Pulsed Electromagnetic Fields to Reduce Diabetic Neuropathic Pain and Stimulate Neuronal Repair: A Randomized Controlled Trial

Design

Multicenter, randomized, parallel-group, double-blind, placebo-controlled study

N= 225

Objective

To determine whether repetitive and cumulative exposure to low-frequency pulsed electromagnetic fields (PEMF) targeting painful feet can reduce neuropathic pain (NP), influence sleep in symptomatic diabetic peripheral neuropathy (DPN), and influence nerve regeneration

Study Groups

PEMF (n= 90)

Placebo (n=104)

Inclusion Criteria

Aged 18-87 years old, Dyck stage II or III diabetic peripheral neuropathy, moderate-severe constant pain (≥4 of visual analog scale [VAS]), neuropathy duration ≥6 months

Exclusion Criteria

Pregnant, used mechanical insulin pumps, had a cardiac pacemaker

Methods

The study was conducted at sixteen academic and clinical sites in thirteen states. Participants were randomly assigned to use identical devices (except the demagnetization procedure) generating PEMF or sham (placebo) for a maximum of 2 hours/day in divided sessions of 10 to 30 minutes for 3 months. The devices were used on the patients' feet.

A subset of participants underwent serial 3-mm punch skin biopsies from three standard lower limb sites for epidermal nerve fiber density (ENFD) quantification. 

Patients were not allowed to use new analgesics or increase dosing during the trial period.

Duration

August 2005 to March 2007

Intervention period: 3 months

Outcome Measures

Primary outcome: VAS score at month 3

Secondary outcomes: Neuropathy Pain Scale (NPS), sleep scores, Patient's Global Impression of Change (PGIC), and ENFD at month 3

Baseline Characteristics

PEMF (n= 90)

Placebo (n= 104)

Age, years

Female

Years since onset of diabetes

HbA1c, %

VAS

Sleep score*

NPS 10

Subjects with abnormal nerve conduction

Epidermal nerve fiber density per mm

Distal leg crossings

Distal thigh crossings

Proximal thigh crossings

1.33 ± 2.04

5.00 ± 1.68

7.32 ± 3.11

1.05 ± 1.64

4.49 ± 1.40

6.58 ± 1.83  

*Seep was also scored via VAS, ranging from 0-10.

Results

Endpoint

PEMF (n=90)

Placebo (n=104)

p-value

VAS*

Secondary outcomes

Sleep score

NPS 10**

PGIC

Epidermal nerve fiber density per mm

Distal leg crossings

Distal thigh crossings

Proximal thigh crossings

3.27 ± 3.08

45.20 ± 21.18

43.7%

1.56 ± 2.34

4.76 ± 2.21

7.18 ± 2.06 

2.96 ± 2.85

44.21 ± 20.85

30.6% 

0.83 ± 1.54

4.44 ± 2.30

7.03 ± 2.41 

0.49

0.58

0.04

-

-

- 

*VAS score was measured three times daily at the same time to represent a mean daily pain level (ranging from 0- no pain to 10- worst possible pain).

**NPS assessed 10 pain descriptors collected at baseline and the end of the study (NPS 10, score ranges from 0 to 100).

At baseline, the correlation between NPS 10 and VAS was significant (r= 0.57, p <0.001). 

At three months, there were significant correlations between NPS 10 and VAS (p <0.001), NPS 10 and PGIC (p<0.001), and VAS and PGIC (p<0.001).

Adverse Events

There were no safety issues or complications except four cases of allodynia (2 vs. 2, respectively) leading to dropout. 

Study Author Conclusions

PEMF at this dosimetry was noneffective in reducing NP. However, neurobiological effects on ENFD, PGIC, and reduced itching scores suggest future studies are indicated with higher dosimetry (3000–5000 G), longer duration of exposure, and larger biopsy cohort.

InpharmD Researcher Critique

The study has its strengths of including patients with stage II and III DPN, the use of 3 validated pain scoring methods, and the inclusion of ENDF outcomes. However, the study has some limitations including possible bias of easily detecting the presence of magnetism as well as the pain reduction only reflected in the PGIC scale. 

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

Design

Multicenter, randomized, double-blind, placebo-controlled, parallel-group study

N= 110

Objective

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

Study Groups

Placebo (n= 56)

FREMS (n= 54)

Inclusion Criteria

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

Exclusion Criteria

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

Methods

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).

Duration

Treatment: maximum of 21 days

Treatment sessions: 30 minutes

Follow-up: 51 weeks

Outcome Measures

Change in NCV at T6 versus baseline, pain, tactile sensation, vibration and thermal sensation thresholds, MDNS, diabetes control and kidney function, safety

Baseline Characteristics

Placebo (n= 51)

FREMS (n= 50)

Age, years

Female

Diabetes

Type 1

Type 2

17.6%

82.4%

20%

80%

Duration of diabetes, years

Body mass index, kg/m²

HbA1c, %

Serum creatinine, μmol/L

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

13.7 ± 5.0

45.2 ± 29.6

40.9 ± 24.0

22.4 ± 23.1

38.0 ± 9.3

26.5 ± 7.6

11.6 ± 4.6

41.3 ± 29.7

31.6 ± 26.3

24.2 ± 26.5

38.5 ± 9.2

26 ± 7.7

NCV, m/s

Sural nerve

Tibial nerve

Deep peroneal nerve

42.2 ± 6.3

42.3 ± 4.6

43.8 ± 4.8

42.0 ± 4.3

40.1 ± 6.8

41.5 ± 5.0

Amplitude

Sural nerve, μV

Tibial nerve, mV

Deep peroneal nerve, mV

4.98 ± 3.29

10.47 ± 5.82

5.43 ± 3.28

4.82 ± 3.91

8.59 ± 5.87

4.8 ± 3.37

Taking medications for painful neuropathy

16%

26%

Results

Endpoint

Placebo (n= 51)

FREMS (n= 50)

p-value

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

- 

0.74 ± 0.71

2.08 ± 0.84

0.8 ± 1.08

-

0.98 ± 0.72

0.76 ± 0.59

1.13 ± 0.87

-

0.06 ± 1.38

0.61 ± 0.43

-0.91 ± 1.13

-

-0.05 ± 0.44

0.58 ± 0.46

0.44 ± 0.96

-

Not significant (NS)

NS

NS

-

0.049

NS

NS

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).

Adverse Events

No treatment-related severe or non-severe adverse events were recorded during the study in either group.

Study Author Conclusions

FREMS proved to be a safe treatment for symptomatic diabetic neuropathy, with immediate, although transient, reduction in pain, and no effect on NCV.

InpharmD Researcher Critique

Evaluation of the efficacy of pulsed electromagnetic field in the management of patients with diabetic polyneuropathy

Design

Randomized, controlled trial

N= 30

Objective

Study Groups

PEMF 600 Hz (n= 10)

PEMF 800 Hz (n= 10)

Control (n= 10)

Inclusion Criteria

Exclusion Criteria

Methods

Patients at an Indian medical college were randomized to receive PEMF of either 600 or 800 Hz, or control which consisted of usual medication treatment of diabetic polyneuropathy. Pain was measured using visual analog scale (VAS) from 0 (no pain) to 10 (worse possible pain). Motor nerve conduction was measured before and after treatment.

Duration

Outcome Measures

Baseline Characteristics

Study patients (N= 30)

Age, years

Duration of diabetes, years

Results

Endpoint

PEMF 600 Hz (n= 10)

PEMF 800 Hz (n= 10)

Control (n= 10)

Percent decrease in VAS score

Before treatment

After treatment

66.6%

8.4

2.8

63.25%

7.9

2.9

22.5%

8

6.2

Nerve conduction study

Distal latency, right peritoneal nerve

Before treatment

After treatment

Distal latency, left peritoneal nerve

Before treatment

After treatment

6.13

3.88*

4.71

3.44*

5.59

4.55*

4.47

4.28

4.45

4.77

4.70

4.80

Nerve conduction velocity, right peritoneal nerve

Before treatment

After treatment

Nerve conduction velocity, left peritoneal nerve

Before treatment

After treatment

36.12

39.44*

36.27

38.92*

37.58

40.98*

38.80

41.38*

38.39

37.86

39.35

37.99

Amplitude, right peritoneal nerve

Before treatment

After treatment

Amplitude, left peritoneal nerve

Before treatment

After treatment

1.93

2.02

2.39

2.40

3.08

3.00

2.93

3.06

2.83

2.67

2.36

2.28

*p< 0.05

Study Author Conclusions

Low-frequency PEMF can be used as an adjunct in reducing neuropathic pain as well as for retarding the progression of neuropathy in a short span of time.

InpharmD Researcher Critique

Effectiveness of frequency-modulated electromagnetic neural stimulation in the treatment of painful diabetic neuropathy

Design

Randomized, double-blind, placebo-controlled, crossover study

N= 31

Objective

To evaluate the efficacy of frequency-modulated electromagnetic neural stimulation (FREMS) as a novel treatment for painful diabetic neuropathy

Study Groups

Sequence 1 (n= 15)

Sequence 2 (n= 16)

Inclusion Criteria

Type 1 or type 2 diabetes according to American Diabetes Association criteria; age between 18 and 70 years; painful diabetic neuropathy with reduced sensory and/or motor nerve conduction velocity (MNCV) of < 40 m/s in at least one nerve trunk of lower limbs

Exclusion Criteria

Presence of any other severe disease; pregnancy; renal disease with serum creatinine levels >1.77 μmol/L; history or actual presence of foot ulcers; lower limb vasculopathy as indicated by an ankle-brachial index ​<0.9 or a transcutaneous partial pressure of oxygen <50 mmHg

Methods

Treatment consisted of ten sessions of placebo followed by ten sessions of FREMS (sequence 1) or vice versa (sequence 2) at random, separated by a wash-out period of 1 week. Each treatment session was administered at intervals of at least 24 hours, with each ten-session series lasting no more than 3 weeks. Treatment with FREMS was done using sequences of monophase-compensated negative potential electrical pulses that are characterized by a sharp spike and an asymmetrical shape (peak amplitude variable from 0-255 V, pulse frequency variable within the range of 1-50 Hz, pulse duration variable within the rate of 10-40 microseconds). Each treatment session lasted for 30 minutes. Placebo consisted of no electric current transmission.

Duration

Primary: change in grading of daytime and night-time pain (assessed by VAS)

Secondary: sensitivity to monofilament; vibration perception threshold (VPT); quality of life; motor nerve conduction velocity (MNCV); sensory nerve conduction velocity (SNCV)

Outcome Measures

Ten-session series: no more than 3 weeks

Intervals between treatment sessions: at least 24 hours

Treatment session: 30 minutes

Baseline Characteristics

Sequence 1 (n= 15)

Sequence 2 (n= 16)

Age, years

Diabetes 

Duration, years 

Type 2 diabetes

HbA1c, %

15.9 ± 3.0

12 (80%)

8.3

16.6 ± 2.7

11 (68.8%)

8.2

VAS

Daytime 

Night-time

32.3 ± 6.8

36.3 ± 6.3

41.4 ± 8.0

45.5 ± 8.2

VPT, V

Monofilament (out of nine standard areas)

MNCV, m/s

SNCV, m/s

Short Form-36 questionnaire (SF36)

No significant differences were noted between the two groups in baseline characteristics. 

Results

Placebo

FREMS

VAS daytime pain score

Pre-treatment

Post-treatment 

p-value

31.2 ± 3.9

31.9 ± 4.2

NS

37.1 ± 5.3

26.2 ± 3.9

0.0025

VAS night-time pain score

Pre-treatment

Post-treatment 

p-value

33.3 ± 3.8

30.4 ± 4.2

NS

38.1 ± 5.5

28.5 ± 3.8

0.0107

VPT, V

Pre-treatment

Post-treatment 

p-value

34.7 ± 1.6

34.2 ± 1.6

NS

35.5 ± 1.6

33.4 ± 1.6

0.0001

Monofilament (out of nine standard areas)

Pre-treatment

Post-treatment 

p-value

5.1 ± 0.9

5.2 ± 0.9

NS

5.8 ± 0.8

4.6 ± 0.9

0.0077

MNCV, m/s

Pre-treatment

Post-treatment 

p-value

37.2 ± 1.2

37.4 ± 1.4

NS

35.7 ± 1.3

40.5 ± 1.8

0.0019

Pre- and post-treatment comparisons were not significantly different in SNCV and SF36 in either FREMS or placebo. 

NS= not significant. 

Adverse Events

No systemic side effects were recorded during the study. Patients reported only a very slight burning sensation at the site of electrode placement during the series of treatments later revealed as FREMS, with no residual skin signs.

Study Author Conclusions

Frequency-modulated electromagnetic neural stimulation is a safe and effective therapy for neuropathic pain in patients with diabetes and is able to modify some parameters of peripheral nerve function.

InpharmD Researcher Critique

The study is limited by its small sample size and single-center experience. Additionally, findings may not be readily extrapolated to peripheral neuropathy caused by different underlying etiology other than diabetes. 

Frequency Rhythmic Electrical Modulation System (FREMS) to alleviate painful diabetic peripheral neuropathy: A pilot, randomised controlled trial (The FREMSTOP study)

Design

Randomized, open-label, controlled, pilot trial

N= 25

Objective

To investigate the place of Frequency Rhythmic Electrical Modulated System (FREMS) in the treatment algorithm for painful diabetic peripheral neuropathy (PDPN)

Study Groups

FREMS + usual care (intervention, n= 13)

Usual care (control, n= 12)

Inclusion Criteria

Aged between 18 and 75 years with type 1 or type 2 diabetes; symptoms and/or signs attributable to PDPN for at least 6 months; a minimum of two abnormalities including reduced vibration perception by a 128-Hz tuning fork, abnormal pressure sensation with 10 g monofilament test, reduced ankle reflexes and reduced pinprick sensation; neuropathic pain, had already tried at least two treatment options including duloxetine, pregabalin, gabapentin, amitriptyline, carbamazepine, opioid analgesics or any other analgesics and been on a stable regimen for the last 3 months

Exclusion Criteria

Evident causes for painful neuropathy, administration of transcutaneous electrical nerve stimulation or any other electrotherapy for the treatment of PDPN within the last 6 weeks of the screening visit, significant peripheral arterial disease, active foot ulceration, current alcohol or other substance abuse, or the presence of cardiac pacemaker and/or implantable cardioverter defibrillator.

Methods

Participants were randomized in a 1:1 ratio to either the intervention group with FREMS + usual care or only usual care by their own healthcare provider. 

The electric signal of FREMS intervention was transmitted subcutaneously through two electrodes that were firmly attached by a small sticky patch at designated sites. Eight electrode pads were applied to sites on both lower legs (calf, shinbone, ankle, and mid-foot) at the beginning of each treatment session. At the start of each treatment session, the maximal intensity voltage required for neuro-stimulation was identified by the participant (supervised by the researcher) by increasing the intensity step-wise by 1V/ step until the participant could perceive the stimulation without it being painful or uncomfortable.

Duration

Recruitment: 12 months

Duration of each session: 35 minutes

One treatment cycle: 10 sessions, corresponding to 10 consecutive days

Follow-up: 12 weeks

Outcome Measures

Primary: change from baseline in perceived pain (assessed by the visual analog scale) at 12 weeks between treatment groups

Secondary: 

• The change in patient-reported outcomes between treatment groups from baseline to 12 through (i) Short-Form McGill Pain Questionnaire (ii) Douleur neuropathique 4 score Questionnaire (iii) EuroQOL five-dimension Questionnaire (iv) Insomnia Severity Inde (v) Total anti-neuropathic and opioid medications (vi) Cumulative percentage of defined daily dose of all pain medications
• Proportion of individuals achieving a 30% clinically significant and 50% ideal response reduction in perceived pain

Baseline Characteristics

Control (n= 12)

Intervention (n= 13)

Age, years

Male

White

Weigh, kg

Body mass index, kg/m²

Diabetes duration, years

HbA1c, %

Pain medications

Paracetamol

Opioids

Neuropathic

Opioid+neuropathic

33%

67%

48%

67%

17%

39%

52%

39%   

Diabetic neuropathy

17%

23%

Cardiovascular disease

67%

67% 

Chronic kidney disease

25%

15%   

Results

Endpoint

Control group (n= 12)

Baseline

12 weeks

Change from baseline

Baseline

12 weeks

Change from baseline

Pain visual analog scale

Short form-McGill pain questionnaire-2

EuroQOL five-dimension questionnaire

Insomnia severity index

Total pain medications

Cumulative percentage of defined daily dose of all pain medications

Percentage change from baseline in perceived pain

<30%

>30%

<50%

>50%

100%

0

100%

0

46%

54%

54%

46%

0.042

-

0.099

-

Data are presented as median (interquartile range).

Adverse Events

No systemic side effects were recorded during the study. One patient reported hyperaesthesia and severe pain in both soles of the feet after 5 days of FREMS treatment and declined to attend further sessions. Severe pain persisted in both feet for 2 weeks and resolved with simple analgesia.

Study Author Conclusions

FREMS might be used to treat individuals with PDPN inadequately controlled on two classes of neuropathic pain medications and is associated with improvements in pain severity and perceived impact of treatment. A larger, appropriately designed trial assessing its impact on this population is needed.

InpharmD Researcher Critique

The findings of this study are limited by its small sample size and lack of blinding in the study and the possibility of a placebo effect due to the FREMS device which could have impacted the magnitude of effect size. Additionally, since the study was only conducted for a short duration of three months, it is uncertain if participants would continue to respond to the repeated treatments with a longer duration of follow-up. 

The 8-Week Efficacy of Frequency Rhythmic Electrical Modulated System (FREMS) as an Add-on Therapy in the Treatment of Symptomatic Diabetic Peripheral Polyneuropathy

Design

Randomized, single-blind, placebo-controlled, single-center (Poland) trial

N= 45

Objective

To determine the efficacy of Frequency Rhythmic Electrical Modulated System (FREMS) in neuropathic pain in diabetes mellitus.

Study Groups

FREMS (n= 24)

Placebo (n= 20)

Inclusion Criteria

Age ≥18 years, diabetes type 1 or 2, diabetic polyneuropathy affecting the lower extremities with ≥1 positive sensory symptom, (pain, burning, paraesthesia, or prickling)

Exclusion Criteria

Ankle-brachial index (ABI) < 0.5; implanted pacemaker, defibrillator, or neurostimulator

Methods

Patients were admitted for treatment for 5 days, were only permitted acetaminophen as a painkiller, received intravenous (IV) alpha-lipoic acid (600 mg daily), and were randomized to receive twice-daily 35-minute sessions of either active real FREMS therapy or an inactive procedure placebo.

The intervention equipment was the Aptiva 4™ device (Lorenz Lifetech, Ozzano dell’Emilia, Italy), with dedicated cables and 4 pairs of disposable electrodes applied to both lower extremities.

The active treatment group received treatment with cycles involving a 25-minute active phase with a high negative voltage spike (variable, max −300 V) and extra short duration (variable, 10-100 μs, mostly ~40 μs), followed by a 10-minute recharging phase of low voltage and long duration (0.9-999 ms) pulses of variable frequency (range: 1-1000 Hz [mainly in the low range 1-50 Hz]).

Patients reported pain in a daily diary every morning (0-10 visual analogue scale [VAS] as a straight horizontal line with numbers from 0 [no pain] to 10 [the worst pain in a lifetime]).

Duration

Intervention: 5 days

Duration of follow-up: 8 weeks

Outcome Measures

Pain score based on VAS scale

Baseline Characteristics

FREMS (n= 24)

Placebo (n= 20)

Age, years

Female

HbA1c, median %

Baseline pain score (VAS 1-10), median points

Results

Endpoint

A

B

p-Value

Pain score (VAS 1-10), points

Day 5:

Days 8-9:

Week 8:

 3.2

 Not Disclosed (ND)

 4

 4

 ND

 ND

 <0.0001

 >0.05

 <0.05

Number of days after treatment initiation before pain reduction was reported:

Adverse Events

No treatment-related adverse events were recorded during the study.

Study Author Conclusions

The findings of the study confirm that FREMS is a safe method of alleviating pain in diabetic patients with diabetic peripheral neuropathy.

InpharmD Researcher Critique

The group assignments may have been obvious to patients who have not progressed to complete numbness in their lower extremities. As the pain improvement was not observed in the immediate days following treatment, continued regular treatment may be required to observe any pain benefit.