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Effectiveness of Frequency-Modulated Electromagnetic Neural Stimulation in the Treatment of Painful Diabetic Neuropathy

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Effectiveness of Frequency-Modulated Electromagnetic Neural Stimulation in the Treatment of Painful Diabetic Neuropathy Diabetologia (2005) 48: 817–823 DOI 10.1007/s00125-005-1734-2 ARTICLE E. Bosi . M. Conti . C. Vermigli . G. Cazzetta . E. Peretti . M. C. Cordoni . G. Galimberti . L. Scionti Effectiveness of frequency-modulated electromagnetic neural stimulation in the treatment of painful diabetic neuropathy Received: 7 December 2004 / Accepted: 23 February 2005 / Published online: 15 April 2005 # Springer-Verlag 2005 Abstract Aims/hypothesis: The largely unsatisfactory p< 0.05). No significant side effects were recorded during results reported for the pharmacological treatment of dia- the study. Conclusions/interpretation: FREMS is a safe betic neuropathy has spurred the search for alternative and effective therapy for neuropathic pain in patients with therapies. The aim of this study was to evaluate the efficacy diabetes and is able to modify some parameters of periph- of frequency-modulated electromagnetic neural stimula- eral nerve function. tion (FREMS) as a novel treatment for painful diabetic neuropathy. Methods: Patients (n=31) with painful neu- Keywords Clinical trial . Diabetes . Electromagnetic ropathy associated with decreased nerve conduction veloc- stimulation . Painful neuropathy ity (<40 m/s) and increased vibration perception threshold (>25 V) were enrolled in a randomised, double-blind, Abbreviations FREMS: frequency-modulated crossover study designed to compare the effects of FREMS electromagnetic neural stimulation . MNCV: motor nerve with those of placebo. Each patient received two series of conduction velocity . SF36: Short Form-36 questionnaire . ten treatments of either FREMS or placebo in random se- SNCV: sensory nerve conduction velocity . TENS: quence, with each series lasting no more than 3 weeks. The transcutaneous electrical nerve stimulation . VAS: visual primary efficacy end point was the change in pain mea- analogue scale . VEGF: vascular endothelial growth factor sured by a visual analogue scale (VAS). Results: FREMS induced a significant reduction in daytime and night-time VAS pain score (all p<0.02). Furthermore, FREMS induced Introduction a significant increase in sensory tactile perception, as as- sessed by monofilament; a decrease in foot vibration per- Peripheral neuropathy is a frequent and disabling micro- ception threshold, as measured by a biothesiometer; and vascular complication of both type 1 and type 2 diabetes [1]. an increase in motor nerve conduction velocity (all p<0.01). This condition may be prevented by good blood glucose No significant changes were observed after placebo. Com- control [2]; however, it is at best halted, once established, parison of measurements at the 4-month follow-up with even after long-term blood glucose normalisation, such as those at baseline revealed that a significant benefit persisted that observed following successful pancreas transplantation for all measures that showed an improvement at the end [3, 4]. The pathological hallmarks of diabetic neuropathy of treatment, with an additional improvement in quality are microangiopathy of the vasa nervorum, loss of axons of life evaluated by the Short Form-36 questionnaire (all and axonal atrophy, all of which are the result of a com- bination of different mechanisms of tissue damage that are common to all long-term complications of diabetes [5]. E. Bosi (*) . M. Conti . E. Peretti . G. Galimberti The pharmacological treatment of diabetic neuropathy is Diabetes and Endocrinology Unit, largely unsatisfactory, mainly due to a lack of drugs that act Department of General Medicine, on the underlying pathogenetic mechanisms. Aldose reduc- Vita-Salute San Raffaele University Hospital, tase inhibitors are among the few compounds with this Via Olgettina, 60, 20132 Milan, Italy mode of action; however, the results of clinical trials per- e-mail: [email protected] formed to date have been disappointing [6]. Consequently, Tel.: +39-02-26432818 current therapy is purely symptomatic, aiming to relieve the Fax: +39-02-26432827 pain associated with neuropathy through the administration C. Vermigli . G. Cazzetta . M. C. Cordoni . L. Scionti of various analgesics, tricyclic antidepressants, anti-arrhyth- Department of Internal Medicine, University of Perugia, mics [7] and, more recently, the new anti-epileptic agents Perugia, Italy gabapentin [8] and lamotrigine [9], and opioids [10]. 818 Non-pharmacological symptomatic treatments have also Characteristics of FREMS Treatment with FREMS was been proposed, including acupuncture [11], near-infrared performed using sequences of monophase-compensated phototherapy [12], low-intensity laser therapy [13], static negative potential electrical pulses that are characterised by and pulsed magnetic field therapies [14, 15], and various a sharp spike and an asymmetrical shape (peak amplitude electrotherapies, including transcutaneous electrical nerve variable from 0–255 V, pulse frequency variable within the stimulation (TENS) [16, 17], percutaneous electrical nerve range 1–50 Hz, pulse duration variable within the range stimulation [18] and spinal cord electrostimulation [19]. 10–40 μs). The rationale for the use of electrical nerve stimulation in diabetic neuropathy is based on its historical, though con- Administration of FREMS and placebo Electrotherapy and troversial, use in various painful clinical conditions [20] and placebo were administered using the Physioflog ETS 501 on some beneficial effects reported in the treatment of other (Lorenz Therapy System; Lorenz Biotech, Medolla, Italy) diabetic complications, such as foot ulcers [21]. via four electrodes applied to the lower extremities; the Frequency-modulated electromagnetic neural stimula- original device was modified by the addition of a switch to tion (FREMS) has recently been developed as a novel elec- apply treatment A (later revealed to be placebo) or treatment trotherapy. This method is different from TENS and other B (later revealed to be FREMS). Each session of either known electrotherapy systems, as it uses sequences of mod- placebo or FREMS lasted for 30 min. Placebo consisted of ulated electrical stimuli that vary automatically in terms no electric current transmission. This placebo was chosen of pulse frequency, duration and voltage amplitude. The after a preliminary study had shown that patients with a FREMS method was designed on the basis of the hypoth- vibration perception threshold higher than 25 V effectively esis that the summation of sub-threshold electrical stimuli, had no perception of the electrical stimuli administered by conveyed through the skin proximal to a motor nerve in a the FREMS device (data not shown). These findings were in non-invasive system, would induce composite motor action accordance with those reported by two other studies show- potentials in excitable tissues. A single impulse of low in- ing a direct correlation between vibration perception thresh- tensity and short duration, such as that used by conventional old measured by a biothesiometer and current perception electrotherapies, is unable to overcome the dielectric skin threshold measured by a Neurometer (Neurotron, Baltimore, barrier to excite the underlying nervous or muscular tissue. MD, USA) across the same range of frequencies used by However, FREMS achieves this effect through specific FREMS [23, 24]. During sessions of either placebo or sequences of weak impulses, characterised by a rapid in- FREMS, patients were invited to modulate the delivery of crease and decrease in pulse frequency and duration, which neurostimulation themselves, by progressively increasing result in the gradual recruitment of membrane potentials in the voltage of electrical stimulation along a scale of 0–255 the stimulated tissues [22]. V through a manually gradable remote control device that These characteristics prompted us to evaluate the thera- increased the voltage by 1 V per step up to the maximal peutic potential of FREMS in human diabetic neuropathy. allowed, which corresponded to the possible perception of In this paper we report the results of a two-centre, random- burning at the site of the electrode. ised, double-blind, placebo-controlled, crossover clinical trial on FREMS treatment of patients with painful diabetic Subjects Patients who met the following criteria were neuropathy. invited to participate in the study: (1) type 1 or type 2 dia- betes according to American Diabetes Association criteria [25]; (2) age between 18 and 70 years; (3) painful diabetic Subjects and methods neuropathy with reduced sensory and/or MNCV (<40 m/s in at least one nerve trunk of lower limbs); and (4) vibration Study design and end points The study had a randomised, perception at big toe >25 V. Exclusion criteria were: (1) the double-blind, placebo-controlled, crossover design. The pri- presence of any other severe disease; (2) pregnancy; (3) mary end point was the change in grading of daytime and renal disease with serum creatinine levels >1.77 μmol/l; (4) night-time pain, as assessed using a visual analogue scale a history or actual presence of foot ulcers; and (5) lower (VAS). Secondary end points were changes in: sensitivity to limb vasculopathy as indicated by an ankle-brachial index monofilament; vibration perception threshold, as measured <0.9 or a transcutaneous partial pressure of oxygen <50 by a biothesiometer; quality of life, as assessed by question- mmHg. Any analgesic or other drug administered for the naire; motor nerve conduction velocity (MNCV); and sen- chronic treatment of painful neuropathy was discontinued at sory nerve conduction velocity
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