Pharmacologic Treatment Options To Prevent Complications

The cornerstone of pharmacologic interventions to prevent complications of diabetic peripheral neuropathy is medications and strategies that improve glucose control.⁸ Key pharmacologic interventions that address comorbid conditions in patients with diabetes are statins and antihypertensives. These agents may also contribute to preventing diabetic peripheral neuropathy complications,⁹ since co-existing peripheral vascular disease can contribute to long-term diabetic complications, such as foot ulcerations.¹⁰ Although diabetic peripheral neuropathy is not an outcome in studies addressing these comorbid conditions, they may be described as important comorbidities in studies of glucose control that report on diabetic neuropathy outcomes.

Nonpharmacologic Treatment Options To Prevent Complications

These interventions include non-pharmacologic glucose control interventions, such as diet and exercise, and interventions to prevent specific complications, such as foot care for prevention of foot ulcers, as well as exercise and balance training for the prevention of falls.

Pharmacologic Treatment Options To Improve Symptoms

A variety of pharmacological approaches has been evaluated to reduce pain and improve health-related quality of life through a number of mechanisms. These include drugs with direct impact on neurotransmitters and inhibitory pathways or drugs that bind to opioid receptors. Several medications are Food And Drug Administration ( FDA) approved for diabetic peripheral neuropathy (e.g., pregabalin) or other types of neuropathy (e.g., gabapentin, lidocaine patches for herpes zoster), but most are approved for other indications (e.g., depression, seizure disorders) and evaluated and used off-label for painful diabetic peripheral neuropathy. For diabetic peripheral neuropathy, pain is the most commonly studied symptom in the literature, although other symptoms, such as paresthesia, that are less commonly addressed in trials are also important to patients.

Nonpharmacologic Treatment Options To Improve Symptoms

These interventions also focus mainly on treating pain. Although there is less evidence in this area, modalities that have been evaluated specifically for diabetic peripheral neuropathy and addressed in previous, reviews include acupuncture, physical therapy and exercise, electrical stimulation, and surgical decompression.

Prevention of Complications (Foot Ulcers, Falls, and Perceived Fall Risk)

For pharmacologic and lifestyle interventions, prior reviews have mainly addressed medications for glucose control [which have been evaluated in multiple reviews, including recent and ongoing Evidence-based Practice Center (EPC) reviews on oral diabetes medications which have generally not evaluated neuropathy as an outcome], ^11–13 lifestyle interventions, and a variety of quality improvement strategies (such as care management) previously included in the EPC review Closing the Quality Gap Series.¹⁴ A recent Cochrane review focused on the prevention of diabetic peripheral neuropathy included 17 randomized controlled trials.¹⁵ The review reported a significantly reduced risk of developing clinical polyneuropathy among patients with type 1 diabetes with intensive glucose control after five years of followup (annualized risk difference −1.84%), but a non-significantly reduced risk of −0.58 percent (95% confidence interval [CI], 0.01 to −1.17) in patients with type 2 diabetes and intensive glucose control. This review is currently being updated.

For nonpharmacologic interventions, some systematic reviews have addressed specific interventions, such as exercise training or improving footwear.^{16, 17} The International Working Group on the Diabetic Foot (IWGDF) conducted a systematic review to investigate the effectiveness of interventions (i.e., care intervention, self-management intervention, medical intervention) to prevent first and recurrent foot ulcers or amputation in persons with diabetes who are at-risk for complications.¹⁸ This review found moderate evidence supporting the home-monitoring of foot skin temperatures with subsequent preventative actions and the use of therapeutic footwear with a demonstrated pressure-relieving effect consistently worn by the patient. There was some evidence to suggest that prevention of a recurrent foot ulcer by integrated foot care is effective. Surgical interventions can be effective in selected patients, but the evidence is limited.

A variety of pharmacological and non-pharmacological approaches have been evaluated for preventing complications of diabetic peripheral neuropathy. However, complications other than foot ulcers and amputations have not been comprehensively addressed in recent reviews or guidelines.

Treatment of Symptoms (Pain, Paresthesia, Numbness)

Treatments for diabetic peripheral neuropathy symptoms were last reviewed comprehensively by an American Association of Neuromuscular and Electrodiagnostic Medicine, American Academy of Neurology, and American Academy of Physical Medicine & Rehabilitation systematic review and guideline, published in 2011, that reviewed literature through 2008. This review addressed a variety of issues with treatment but focused mainly on pharmacotherapy and the outcome of pain. The guideline recommended only pregabalin as an effective treatment and recommended several other antidepressants and anticonvulsants, tramadol, and capsaicin, as well as opioids, as probably effective. For non-pharmacological interventions, only percutaneous electrical nerve stimulation was recommended as “should be considered”.

Since the completion of this review and guideline, new trials have been conducted on the drugs evaluated in this review and related medications. One additional agent has been FDA-approved for treatment of painful neuropathy: the high-dose capsaicin patch.

Many newer reviews focusing on pharmacologic treatment of painful neuropathy have reported on effectiveness for a number of agents, but not for diabetic peripheral neuropathy specifically, or addressed only certain drug classes or specific drugs.^19–24 The most recently published review (published in February 2015), developed by the NeuPSIG (Special Interest Group on Neuropathic Pain of the International Association for the Study of Pain) to update their clinical recommendations, addressed all causes of peripheral neuropathy and recommended a number of agents.²² The review assessed a broad range of interventions as moderate- to high-quality evidence, including serotonin-norepinephrine reuptake inhibitors (specifically, duloxetine) and gabapentin. Two comprehensive systematic reviews focusing solely on pharmacologic interventions for painful diabetic peripheral neuropathy were published in 2014,^2,,25 but these reviews focused only on pain, did not synthesize evidence on other symptoms (numbness and paresthesia), health-related quality of life or dropouts due to adverse effects, and did not search for unpublished studies, which are common in this area. No recent reviews have comprehensively covered nonpharmacologic interventions.