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
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Design
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Multicenter, randomized, double-blind, placebo-controlled, parallel-group study
N= 110
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Objective
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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
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Study Groups
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Placebo (n= 56)
FREMS (n= 54)
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Inclusion Criteria
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Documented diagnosis of type or type 2 diabetes according American Diabetes Association (ADA) criteria, with duration of disease of at least 1 year and HbA1c < 11.0%; age between 18 and 75 years; symptomatic diabetic polyneuropathy affecting lower extremities with at least one positive sensory symptom such as pain, burning, paresthesia or prickling; abnormalities in amplitude (<6 mv), latency (>6.5 ms) or conduction velocity (<40 m/s) in at least one motor nerve and/or in the sural nerve; measurable sensitive nerve conduction velocity (NCV) and revocable potential in the sural nerve; Michigan Diabetes Neuropathy Score (MDNS) equal to or greater than 7 points; stable dose of pain medications or other medications prescribed for diabetic neuropathy in the month leading up to enrollment
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Exclusion Criteria
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Previous treatment with transcutaneous electrical nerve stimulation (TENS) or other electrotherapy for diabetic neuropathy; presence of an implanted pacemaker, defibrillator or neurostimulator; presence of an active foot ulcer and/or previous major amputation of the lower extremities; any concomitant severe disease limiting compliance to study procedures or life expectancy
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Methods
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Patients were randomized (1:1) to receive three series of FREMS or placebo at 3-month intervals (12-13 weeks). Each series consisted of ten consecutive treatment sessions administered at least 24 hours apart for a maximum of 21 days.
Treatment with FREMS consisted of sequences of biphasic (negative and positive), asymmetric and electrically balanced pulses composed of an active phase of high negative voltage spike (variable, max 300 V) and extra short duration (variable, 10 to 100 microseconds, mostly ~40 microseconds) followed by a recharging phase of low voltage and long duration (0.9 to 999 ms). Pulse frequency was variable in the range of 1 to 1,000 Hz. Patients randomized to placebo received no electrical pulses. Treatment consisted of three series of ten consecutive (one a day for 5 days/week FREMS or placebo to both lower limbs.
Participants were assessed at T-1 (study enrollment visit), T0 (week 0, within 2 weeks after T-1: start of therapeutic cycle), T1 (week 3, after the first therapeutic cycle), T2 (week 17: start of second therapeutic cycle), T3 (week 20, after the second therapeutic cycle), T4 (week 34: start of third therapeutic cycle), T5 (week 37, after the third therapeutic cycle), and T6 (week 51).
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Duration
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Treatment: maximum of 21 days
Treatment sessions: 30 minutes
Follow-up: 51 weeks
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Outcome Measures
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Change in NCV at T6 versus baseline, pain, tactile sensation, vibration and thermal sensation thresholds, MDNS, diabetes control and kidney function, safety
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Baseline Characteristics
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Placebo (n= 51)
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FREMS (n= 50)
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Age, years
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61.3 ± 8.3 |
59.0 ± 10.6 |
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Female
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39% |
28% |
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Diabetes
Type 1
Type 2
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17.6%
82.4%
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20%
80%
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Duration of diabetes, years
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12 |
13 |
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Body mass index, kg/m2
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28.5 ± 4.8 |
28.8 ± 4.8 |
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HbA1c, %
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7.6 ± 1.2 |
7.9 ± 1.2 |
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Serum creatinine, μmol/L
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83.1 ± 18.5 |
85.7 ± 24.7 |
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Scores and baseline values
MDNS
Nigh-time pain on visual analog scale (VAS)
Daytime pain on VAS
Vibration perception threshold, μm
Warm sensation threshold, °C
Cold sensation threshold, °C
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13.7 ± 5.0
45.2 ± 29.6
40.9 ± 24.0
22.4 ± 23.1
38.0 ± 9.3
26.5 ± 7.6
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11.6 ± 4.6
41.3 ± 29.7
31.6 ± 26.3
24.2 ± 26.5
38.5 ± 9.2
26 ± 7.7
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NCV, m/s
Sural nerve
Tibial nerve
Deep peroneal nerve
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42.2 ± 6.3
42.3 ± 4.6
43.8 ± 4.8
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42.0 ± 4.3
40.1 ± 6.8
41.5 ± 5.0
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Amplitude
Sural nerve, μV
Tibial nerve, mV
Deep peroneal nerve, mV
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4.98 ± 3.29
10.47 ± 5.82
5.43 ± 3.28
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4.82 ± 3.91
8.59 ± 5.87
4.8 ± 3.37
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Taking medications for painful neuropathy
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16%
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26%
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Results
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Endpoint
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Placebo (n= 51)
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FREMS (n= 50)
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p-value
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Adjusted mean change in NCV at T6 versus baseline
Intention-to-treat (ITT) population
Deep peroneal
Tibial
Sural
Per-protocol (PP) population
Deep peroneal
Tibial
Sural
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-
0.74 ± 0.71
2.08 ± 0.84
0.8 ± 1.08
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0.98 ± 0.72
0.76 ± 0.59
1.13 ± 0.87
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0.06 ± 1.38
0.61 ± 0.43
-0.91 ± 1.13
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-0.05 ± 0.44
0.58 ± 0.46
0.44 ± 0.96
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-
Not significant (NS)
NS
NS
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0.049
NS
NS
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Data evaluating pain were represented in graphical figures. Both night-time pain and daytime pain measured as VAS were significantly reduced in the FREMS group compared with the placebo group at T1 (both p < 0.001), T3 (both p < 0.001), and T5 (p < 0.001 and p= 0.02, respectively). Similar results were observed in the PP population (data not shown). Four additional participants (n= 3 in the placebo group, n= 1 in the FREMS group) were prescribed medication for painful neuropathy.
Patients in the FREMS group experienced a significant increase in cold sensation threshold compared to placebo in both the ITT population (adjusted mean change at T5 vs. baseline 2.3 ± 1.4°C vs. -1.0 ± 1.2°C; p= 0.041) and PP population (0.8 ± 0.9°C vs. -0.05 ± 0.9°C; p= 0.008). Non-significant trends were observed in the FREMS group compared with placebo for changes in warm sensation and vibration threshold (data not shown).
There were reported to be no significant differences in the changes of tactile sensation, MDNS, HbA1c, or serum creatinine between FREMS and placebo groups (data not shown).
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Adverse Events
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No treatment-related severe or non-severe adverse events were recorded during the study in either group.
Patients reported a slight burning sensation at the site of electrode placement during the series of treatments later revealed as FREMS, with no residual skin signs. No such perception was recorded during placebo sessions.
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Study Author Conclusions
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FREMS proved to be a safe treatment for symptomatic diabetic neuropathy, with immediate, although transient, reduction in pain, and no effect on NCV.
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InpharmD Researcher Critique
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Patients were selected who had relatively mild symptomatic painful neuropathy; thus, the findings may not be generalizable to patients with more severe diabetic neuropathy. |