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Emerging Modalities For Diabetic Peripheral Neuropathy

While glycemic control, lifestyle modifications and pharmacotherapy play key roles in the treatment of distal symmetric sensorimotor polyneuropathy, clinicians may be able to consider other emerging treatment options as well to help patients manage this condition. Accordingly, these authors review recent research on modalities ranging from exercise training and acupuncture to cognitive behavioral therapy and pulsed electromagnetic field therapy.

The majority of people with diabetes will develop peripheral neuropathy during their lifetime.1 Distal symmetric sensorimotor polyneuropathy is the most common form of neuropathy, accounting for up to one-third of all diabetes-related neuropathies diagnosed in the United States.2,3

Distal symmetric sensorimotor polyneuropathy initially affects the hands and feet due to damage to the smaller unmyelinated C fibers that control light touch, pain and temperature sensation.4,5 Then there is a progression of damage to the larger myelinated A delta fibers, which convey vibratory sensation, proprioception and joint position. Advanced distal symmetric sensorimotor polyneuropathy is a precursor to Charcot and is one of the components in the triad of diabetic foot ulceration (DFU) development.

Both neuropathy and diabetic foot ulcers are associated with increased morbidity, mortality and healthcare costs.3,6-8 In addition, approximately half of those with distal symmetric sensorimotor polyneuropathy will have accompanying pain and 90 percent of those with type 2 diabetes have neuropathic pain in comparison to 5 to 10 percent of those with type 1 diabetes.4,5 Patients have described the pain associated with diabetic peripheral neuropathy as burning, lancinating, tingling and shooting, and the pain is often worse at night. Hyperalgesia and allodynia may also be present.2,4 Painful diabetic neuropathy impedes the performance of activities of daily living and is associated with disability, psychosocial impairment and a reduced quality of life.2,4,9

First-line treatment for distal symmetric sensorimotor polyneuropathy is patient education, glycemic control and lifestyle modifications. Neuropathy progression parallels diabetes control. The combination of pro-inflammatory cytokines, oxidative stress factors and toxic metabolic byproducts associated with prolonged exposures to high levels of glucose and abnormal fat levels results in neuropathy by direct nerve injury and indirect injury via neurovascular damage.10 Lifestyle alterations and cardiovascular risk reduction may prove to be useful strategies in retarding disease progression, thereby delaying the onset of neuropathy-related morbidity and mortality.11 The benefits of tight glycemic control, however, tend to be more beneficial for those with type 1 diabetes as opposed to type 2 diabetes.12

Pharmacotherapy is often the next step in treatment of distal symmetric sensorimotor polyneuropathy, particularly when patients are in pain. Duloxetine (Cymbalta, Lilly) and pregabalin (Lyrica, Pfizer) are the only two agents that have U.S. Food and Drug Administration (FDA) approval for the treatment of painful neuropathy. Tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and anticonvulsants are other agents that physicians often prescribe for the treatment of painful distal symmetric sensorimotor polyneuropathy.2,3 Pain scores reportedly improve by 30 to 50 percent with these agents although up to 50 percent of patients may discontinue their use due to adverse side effects.1,3,13 Topical analgesics reportedly have similar effects on pain reduction with less adverse effects but patient adherence with application limits the benefit of using topical analgesics.13 Systemic therapy and topical analgesics, however, only address symptom management and not disease modification.2-4

While some emerging modalities for the treatment of diabetic peripheral neuropathy are for symptom management only, the majority focus on disease modification to prevent or delay distal symmetric sensorimotor polyneuropathy and its associated symptoms by increasing microcirculation to the nerves. These emerging modalities include exercise, physical therapy, cognitive behavioral therapy, acupuncture, electrical stimulation, medical food and cannabis products.14-39

How Exercise Training Can Benefit Patients With Diabetic Neuropathy

Several meta-analyses have reported the benefits of exercise training on improvement of functional capacity, strength and glycemic control independent of weight control, particularly in those with type 2 diabetes. Yoo and colleagues postulate that exercise training can prevent or delay distal symmetric sensorimotor polyneuropathy through various alterations that result in enhanced microvascular flow.15

In a pilot study on the effects of a 16-week program consisting of supervised exercise activity three times per week, Yoo and coworkers reported improvement in walking, normal work, relationships with other people and sleep (four of seven pain interferences items on the validated Brief Pain Inventory Short Form for Diabetic Peripheral Neuropathy).16 Patients attained these improvements despite continued pain and a lack of reduction in glycosylated hemoglobin levels. Adherence was also high with more than 70 percent of participants completing the 16-week study.

In the future, it is necessary to have large randomized controlled trials utilizing validated outcome measures to evaluate the potential long-term benefits of exercise therapy on diabetic peripheral neuropathy.

A Closer Look At The Potential Of Physical Therapy

Intraneural Facilitation™ is a new physical therapy modality in which specific manual holds can improve microvascular flow to targeted nerves and improve diabetic neuropathy and its symptoms.

The first hold is called the facilitation hold, which involves putting the contralateral joint in a maximal loose-pack position that is comfortable for the patient. The patient maintains this position for the entire treatment session. Researchers postulate that this position enlarges the opening at the junction of the artery and the nutrient vessel to the stretched nerve, resulting in shunting blood flow to the neural epineurial capillaries.20 The secondary hold, or mild stretch, then directs this pressurized blood flow into the endoneurial capillaries.

Typical Intraneural Facilitation treatment plans involve 10 to 20 one-hour physical therapy sessions over one to two months. A study of 17 patients who had Intraneural Facilitation treatment reported significant reduction in scores utilizing a modified version of the Total Neuropathy Scale, a validated measure of peripheral nerve function.21 The treatment modality is still in its infancy and currently only Loma Linda University offers it.20

How Effective Is Cognitive Behavioral Therapy For Neuropathy?

Cognitive behavioral therapy is a time-limited, goal-oriented psychological intervention with the goal of teaching patients how to identify and modify dysfunctional thoughts and behaviors. A meta-analysis of randomized controlled trials on cognitive behavioral therapy specific to chronic low back pain has found the modality to be efficacious in pain reduction.22 Other studies have noted the therapy’s effectiveness in teaching people how to manage their diabetes.23,24

In a randomized controlled pilot study of a veteran population with painful diabetic neuropathy, Otis and colleagues noted that study participants who completed an 11-week course of once a week 60-minute cognitive behavioral therapy sessions had a significant reduction in pain interference and intensity scores in comparison to those who had standard treatment.19 More than 60 percent of the participants in the cognitive behavioral therapy group reported at least a 20 percent reduction in pain severity with 25 percent of these study participants reporting a reduction of 50 percent or more. Large randomized controlled trials are necessary in the future to validate the benefit of cognitive behavioral therapy in the treatment of painful distal symmetric sensorimotor polyneuropathy.

What Two Systematic Reviews Reveal About The Use Of Acupuncture In Treating Distal Symmetric Sensorimotor Polyneuropathy

Two systematic reviews, one of which included a meta-analysis, have evaluated the use of acupuncture for the treatment of distal symmetric sensorimotor polyneuropathy.14,25

In a systematic review focused solely on manual acupuncture, Chen and colleagues analyzed 23 studies with a total of 1,649 patients.25 Control groups in the randomized controlled clinical trials analyzed received either mecobalamin, B1, B12, inositol or no treatment. Global symptom improvement occurred in all treatment groups in comparison to control patients. Fourteen of 15 studies also looked at nerve conduction velocity and noted improvement in the treatment group in comparison to the control group.14 The nerves tested varied from study to study, making the benefit of acupuncture on nerve function inconclusive.

In their systematic review, Chen and coworkers also concluded that manual acupuncture may have some beneficial effects.25 However, the authors warned that providers should proceed with caution due to poor methods of randomization, variability in acupuncture protocols, lack of sham-acupuncture intervention and potential publication bias in the included studies.

The second systematic review included peripheral neuropathies of various etiologies although the review did include a meta-analysis of acupuncture treatment for diabetic neuropathy.14 The authors reported a combined odds ratio of 4.23 favoring acupuncture over standard treatment for neuropathy symptom management but the study had the same issues with methodological design.

What You Should Know About Pulsed Electromagnetic Field Therapy

Researchers have reported that electrical stimulation significantly improves symptoms of painful distal symmetric sensorimotor polyneuropathy. However, the small sample sizes in currently published studies and limited treatment duration leave the potential question of long-term benefit unanswered. Many of the devices are also invasive, which can contribute to potential patient reluctance to utilize these modalities.17

Pulsed electromagnetic field therapy is a noninvasive method of electrical stimulation. A randomized controlled trial on the effects of pulsed electromagnetic field therapy found a significant reduction in moderate to severe itchy and burning type pain with active treatment despite only displaying an increasing trend in intraepidermal nerve fiber density at three months.5 The study authors did not assess nerve function and perfusion.

Another randomized, double-blind, sham-controlled study of pulsed electromagnetic field therapy determined that patients tolerated the therapy well and twice daily use was feasible.26 Despite the small sample size and no observed change in intraepidermal nerve fiber density or average reductions in pain intensity scores, improved nerve function was evident in the nerve distribution when physicians applied the treatment pad. The study also noted improved perfusion to the dorsal aspect of the foot. While patients did not have a significant change in pain intensity scores, the active group started with a much higher average pain intensity score than the patients in the sham control group and were also more adherent with device use. This adherence may speak to a potential patient perceived benefit with the use of this modality.

In the future, it is necessary to have large randomized controlled trials with cross comparisons between active and control groups to evaluate pulsed electromagnetic field therapy’s potential long-term benefits in the treatment of diabetic neuropathy.

A Closer Look At The Efficacy Of A Medical Food Product For Treating Neuropathy-Related Symptoms

Deficiency in vitamin B12 is a known causative factor in the development of peripheral neuropathy. Metformin use, particularly in patients with type 2 diabetes, can reduce the serum level of vitamin B12, which may potentiate the development and effects of distal symmetric sensorimotor polyneuropathy.27-33

The FDA deems Metanx (Alfasigma USA) a “medical food.” Metanx is a combination product containing L-methylfolate, pyridoxal 5’-phosphate and methylcobalamin, a form of vitamin B12. While it is not a FDA-approved drug, Metanx does require a prescription for use. Authors propose that the individual ingredients in the product improve the bioavailability of nitric oxide, enhancing perfusion and alleviating paresthesias and dysesthesias in patients with diabetic peripheral neuropathy.34 In an animal study of Metanx use, Shevalye and coworkers reported reduction of several biochemical mechanisms implicated in the development of diabetic peripheral neuropathy.34

The first randomized, placebo-controlled study of Metanx in humans with type 2 diabetes reported significant improvement in neuropathy symptoms at 16 and 24 weeks using the validated Neuropathy Total Symptom Score-6.35 Researchers also noted improvement in diabetic peripheral neuropathy-associated disability at 16 weeks. The mental component of Short Form 36, a validated outcome tool, was also significantly improved. Adverse effects were similar to that reported with placebo at less than 2 percent, the majority of which were a rash and gastrointestinal upset.35,36

Can Cannabis Products Have An Impact For Patients With Diabetic Neuropathy?

Cannabis products are emerging on the market as modalities for the treatment of various chronic pain conditions, including painful distal symmetric sensorimotor polyneuropathy.
Researchers conducted an animal study of extract with a high cannabidiol content, including 64.5% high cannabidiol, 4% tetrahydrocannabinol (THC) and less than 4% percent of other cannabinoids in the treatment of type 1 diabetes-induced neuropathy.37 The authors found that repeated treatment with a dose of 30 mg/kg resulted in significant attenuation of mechanical allodynia and restoration of physiological thermal nociceptive perception.

The first randomized controlled trial studying the use of a cannabis product for painful diabetic neuropathy evaluated the efficacy of Sativex® (GW Pharmaceuticals).38 This product is an oromucosal peppermint-flavored spray that contains a 1:1 ratio of THC and cannabidiol. Study authors reported no difference in pain scores between the active treatment and placebo groups. However, depression was a major confounding variable. Patients with depression had higher baseline pain scores and greater reduction in pain scores whether they were treated with Sativex or placebo.

In a randomized, double-blinded, placebo-controlled crossover study, Wallace and colleagues investigated the efficacy and tolerability of low- (1% THC), medium- (4% THC) and high-dose (7% THC) inhaled vaporized cannabis for the treatment of painful diabetic neuropathy.39 All three doses resulted in a greater reduction in pain intensity in comparison to placebo and the high-dose version resulted in greater pain reduction than the medium and low doses of inhaled vaporized cannabis. However, activities requiring intact attention and speeded processing like driving may be impaired with higher doses.  
Large, high-quality studies are necessary to assess the potential benefit of cannabis products in the treatment of diabetic neuropathy.

In Conclusion

Diabetic peripheral neuropathy is a complex chronic disease that has the potential to exert long-term detrimental effects on the diabetic foot. Common comorbidities arising in the diabetic population contribute to the development and severity of this problem. Along with poor blood sugar control, certain medical therapies for diabetes may contribute to the development of diabetic peripheral neuropathy. Diagnosis is relatively straightforward.

Multiple emerging modalities may benefit patients not only in symptom management but disease modification as well. However, these modalities all require large, high-quality studies to assess their true benefit in the treatment of diabetic neuropathy.

Currently, we favor an individualized team approach emphasizing early recognition, education and optimization of blood sugar levels. This approach combined with close monitoring and preventive measures may decrease the likelihood of serious complications associated with the disease process of diabetic neuropathy.

Dr. Marmolejo is a medical writer based in University Place, Wash.

Dr. Arnold is the Medical Director of Great River Wound and Hyperbaric Medicine Clinic at Great River Medical Center in West Burlington, Iowa.

References

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For further reading, see “Current And Emerging Insights On Treating Diabetic Peripheral Neuropathy” in the March 2013 issue of Podiatry Today.

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Valerie Marmolejo, DPM, and Jonathan F. Arnold, MD, ABPM-UHM, CWS-P
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