Frequency-modulated electromagnetic neural stimulation (FREMS) as a treatment for symptomatic diabetic neuropathy: results from a double-blind, randomised, multicentre, long-term, placebo-controlled clinical trial

• Published in: Diabetologia Vol. 56; no. 3; pp. 467 - 475
• Main Authors: Bosi, E., Bax, G., Scionti, L., Spallone, V., Tesfaye, S., Valensi, P., Ziegler, D.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-03-2013; Springer; Springer Nature B.V
• Subjects: Adolescent; Adult; Aged; Biological and medical sciences; Clinical trials; Cranial nerves. Spinal roots. Peripheral nerves. Autonomic nervous system. Gustation. Olfaction; Diabetes; Diabetes. Impaired glucose tolerance; Diabetic Neuropathies - therapy; Diabetic neuropathy; Double-Blind Method; Drug dosages; Electromagnetic Fields; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Human Physiology; Humans; Internal Medicine; Kinases; Magnetic Field Therapy - methods; Magnetic fields; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Middle Aged; Nervous system (semeiology, syndromes); Neurology; Pain; Transcutaneous electrical nerve stimulation-TENS; Young Adult; United States > US; Italy; Michigan; Electrical stimulation; Diabetic neuropathy; Neurostimulation therapy; Randomised clinical trial; Nerve conduction studies; Neuropathic pain; Endocrinopathy; Nervous system diseases; Diabetes mellitus; Electrical stimulus; Neuropathy; Long term; Nerve conduction; Pain; Treatment; Clinical trial; Neuralgia; Neurological disorder
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-012-2795-7

Aims/hypothesis
The aim was to evaluate the efficacy and safety of transcutaneous frequency-modulated electromagnetic neural stimulation (frequency rhythmic electrical modulation system, FREMS) as a treatment for symptomatic peripheral neuropathy in patients with diabetes mellitus.
Methods
This was a double-blind, randomised, multicentre, parallel-group study of three series, each of ten treatment sessions of FREMS or placebo administered within 3 weeks, 3 months apart, with an overall follow-up of about 51 weeks. The primary endpoint was the change in nerve conduction velocity (NCV) of deep peroneal, tibial and sural nerves. Secondary endpoints included the effects of treatment on pain, tactile, thermal and vibration sensations. Patients eligible to participate were aged 18–75 years with diabetes for ≥1 year, HbA
1c
<11.0% (97 mmol/mol), with symptomatic diabetic polyneuropathy at the lower extremities (i.e. abnormal amplitude, latency or NCV of either tibial, deep peroneal or sural nerve, but with an evocable potential and measurable NCV of the sural nerve), a Michigan Diabetes Neuropathy Score ≥7 and on a stable dose of medications for diabetic neuropathy in the month prior to enrolment. Data were collected in an outpatient setting. Participants were allocated to the FREMS or placebo arm (1:1 ratio) according to a sequence generated by a computer random number generator, without block or stratification factors. Investigators digitised patients’ date of birth and site number into an interactive voice recording system to obtain the assigned treatment. Participants, investigators conducting the trial, or people assessing the outcomes were blinded to group assignment.
Results
Patients (
n =
 110) with symptomatic neuropathy were randomised to FREMS (
n =
 54) or placebo (
n =
 56). In the intention-to-treat population (50 FREMS, 51 placebo), changes in NCV of the three examined nerves were not different between FREMS and placebo (deep peroneal [means ± SE]: 0.74 ± 0.71 vs 0.06 ± 1.38 m/s; tibial: 2.08 ± 0.84 vs 0.61 ± 0.43 m/s; and sural: 0.80 ± 1.08 vs −0.91 ± 1.13 m/s; FREMS vs placebo, respectively). FREMS induced a significant reduction in day and night pain as measured by a visual analogue scale immediately after each treatment session, although this beneficial effect was no longer measurable 3 months after treatment. Compared with the placebo group, in the FREMS group the cold sensation threshold was significantly improved, while non-significant differences were observed in the vibration and warm sensation thresholds. No relevant side effects were recorded during the study.
Conclusions/interpretation
FREMS proved to be a safe treatment for symptomatic diabetic neuropathy, with immediate, although transient, reduction in pain, and no effect on NCV.
Trial registration
ClinicalTrials.gov NCT01628627
Funding
The clinical trial was sponsored by Lorenz Biotech (Medolla, Italy), lately Lorenz Lifetech (Ozzano dell’Emilia, Italy).