Diabetic Peripheral Neuropathy - treatment

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Part 3 - Treatment of diabetic peripheral neuropathy

Objective -

Diabetic peripheral neuropathy is the most common complication of both type 1 (T2DM) and type 2 (T2DM) diabetes. Diabetes causes a number of different neuropathic complications to include sympathetic and parasympathetic autonomic dysfunction. This blog post focuses on the treatment of diabetic peripheral. This post is intended to act as a guideline for lower extremity health practitioners including podiatrists, primary care physicians, NP’s and PA’s. The objective of this post is to create a framework for a meaningful patient treatment of patients with diabetic peripheral neuropathy.

Click this link to print patient guidelines for diabetic foot care.
Click this link to print patient guidelines for treatment of diabetic peripheral neuropathy.

Treatment of diabetic peripheral neuropathy requires first and foremost management and control of elevated blood sugars. But to effectively treat neuropathic pain that is due to diabetes, the lower extremity health practitioner needs to have an understanding of the pathophysiology of diabetic peripheral neuropathy and an ability to blend treatment options for each patient. Treatment of diabetic peripheral neuropathy can be broken into four categories of care. Those four categories are -

Education
Treatment of underlying pathophysiology
Treatment of sleep deprivation
Treatment of neuropathic pain

Education

Each and every patient that you treat for diabetic peripheral neuropathy (DPN) is going to go on their own personal voyage that involves discovery, success, perseverance and in some cases, disappointment. Your role as a diabetes educator is a very important one in that you not only help each patient understand more about their diabetes and DPN, but you also play a significant role in saving limbs and lives.

Loss of protective sensation (LOPS) is the single most important contributing factor to diabetic ulcerations and limb loss in diabetic patients. (1) Helping your patients understand the significance of LOPS is the key conversation in diabetes peripheral neuropathy education. As previously discussed in the physical exam of the diabetic neuropathy patient, use of a Weinstein monofilament testing device can help patient actually see the extent of their LOPS. Take the opportunity during your physical exam to share with the patient their extent of LOPS.

Topics to highlight in diabetes peripheral neuropathy education include –

Loss of protective sensation
Daily visual foot checks when socks are put on and when socks are taken off
Diabetic shoe counseling
Building your team of diabetes care providers (primary care, podiatry, etc) and how to access those providers when you have a question or problem
Fall prevention
Treatment of underlying pathophysiology

In part 1 of this three part blog, we briefly discussed the current theories regarding diabetic peripheral neuropathy. What may be the most important key to understanding these theories is that DPN may not be caused by just one theory, but rather DPN is likely due to a combination of these theories in each patient. Where one patient may have more micro vessel disease, another patient may have DPN that is due to hyperlipidemia. Let’s look at each of these theories again and describe some specific treatment plans.

Polyal pathway activity – the polyal (sorbital) pathway was first described in 1966 as a mechanism of cell injury due to hyperglycemia. (2) Aldose reductase is the enzyme in this pathway that is responsible for fructose formation from glucose. In tissues that are not sensitive to insulin (lenses, peripheral nerves and glomerulus), increased levels of aldose reductase results in sorbital levels that cause osmotic cell damage. Therefore, use of aldose reductase inhibitors may help to decrease peripheral nerve cell damage due to DPN.
Lab studies – There are no lab studies that determine levels of sorbital or aldose reductase in tissue.
Treatment recommendations - Natural sources of aldose reductase inhibitors include Indian gooseberry, spinach, cumin seed, fennel seed, basil leaves, lemon, black pepper, orange, curry leaves, cannabis and cinnamon. (3,4,5,6) The source of aldose reductase inhibitor in these foods is luteolin, a flavonoid found within the plants leaves.(7)

Oxidative and nitrosative stress –
A. Oxidative stress – oxidative stress is described in a complex relationship of chemical pathways as both a contributing factor to each of the pathways described here and as an outcome of each of these pathways. Oxidative stress results from the release of free oxygen radicals produced during glycolosis. Free oxygen radicals cause damage that is significant to mitochondria, DNA and cell membranes. (8)
Lab studies – there are no lab test used to monitor oxidative stress.
Treatment recommendations – glutathione 250-500mg/day or alpha lipoic acid 600mg/day have shown anecdotal evidence of improving symptoms of oxidative stress in patients with DPN.(9)

B. Nitrosative stress – Nitric oxide (NO) acts to actively control vasodilatation and prevents thrombosis. Low levels of NO result in vasoconstriction of the blood vessels within the peripheral nerves resulting in altered conductivity of the peripheral nerve.
Lab studies – OTC saliva test strips are available to determine NO levels but produce unreliable results. NO respiratory testing is used to evaluate asthma and is not intended to be used to quantify NO levels that may contribute to vascular disease.
Treatment recommendations – cardiovascular exercise can prompt the formation of nitric oxide in your body while exposure to sunshine can release unavailable NO in the body. (10, 11) Fresh vegetables and food that are high in arginine can be broken down to NO. Those foods include kale, spinach, broccoli, brussel sprouts, beets, legumes, nuts, beans, salmon, chicken, beef, cheese and eggs. (12)

Microvascular changes – Microvascular changes within the peripheral nerve are a significant contributing factor to DPN. Microvascular changes can be caused by hyperlipidemia, oxidative and nitrosative contributing factors. Microvascular nerve disease is significantly affected by hyperglycemia. Microvascular disease is a hallmark of diabetes.(13)
Laboratory testing – there is no definitive test for microvascular disease in DPN.
Treatment recommendations – Control of hyperglycemia is the most important tool in preventing microvascular disease in DPN. Type 2 diabetes typically occurs in the setting of the metabolic syndrome, which also includes abdominal obesity, hypertension, hyperlipidemia, and increased coagulability. Weight control, management of hypertension and control of hyperlipidemia is essential in the prevention of microvascular disease in diabetic patients.

Channels Spouting – damage to the nerve ending results in dysthesia and hyperexcitability of the peripheral nerve particularly in the dermis. Damage from hyperglycemia results in changes of ion expression of both sodium channels and calcium channels. The up-regulation of sodium channels has been described as the primary cause of DPN. (14,15,16,17,18)
Laboratory testing – there is no clinical test available to assess channels sprouting.
Treatment recommendations – active management of blood sugar levels is the most effective way to prevent and treat DPN secondary to channels sprouting.

Microglial activation – glia comprises a group of cells in the central nervous system that maintain homeostasis, form myelin and provide support for cells of both the central and peripheral nervous systems. Stimulation of the microglial cells by diabetes results in compromised management of the cells of the peripheral nervous system, particularly the sodium ion exchange.(19,20)
Laboratory testing – there is no current test to identify microglia activation.
Treatment recommendations- aggressive management of blood glucose levels.

Central sensitization – the central nervous system is known to respond to DPN in a number of ways that create increased sensitivity, thereby resulting in increased peripheral nerve sensitivity. These complex chemical pathways include spinal N-Methyl-D-aspartate (NMDA) receptor expression and activation of GABA_B receptors resulting in inhibition of NMDA receptor activity. (21,22,23)
Laboratory testing – there is no direct testing for central sensitization.
Treatment recommendations - aggressive management of blood glucose levels.

Brain plasticity - The ventral posterolateral nucleus (VPL) of the thalamus is the main receiving area of nociceptive stimuli that is processed in the spinal cord. Changes within the thalamus due to DPN change the receptive properties of the brain thereby increasing DPN pain. Multiple chemical pathways are described in brain plasticity and its contribution to DPN pain. (24,25,26)
Laboratory testing – there is no clinical test for brain plasticity.
Treatment recommendations – increased levels of GABA can help with the treatment of brain plasticity.

Treatment of sleep deprivation in diabetic peripheral neuropathy

As I described in part 1 of this three part blog post, DPN can be broken into three stages. Stage three is the stage of DPN that is defined by painful paresthesia when the patient is at rest. When active, the patient is distracted and doesn’t feel his/her neuropathy. But when the patient tries to relax, rest or fall asleep, the symptoms of DPN become obvious and result in sleep deprivation. Disruption of the normal sleep cycle can have significant systemic effects that include cardiac arrhythmias, increased insulin resistance and metabolic syndrome. Additional problems include depression, emotional /psychological changes, loss of employment and safety issues like falling asleep while driving.

Restoration of a normal sleep cycle in patients with DPN can be accomplished by treating the symptoms of DPN, by treating the sleep disorder or a combination of both therapies.

Medications used for treatment of symptoms of diabetic peripheral neuropathy symptoms –

Topical medications

capsaicin cream
CBD cream
lidocaine patches

Anticonvulsants

pregabalin
gabapentin

Antidepressants

duloxetine
venlafaxine
amitriptyline
nortriptyline

Medications used in sleep disorder management –

OTC medications

Melatonin

Rx hypnotic medications

Ambien®, Ambien® CR (zolpidem tartrate)

Dalmane® (flurazepam hydrochloride)

Halcion® (triazolam)

Lunesta® (eszopiclone)

Prosom® (estazolam)

Restoril® (temazepam)

Rozerem® (ramelteon)

Silenor® (doxepin)

Treatment of neuropathic pain in diabetic peripheral neuropathy

We’ll divide the treatment of diabetic neuropathy pain into based on the absence or presence of treatment induced neuropathy in diabetes (TIND). TIND is also known as insulin neuritis.

Diabetic neuropathy pain treatment – (non-TIND)

The first step in treatment of lower extremity pain in diabetic patients is the exclusion of other conditions that may cause pain. The differential diagnosis for lower extremity pain in diabetic patient may include but is not limited to:

lumbo-sacral radiculitis
referred hip or knee pain
secondary arthritis ankle or foot
Charcot arthropathy
fracture or sprain

Once the differential diagnosis excludes these conditions, treatment of neuropathic pain in the non-TIND diabetic patient should include one or more of the following;

Topical medications

capsaicin cream
CBD cream
lidocaine patches

Anticonvulsants

pregabalin
gabapentin

Antidepressants

duloxetine
venlafaxine
amitriptyline
nortriptyline

Diabetic neuropathy pain treatment – (TIND)

Treatment induced neuropathy in diabetes (TIND) results from aggressive management of blood sugars resulting in a 2% point or greater reduction in HbA1c levels in less than 90 days. Improved focus on diabetes care by primary care providers and pressure from insurers for tighter management of diabetes has created a climate of care which we may see an increased prevalence of TIND. TIND is reported to occur in great than 10% of T1DM and T2DM patients at the onset of care. (27,28,29,30) Symptoms include lower extremity autonomic dysfunction and significant lower extremity pain.

Treatment of peripheral neuropathy in patient with suspected TIND is different in light severe but self limiting pain. In addition to the methods of treatment described for the non-TIND diabetic patients, DPN neuropathic pain in patients with TIND need increase intensity of care with use of opioids to control pain. TIND is self limiting with symptoms resolving in 6-12 months from onset.