another 79 million are prediabetic. Of the diabetes patients, 60-70% suffer from mild to severe neuropathy and the prevalence is greater in type 2 diabetes and women.

 

Patients report intermittent or continuous symptoms of pain described as burning, stabbing, tingling, numb, hot, cold or itching in a distal-to-proximal ‘glove-and-stock- ing’ distribution, usually beginning in the feet. The pain is typically symmetrical and worse at night. Abnormal sensory perception, such as reduced or heightened perception of hot, cold, touch or pin-prick sensation, or allodynia, may be experienced. Those suffering from DPN are at significantly higher risk for development of foot ulceration which frequently leads to infection and minor or major limb amputation.

 

Management of Diabetic Peripheral Neuropathy

The prevention and management of DPN is primarily based in the treatment of the underlying diabetes and the control of blood sugar levels since the development of DPN is largely related to nerve damage related to hyperglycemia (elevated levels of blood sugar). As such, the management of diabetes is referred to other sites and this section will be directed towards the treatment of the pain associated with DPN.

 

The pain of DPN is nerve pain or “neuropathic” pain. An extensive review of the medications and supplements useful for treating neuropathic pain are covered elsewhere, See Neuropathic (Nerve) Pain. This section will focus on treatment options specifically directed at DPN pain.

 

The Neurobiology of Diabetic Peripheral Neuropathy

 

Nerve Swelling and Oxidative Stress

Current thinking of the development of DPN proposes that changes related to hyperglycemia result in edema and swelling of nerves, contributing to damage to the nerves along with breakdown in function. In addition, hyperglycemia overpowers cellular mitochondria, impairing their energy production and hampering their production of antioxidants. This results in oxidative stress and further damage and swelling to nerves due to increased exposure to elevated levels of free radicals (reactive oxygen and nitrogen species).

See:

Antioxidants and Oxidative Stress

Mitochondrial Dysfunction

 

Nerve Entrapment as a Contributing Factor in DPN

While DPN is a disease of small nerve fibers, recent research has identified an additional potential contribution to DPN-related nerve dysfunction from large nerve entrapments. Large nerve function can be compromised as a result of nerve entrapment and compression as they pass through anatomically restricted fibrous or bony channels. This is commonly seen in carpal tunnel syndrome, for example, when median nerve dysfunction occurs as a result of compression by the carpal bones in the wrist resulting in pain, numbness and weakness in the hand. Other examples include spinal radiculopathies such as sciatica and other entrapment neuropathies such as ulnar nerve entrapment at the elbow, peroneal  nerve entrapment in the lower leg and tarsal nerve entrapment in the foot. 


As a result of diabetes-induced nerve swelling, it has been shown that in many cases of DPN there is a coexisting, often subclinical, impairment of a nerve function that is a result of large nerve entrapment and  compression. When these large nerve entrapments are identified and surgically decompressed, the symptoms of DPN thought to be solely related to small fiber dysfunction sometimes can be reversed. In fact, decompression surgery may relieve not just pain but restore sensation and provide significant protection against many serious diabetic foot complications resulting in fewer infections and amputations. While DPN is usually considered an irreversible, progressive process, newer understanding of these contributing factors to the development of DPN now show that some DPN symptoms and complications are potentially partially reversible or preventable.

 

Treatment of DPN

Because in DPN, nerves are vulnerable to dysfunction from both external compression forces from entrapment and internal forces from swelling, mitochondrial dysfunction and neuro-inflammation, effective treatment must be directed at all.

 

Nerve Entrapment

In the presence of lower extremity symptoms of DPN, one must evaluate anatomically restricted fibro-osseous locations for the presence of large nerve entrapments of the lower extremities that may contribute to the DPN symptoms, including around the neck of the fibula, tarsal tunnel, and medial and lateral plantar tunnels. In the presence of upper extremity symptoms of DPN, anatomically restricted fibro-osseous locations, such as the carpal tunnel and cubital tunnel should be evaluated.

 

When concern is present for possible nerve entrapment, referral to an appropriate surgeon is mandated for further assessment.

 

Oxidative Stress and Mitochondrial Dysfunction

Treatment of DPN must be multi-modal, incorporating dietary and medical management of not just hyperglycemia, but also of oxidative stress, mitochondrial dysfunction and neuro-inflammation. Agents that have evidence for effectiveness in treating DPN through their antioxidant  benefit and/or mitochondrial support include:

CoQ10

Alpha Lipoic acid

Acetyl L-Carnitine

NRF2 activators including: Curcumin and Quercetin

 

Neuro-inflammation

Agents that have evidence for effectiveness in treating DPN related to neuro-inflammation include:

 

Palmitoylethanolamide (PEA)

Other

NMDA Antagonists – Dextromethorphan

While informtion is very limited regarding the benefit of dextromethorphan in DPN, one study showed that many patients with painful DPN experience pain relief from high-dose dextromethorphan (100-960mg/day in four divided doses). Dextromethorphan reduced pain by 35% compared with placebo. The “number needed to treat” was 3.2, comparable to gabapentin, tricyclics, tramadol, and opioids in neuropathic pain. The “number needed to treat” is the number of patients that would need to be given a treatment for one of them to achieve 50% pain relief, who would not have achieved it with a control.

 

In contrast to opioids and tricyclic antidepressants, dextromethorphan is “virtually devoid” of potential for fatal overdose or organ toxicity. Dextromethorphan is primarily metabolized by the CYP 2D6 liver enzyme, which is associated with multiple genetic variants that cause great variability in dose requirements. Approximately 6% of whites are slow metabolizers of CYP 2D6 and may require longer dosing intervals to avoid side effects. Use of high dose dextromethorphan may cause severe sedation or dissociative reactions, especially in combination with opioids or other sedative medications.

 

Vitamin B12

Vitamin B12 deficiency and folate deficiency are associated with increased oxidative stress secondary to low levels of glutathione, decreased total antioxidant activity and increased levels of homocysteine. Homocysteine, when elevated, results in blood vessel damage with decreased blood flow to peripheral nerves due to blood clot formation within the blood supply to the nerve and increases risk of DPN. Metformin, the most common drug used for the treatment of diabetes, is associated with worsening of DPN due to the inhibition of folic acid and B12 absorption in the gut. Vitamin B12 deficiency is common in the elderly and common in 62 percent of patients with DPN. Vitamin B12 supplementation can be helpful in the reversal of this deficiency and improvement of DPN.

 

Vitamin D

Vitamin D has been shown to play a role in the treatment of DPN pain. Studies have demonstrated that the pain of DPN is improved with Vitamin D supplementation in those patients who are Vitamin D deficient (blood level <30 ng/ml) but it is not clear if Vitamin D supplementation is effective in patients with blood level >30 ng/ml. While there is controversy regarding the optimal level of Vitamin D, it is often recommended that benefits, including pain, are obtained when blood levels are maintained between 50-80ng/ml.

 

The mechanism as to how Vitamin D affects pain is not understood. However, there does appear to be a relationship between elevated blood levels of pro-inflammatory cytokines (IL-8, IFN-γ, IL-8, and TNF-α) and reduced blood levels of Vitamin D, suggesting that Vitamin D may have an anti-inflammatory benefit via regulatory effects on cytokine production.

See Vitamin D

 

Resources:

  1. Association of Extremity Nerve Surgeons – Brochure

 

References:

 

DPN – Overviews

  1. diabetic-neuropathic-pain-physiopathology-and-treatment-2015
  2. pharmacological-treatment-of-diabetic-peripheral-neuropathy-2015
  3. metabolic-correction-in-the-management-of-diabetic-peripheral-neuropathy-improving-clinical-results-beyond-symptom-control-2011
  4. painful-diabetic-neuropathy-an-update-2011
  5. diabetic-neuropathy-mechanisms-to-management – 2008
  6. oxidative-stress-a-cause-and-therapeutic-target-of-diabetic-complications-2010
  7. Comparison of Amitriptyline, Duloxetine, and Pregabalin in DPN
  8. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose-response trials. – PubMed – NCBI
  9. effect-of-cosmos-caudatus-ulam-raja-supplementation-in-patients-with-type-2-diabetes-2016
  10. Biologic Basis of Nerve Decompression Surgery for Focal Entrapments in Diabetic Peripheral Neuropathy – 2014



DPN – Alpa Lipoic Acid

  1. oxidative-stress-a-cause-and-therapeutic-target-of-diabetic-complications-2010
  2. A systematic review and meta-analysis of a-lipoic acid in the treatment of diabetic peripheral neuropathy
  3. switching-from-pathogenetic-treatment-with-alpha-lipoic-acid-to-gabapentin-and-other-analgesics-in-painful-diabetic-neuropathy-2009
  4. alpha-lipoic-acid-supplementation-and-diabetes
  5. critical-appraisal-of-the-use-of-alpha-lipoic-acid-thioctic-acid-in-the-treatment-of-symptomatic-diabetic-polyneuropathy-2011
  6. efficacy-and-safety-of-antioxidant-treatment-with-lipoic-acid-over-4-years-in-diabetic-polyneuropathy-the-nathan-1-trial
  7. alpha-lipoic-acid-may-improve-symptomatic-diabetic-polyneuropathy-pubmed-ncbi
  8. Oral Treatment With Alpha-Lipoic Acid Improves Symptomatic Diabetic Polyneuropathy
  9. Thioctic acid for patients with symptomatic… [Treat Endocrinol. 2004] – PubMed – NCBI
  10. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study) – 1995
  11. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid- a meta-analysis – 2004

 

DPN – Acetyl-L-Carnitine

  1. Carnitine (L-carnitine) | University of Maryland Medical Center
  2. Acetyl-L-Carnitine in the Treatment of Peripheral Neuropathic Pain – A Systematic Review and Meta-Analysis of Randomized Controlled Trials
  3. Role of acetyl-L-carnitine in the treatment… [Ann Pharmacother. 2008] – PubMed – NCBI

 

DPN – Botulism Toxin (Botox)

  1. Botulinum Toxin Type A for the Treatment of Neuropathic Pain in Neuro-Rehabilitation – 2015
  2. [Botulinum toxin and painful peripheral neuropathies: what should be expected?]. – PubMed – NCBI
  3. Botulinum Toxin Treatment of Neuropathic Pain – 2016
  4. Botulinum Toxin Type A—A Modulator of Spinal Neuron–Glia Interactions under Neuropathic Pain Conditions – 2018


 DPN – Dextromethorphan

  1. Dextromethorphan_and_Memantine_in_Painful_Diabetic – 2002

 

DPN – Lipoic Acid

  1. Alpha-lipoic acid | University of Maryland Medical Center
  2. A systematic review and meta-analysis of a-lipoic acid in the treatment of diabetic peripheral neuropathy
  3. Oral Treatment With Alpha-Lipoic Acid Improves Symptomatic Diabetic Polyneuropathy
  4. Efficacy and Safety of Antioxidant Treatment With -Lipoic Acid Over 4 Years in Diabetic Polyneuropathy: The NATHAN 1 trial

 

 

DPN – Nerve Entrapment

  1. Biologic Basis of Nerve Decompression Surgery for Focal Entrapments in Diabetic Peripheral Neuropathy – 2014

 

Tarsal Tunnel Syndrome

You Tube Videos

  1. Tarsal Tunnel Syndrome Overview
  2. Triple Compression Stress Test for Tarsal  Tunnel Syndrome
  3. Dorsiflexion Eversion Test for Tarsal Tunnel Syndrome

DPN – Oxidative Stress

  1. oxidative-stress-a-cause-and-therapeutic-target-of-diabetic-complications-2010

 

DPN – Vitamin B12

  1. Why You Should Consider The Use Of Supplements In The Management Of Diabetic Neuropathy | Podiatry Today
  2. Safety and efficacy of intravenous ultra-high dose methylcobalamin treatment for peripheral neuropathy
  3. Combined Therapy of Diabetic Peripheral Neuropathy with Breviscapine and Mecobalamin – A Systematic Review and a Meta-Analysis of Chinese Studies
  4. Metanx Alleviates Multiple Manifestations of Peripheral Neuropathy and Increases Intraepidermal Nerve Fiber Density in Zucker Diabetic Fatty Rats
  5. Vitamin B for treating peripheral neuropathy. – PubMed – NCBI

 

DPN – Vitamin D

  1. Vitamin D for the treatment of painful diabetic neuropathy – 2016
  2. Reversal of the Symptoms of Diabetic Neuropathy through Correction of Vitamin D Deficiency in a Type 1 Diabetic Patient – 2012
  3. Association of self-reported symptoms with serum levels of vitamin D and multivariate cytokine profile in healthy women – 2017
  4. Improvement of Pain, Sleep, and Quality of Life in Chronic Pain Patients With Vitamin D Supplementation – 2012
  5. Improvement in Neuropathy Specific Quality of Life in Patients with Diabetes after Vitamin D Supplementation – 2017

Emphasis on Education

 

Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.

 

For medical-legal reasons, access to these links is limited to patients enrolled in an Accurate Clinic medical program.

 

Should you wish more information regarding any of the subjects listed – or not listed –  here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.

 

For more information, please contact Accurate Clinic.

 

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