Aim of this study is to evaluate safety and efficacy of transcutaneous frequency modulated electromagnetic neural stimulation (FREMS) to treat symptomatic peripheral neuropathy in patients with diabetes mellitus.

Diabetic neuropathy is a common and potentially disabling complication of patients with type 1 or type 2 diabetes due to the damage of peripheral nerves caused by chronic hyperglycemia. The most common clinical signs and symptoms of diabetic neuropathy include numbness, diminished sensation and painful symptoms, such as burning, pins and needles, intolerable pain and hyperaesthesia of the lower extremities.

Different classes of drugs, such as analgesics, antidepressants and anti-epileptics are variably efficacious in pain relief, but are unfortunately unable to revert the natural history of the disease.

A wide range of electrotherapies have been proposed for the non-pharmacological treatment of diabetic neuropathy. The rationale of using electric or magnetic stimulation is the potential enhancement of microcirculation and endoneural blood flow, possibly counteracting the nerve ischemic damage, together with other yet poorly understood mechanisms, such as masking pain by interfering with pain gate control.

A number of studies have reported the efficacy of different electrotherapies, such as transcutaneous electrical nerve stimulation (TENS), pulsed-dose electrical stimulation, peripheral nerve, nerve root, spinal cord, deep brain and epidural motor cortex stimulations, pulsed (electro-)magnetic fields and static magnetic fields, high-frequency external muscle stimulation, high-tone external muscle stimulation and external muscle stimulation. However, of all these electrotherapies, only TENS is currently recommended as a treatment for painful diabetic neuropathy by the American Academy of Neurology.

Recently, a novel transcutaneous frequency-modulated electromagnetic neural stimulation (also named as Frequency Rhythmic Electrical Modulation System, FREMS), has been developed. FREMS consists of a sequence of modulated electrical stimuli that varies automatically in terms of pulse frequency, duration and voltage amplitude. FREMS was tested in a pilot randomized, cross-over study, and reduced diabetic neuropathy pain and ameliorated the sensory tactile and vibration perception threshold and motor nerve conduction velocity compared to a sham treatment.

The aim of this study was to test the efficacy and safety of FREMS in a multicentre, randomized, double-blind, placebo-controlled study enrolling a large population with symptomatic diabetic polyneuropathy, with repeated treatment sessions and a post-treatment follow-up of adequate length.

Inclusion Criteria:

• Type 1 or Type 2 diabetes
• Diabetes duration of > 1 year
• Age: 18 to 75 years
• Symptomatic neuropathy
• Abnormal amplitude, latency or conduction velocity in at least one motor nerve (Tibial or Peroneal) or in the Sural Nerve
• A measurable Sural Nerve conduction velocity
• Stable glycemic control in the last 3 months, HbA1C < 11%
• MDNS score > 7
• Stable dose of analgesic medications, if any, in the month prior enrollment

Exclusion Criteria:

• Previous treatment with TENS or other electrotherapy
• Motor or Sensitive nerve conduction velocity < 30 non recordable/evocable
• Unstable glycemic control during last 3 months
• Pregnancy
• Implanted pacemaker or defibrillator or neurostimulator
• Cancer diagnosed in the last 5 years
• Psychological or psychiatric disorders that in the Investigator's opinion may interfere with patient's compliance to study procedures
• Active foot ulcer and/or major lower limb amputation
• Diabetic mononeuropathy
• Severe peripheral artery disease (Leriche Fontaine scale grade 3 and 4)
• Ankle-brachial index (ABI) < 0.7
• Uremic neuropathy or end-stage renal disease
• Toxic neuropathies
• Severe hepatic disease
• Alcohol consumption ≥ 40 g/day or 30 units/week