Health, 2020, 12, 738-749

https://www.scirp.org/journal/health
ISSN Online: 1949-5005
ISSN Print: 1949-4998

A Randomized Longitudinal Double-Blind

Clinical Trial on Long-Term Neuropathic
Symptomatology Relief & Pain Analgesia

Xanya Sofra1 , Nuris Lampe2

Department of Signaling, IELLIOS Research Center, Ipswich, UK

1

Clinical Dermatology, Horatio Oduber Hospital, Lg Smith Blvd, Orangestad, Aruba

2

How to cite this paper: Sofra, X. and Abstract

Lampe, N. (2020) A Randomized Longitu-
dinal Double-Blind Clinical Trial on Long- Diabetic neuropathic pain is one of the most difficult to treat with high levels
Term Neuropathic Symptomatology Relief of reoccurrence and a substantial increase with aging. It involves expensive
& Pain Analgesia. Health, 12, 738-749.
hospitalizations, often resulting in an amputated lower limb. We explored a
https://doi.org/10.4236/health.2020.127054
variety of methods treating neuropathic pain such as low-level laser, mono-
Received: June 8, 2020 chromatic near-infrared treatment, TENS, acupuncture and pulsed electro-
Accepted: July 5, 2020
magnetic fields that demonstrated inconclusive, limited or temporary pain re-
Published: July 8, 2020
lief with minor or short-term improvements in mobility. Research conducted
Copyright © 2020 by author(s) and by ultra-low energy technologies reports pain relief and reduction of inflam-
Scientific Research Publishing Inc. mation as a result of anti-oxidant electron donation transforming free radi-
This work is licensed under the Creative
cals into stable molecules. We report the results of a randomized double blind
Commons Attribution International
License (CC BY 4.0). one-year-long longitudinal clinical study on 10 diabetic mellitus (DM) sub-
http://creativecommons.org/licenses/by/4.0/ jects with chronic neuropathy, treated with ultra-low energy nanotechnol-
Open Access ogy who experienced substantial long-term neuropathic pain relief. Importantly,
pain analgesia and improvement in neuropathic symptomatology were not age-
contingent. This contradicts past research postulating that age-accumulated in-
flammation and endothelial dysfunction can further exacerbate diabetic neu-
ropathy. Importantly, a method offering age-independent, cost-effective, long-
term neuropathic pain relief and increased mobility has major implications in
reducing hospitalization time and overall expenses by offering a solution that
enhances quality of life.

Keywords
Aging, Pain Relief, Diabetes Mellitus, Neuropathy, TENS,
Ultra-Low Energy Technologies, Nanotechnology, Limp Amputation,
Neuropathic Pain

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 X. Sofra, N. Lampe

1. Introduction
Diabetic neuropathy has always been a challenge, because it increases with age
and traditional treatments result in temporary symptoms’ relief, without pre-
venting or halting the neuropathic condition. Diabetes patients experience neu-
ropathic pain as a direct consequence of abnormalities in the peripheral nerves’
network, leading to an imbalance between excitatory and inhibitory somatosen-
sory signalling. This involves ion channels’ alterations and hence dysregulation
of pain messages transmitted from the thalamic nucleus to the cerebral cortex
[1] [2]. Neuropathy typically causes numbness, tingling, sharp pain, muscle weak-
ness, poor mobility, paraesthesia or hyperesthesia. Diabetic neuropathy is asso-
ciated with susceptibility to foot or ankle fractures and ischemic ulceration lead-
ing to lower-limb amputations, often accompanied by negative mood and de-
pression that further exacerbate discomfort [3] [4], locking these patients into a
vicious circle of poor quality of life with little hope for escape.
The pathological basis for DM neuropathy includes both metabolic, vascular
and immune pathogenesis models [5]. Experimental models of metabolic pa-
thogenesis of neuropathy postulate that severe hyperglycemia can produce re-
duction in nerve conduction velocity and axonal shrinkage. Vascular pathogene-
sis models demonstrate that the severity of polyneuropathy is associated with an
increase in basement membrane area and endothelial cell degeneration. The
immunologic/inflammatory pathogenesis demonstrates asymmetric nerve fiber
loss and lymphocytic epineural inflammation resembling vasculitis [6]. Vincent
et al. (2011) explored the cellular mechanics of mitochondrial function, imbal-
ances of cellular metabolites of glucose and lipids, impaired insulin signalling
and sensory neurons’ vulnerability to oxidative and inflammatory stress. They
outlined therapeutic targets focusing on inflammation and functional balance
within mitochondrial mechanisms [7]. Overall, inflammation and oxidative
stress appear to be closely related to diabetic neuropathy.
Low-level laser therapy has been reported to alleviate neuropathic pain on the
basis of the significant reduction of the hypoxia-inducible factor 1α (HIF-1a)
that is related to increased inflammation. The chronic constrictive injury model
on rats used, demonstrated decreased inflammation after low-laser therapy tre-
atments for 7 consecutive days [8]. However, adopting an animal model does
not allow for participants’ confirmation that decreased inflammation is in fact
accompanied by pain relief. Beckerman et al. looked at the efficacy of laser ther-
apy on diabetic neuropathy, diabetic wounds and other skin lesions on the basis
of 36 randomized clinical trials involving 1704 subjects. They conclude that laser
studies were characterized by low methodological quality with no follow up, of-
fering no definite conclusions on the efficacy of lasers on pain relief and skin
disorders [9].
Reduced neuropathic pain, improved balance and restoration of sensation was
reported after 12 treatments with a monochromatic near-infrared technology on
27 patients with diabetic peripheral neuropathy in a double-blind, randomized

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X. Sofra, N. Lampe

placebo-controlled clinical trial [10]. However, it would appear that balance im-
provement was reported on 83% of the patients, a non-significant statistical re-
sult, in the absence of a longitudinal follow up to determine neuropathic pain
re-occurrence.
Results from anti-nervous drugs, such as tricyclic antidepressants, anticon-
vulsants, topical agents, and sympathomimetics, seeking improvements in nerve
function and blocking the transmission of pain impulses offer some promising
results when combining pathogenetic and symptomatic therapy, specifically the
aldose reductase inhibitor ranirestat and duloxetine [11]. However, drug treat-
ments have side effects, and benefits often dissipate when the pharmaceutical is
halted or discontinued.
Transcutaneous Electrical Nerve Stimulation (TENS) devices have been wide-
ly used for analgesia with or without pharmaceuticals, however, there is little
evidence of their efficacy with DM neuropathic pain [12]. A review of Acupunc-
ture-like TENS devices (AL-TENS) in the management of pain using low fre-
quency (1 - 10 Hz) electrical currents, has rendered inconsistent results due to
insufficient details describing various TENS treatment interventions and often
the lack of follow up [13]. Acupuncture studies report pain reduction that is not
maintained over time or offers results that are not statistically significant. For
example, Abuaisha et al.’s research [14] reports that 77% of subjects with peri-
pheral neuropathy expressed pain relief and symptomatic improvement, a statis-
tically, non-significant result.
Low-frequency pulsed electromagnetic fields (PEMF) with 225 diabetic neu-
ropathy subjects showed some positive results in terms of neuropathic sympto-
matology, especially itching. Twenty seven subjects underwent 3-mm skin biop-
sies from 3 standard lower limb sites and showed an increase in distal leg epi-
dermal nerve fiber density quantification which were correlated with decreased
pain. Despite the neuropathic symptomatology reduction, these investigators
conclude that the overall effect of PEMF on neuropathic pain was not significant
[15].
A lot of research starting with Cheng et al. in 1982 [16] has postulated that ul-
tra-low currents increase adenosine triphosphate (ATP) one of the main biolog-
ical energy currencies as well as overall protein synthesis which is crucial for
neuro-communications and systemic balance. More recently ultra-low energy
technologies have been shown to decrease inflammation, alleviate neuropathic
pain, increase mobility, and speed up the healing of wounds [17] [18] [19] [20].
These investigators postulate that diabetic wound healing and neuropathic pain
relief is the result of electron flow into the ion channels of the cells, acting as a
mega antioxidant by donating electrons to free radicals, the group of atoms with
unpaired electrons, rendered unstable and highly reactive. Electron donation,
fills in the gaps of unpaired electrons transforming free radicals into stable mo-
lecules. This electron-driven antioxidant process, reduces both oxidative stress
and inflammation. Inflammation and oxidative stress are simultaneously present
in neuropathy as well as several other pathological conditions. Inflammatory

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 X. Sofra, N. Lampe

cells release reactive oxygen species reinforcing oxidative stress [21]. Reactive
oxygen/nitrogen species also initiate intracellular signalling cascades enhancing
proinflammatory gene expression [22] [23]. Previously mentioned research by
Vincent et al. [7] has associated neuropathy with sensory neurons’ vulnerability
to oxidative and inflammatory stress.
The rationale for using such extremely low energy technology in wound heal-
ing is related to the concept of power frequency windows in the human body
that appears to be affected by weak oscillating fields, unlike non-living systems
that primarily respond to strong oscillating electromagnetic fields [24] [25] [26].
In his book “Electron Gated Ion Channels” Wilson Ranston [27] presents a new
quantum-mechanical approach to the intrinsic simplicity of electrons control-
ling ion channels at ultra-low energies below thermal noise, reinforcing me-
chanisms important to cellular function and intercellular signaling.
Overall, chronic pain associated with diabetic neuropathy is one of the most
difficult to treat with high levels of reoccurrence, long hospitalization times,
mounting expenses, and the often inevitable possibility of an amputated limb. In
search of solutions that can offer relatively inexpensive neuropathic pain relief
and increased mobility, we tested the hypothesis that ultra-low energy nano-
technology can offer long term pain analgesia and increased mobility enhancing
quality of life.

2. Methodology
We used an ultra-low energy nanotechnology originally invented in London
University for cellular regeneration in 1992. The technology was subsequently
modified over a period of 20 years on the basis of a series of original proprietary
mathematical formulae based on unpublished in vitro and in vivo, clinical and
electronic research. The technology has been used for over 10 years in clinical
practice by over 800 physicians around the world with no reported adverse reac-
tions or side effects. It is subjectively experienced as relaxing despite being im-
perceptible. Contraindications, warnings and cautions are according to the list
provided under TENS devices by the FDA, although this novel technology has a
nanoamp output (nanoamp = 10−9 Amperes) that is substantially lower than any
other TENS devices which are usually in the milliamp range (milliamp = 10−3
Amperes). The technology stores 9600 sine and square waveforms combinations
synthesized on the basis of an original mathematical formula with resultant fre-
quencies ranging from 0.25 - 10,000 Hz. The technology is designed to emit four
different resonant composite waveforms simultaneously out of the four virtual
channels generated by prototypical software, at a predesigned variety of discrete
specific times that range from 4 secs to 24 secs. Timing is calculated by a proto-
typical formula partly derived from the mathematical calculations describing how
tunneling electrons control ion gates and the timing of circadian rhythms dis-
cussed earlier [27]. The sequence in which the four signals are emitted at a time,
which varies in the technology’s 8 different programs, is regulated by an original

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X. Sofra, N. Lampe

mathematical formula invented after 20 years of clinical and electronic research.

The four resonant waveform composites that constantly alternate with respect to
the timing formula, are transmitted via a single physical channel, and through a
pair of tour grade ultra-silver-plated microphone cables with attached stainless
surgical steel probes that make contact with the patient’s skin. Probes are sanitized
prior to each usage. During treatment, the device’s voltage output is estimated to
range from 0.003 µV to 0.5 µV (µV = 10−6 Volts) depending on the resultant fre-
quency and skin resistance. The device’s current output reaching the skin is esti-
mated to range from 10 nanoamps to 60 nanoamps depending on skin resistance.
Testing measures included: 1) A structured clinical interview conducted by a
licensed dermatologist; 2) A neuropathic symptomatology checklist; 3) A physi-
cal examination 4) A comprehensive medical history questionnaire; 5) The sub-
jective peripheral neuropathy screen (SPNS) questionnaire which has been
successfully tested for validity and reliability. Research on the SPNS has demon-
strated reliability, internal consistency, construct validity, and criterion-re-
lated validity for this instrument [28]; 6) The Pain Detect Questionnaire
(PD-Q) offered before and after treatment completion. The PD-Q is a reliable
screening tool with high sensitivity, specificity and positive predictive accuracy
[29].

3. Procedure
Ten diabetic neuropathy subjects, four females and six males ages 40 - 78 years
old were randomly selected out of patients who had sought treatments for neu-
ropathic symptomatology in the hospital and private clinic over a period of 2
years. All participants were randomly selected after their treatments were com-
pleted at which point they were asked if they would allow their results to be used
for clinical research, and upon accepting to participate, they signed a consent
form. All subjects had been diagnosed with DM Neuropathy for an average of 8
years and had been previously treated with a variety of methodologies that had
only offered them temporary relief. All subjects were hyperglycaemic and pre-
sented persistent inflammation on the site of pain. The neuropathy diagnosis
was based on a physical examination and clinical interview conducted by their
treating dermatologist, two self-report questionnaires, the SPNS and PD-Q, and
a neuropathic symptomatology checklist that specifically explored the subjective
experience of numbness, pain sharpness, burning sensation, tingling sensation,
sensitivity to touch, muscle weakness and mobility. All subjects had scored
higher than 19 on the SPNS, confirming the incidence of neuropathy and had
fulfilled all the criteria for chronic pain and neuropathic symptomatology on the
PD-Q, the physical examination, the clinical interview and the symptomatology
checklist. Subjects were given six 30-min ultra-low energy nanotechnology
treatments on each leg (6 one-hour treatments on both legs), delivered every
three days. After the six treatments, the subjects were once again given the SPNS,
the PD-Q, the physical examination and clinical interview by the treating der-

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 X. Sofra, N. Lampe

matologist, and the neuropathic symptomatology checklist. The subjects were

followed up for one year after the six treatments and were re-examined to inves-
tigate the possibility of neuropathic pain and symptomatology reoccurrence.
Treatments and the scoring of the two questionnaires were completed by
technicians who had no bias or personal interest in the direction of the results
and were not aware that the data was eventually going to be used for research.
None of the subjects had an implanted device such as a cardiac pacemaker, was
pregnant, or was trying to get pregnant. The ultra-low energies emitted by the
nanotechnology device are imperceptible, therefore the subjects were not aware
whether the device was on or off, serving as their own control group. All subjects
were instructed to suspend all pain medication two days prior and during the
entire course of the six treatments.

4. Results
Subjects’ results on the SPNS and PD-Q with the percentages of neuropathic
pain relief are listed in Table 1. After treatment results provided values from 15
down to 6 which were substantially below the cut off value of 19+ indicating the
presence of neuropathic pain.
Subjects’ reports on pain relief and symptomatology improvement imme-
diately after the 6th treatment, are given in Table 2.
Subjects’ reports on the long-term neuropathic symptomatology, pain relief
and increased mobility one year after the treatment are given in Table 3.
The results were analyzed with the Mann Whitney U test and ANOVA, one-way
analysis of variance for repeated measures.
The ANOVA yielded statistically significant results at p < 0.01 as shown in
more detail in Table 4. The Mann Whitney U test for the SPNS before and after
scores yielded highly significant results where p = 0.00009. The U-value was 0.
The critical value of U at 0 < 0.01 was 19. Therefore, the results were significant
at 0 < 0.01. The z-score was 3.74185 indicating statistical significance at p < 0.01.
A graphic representation of the SPNS results before and after the ultra-low
energy nanotechnology treatment is illustrated by Figure 1.
The Mann Whitney U test for the PD-Q before and after scores also yielded
highly significant results where p = 0.000087. The U-value was 0. The critical
value of U at 0 < 0.01 was 19.
Therefore, the results were significant at 0 < 0.01. The z-score was 3.74184 in-
dicating statistical significance at p < 0.01. Figure 2 depicts the PD-Q results on
neuropathic pain relief before and after the treatment.
Results analysis on both SPNS and PD-Q as shown in both Tables 1-3, Figure
1 and Figure 2 revealed that age was not a factor in terms of degree of neuro-
pathic symptomatology and pain relief. For example, 66 - 78 years old subjects
appeared to have greater pain analgesia than younger subjects. The physical ex-
amination after the 6 treatments and a year later revealed less inflammation at
the site where pain was reported prior to the ultra-low energy nanotechnology
intervention.

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X. Sofra, N. Lampe

SPNS Neuropathic Pain Decrease after Treatments

40 38
32 34
35
30 28
25 23 26
22
20 23
12 15 20 22
15 16
10 13
6 8
5 9 9
0 7 8
40 41
Age 45 53 60 66 66 73 75
78

SPNS Prior SPNS After

Figure 1. All subjects reported significant neuropathic pain relief on the SPNS,
independent of age.

PD-Q Neuropathic Pain Decrease after Treatments

40
35 32 36
30 30
30
25 24
25
20 21 24
24
15 12 14
14 19
10 8 9 12
5 11
8
0 8
6
40 41 45
Age 53 60 66 66 73 75
78

PD-Q Before PR-Q After

Figure 2. All subjects reported significant neuropathic pain relief on the PD-Q,
Age did not seem to play a significant difference with respect to relief from neu-
ropathic symptomatology. For ex., a 66-year-old subject showed greater improve-
ment than younger subjects.

Table 1. Inflammation, SPNS and PD-Q values before and after treatments.

Inflammation Inflammation SPNS SPNS % Pain PD-Q PD-Q % Pain

Gender Age
Prior After Prior After Decrease Prior After Decrease
Male 40 Yes No 32 12 62.5% 30 10 66.6%
Female 41 Yes No 34 15 55.8% 32 14 56.25%
Male 45 Yes No 28 6 78.57% 30 8 73.3%
Female 53 Yes No 23 8 65.21% 24 9 62.5
Male 60 Yes No 22 16 27.27% 21 14 33.3%
Female 66 Yes No 38 13 65.78% 36 12 66.6%
Female 66 Yes No 26 9 65.38% 25 8 68%
Male 73 Yes No 23 9 60.86% 24 11 54.16%
Male 75 Yes No 20 7 65% 19 8 57.89%
Male 78 Yes No 22 8 63.6% 24 6 75%
Mean Average 26.8 10.5 61% 26 11.5 67.9%

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 X. Sofra, N. Lampe

Table 2. Subjects results on reported percentage of neuropathic symptomatology relief

based on the clinical interview and symptomatology checklist after treatments.
Sharp Tingling Sensitive Muscle Poor
Numbness Pain
Gender Age Sensation Sensation To Touch Weakness Mobility
% %
% % % % %
Male 40 70% 70% 70% 80% 80% 70% 70%
Female 41 65% 60% 60% 65% 70% 65% 65%
Male 45 80% 70% 80% 75% 80% 70% 70%
Female 53 75% 75% 80% 65% 75% 75% 65%
Male 60 55% 57% 60% 70% 70% 60% 60%
Female 66 60% 65% 60% 70% 70% 70% 65%
Female 66 68% 70% 68% 68% 78% 70% 70%
Male 73 73% 70% 75% 75% 80% 75% 75%
Male 75 70% 70% 70% 75% 80% 70% 65%
Male 78 75% 70% 75% 75% 85% 75% 70%
Mean Average % 69% 68% 70% 72% 77% 70% 66%

Table 3. Subjects results on reported percentage of neuropathic symptomatology relief

based on the clinical interview and symptomatology checklist after one year.
Sharp Tingling Sensitive Muscle Poor
Numbness Pain
Gender Age Sensation Sensation To Touch Weakness Mobility
% %
% % % % %
Male 40 70% 70% 75% 90% 80% 80% 75%
Female 41 60% 55% 60% 55% 55% 65% 65%
Male 45 80% 70% 80% 80% 80% 80% 80%
Female 53 50% 50% 50% 50% 50% 50% 50%
Male 60 55% 57% 70% 70% 70% 60% 60%
Female 66 60% 65% 65% 65% 65% 60% 60%
Female 66 68% 70% 78% 78% 78% 70% 70%
Male 73 70% 70% 70% 70% 70% 65% 65%
Male 75 70% 70% 80% 80% 80% 70% 70%
Male 78 70% 60% 70% 70% 70% 60% 60%
Mean Average 65% 64% 70% 71% 70% 66% 66%

Table 4. Summary of data. Results analysis with ANOVA for repeated measures.

Treatments
1 2 3 4 Total
N 10 10 10 10 40
∑X 268 103 265 102 738
Mean 26.8 10.3 26.5 10.2 18.45
∑X2 7510 1169 7275 1110 17064
Std. Dev. 6.0332 3.4657 5.2967 2.7809 9.4025
Result Details
Source SS df MS
Between-treatments 2690.1 3 896.7 F = 93.51448
Within-treatments 757.8 36 21.05
Error 258.9 27 9.5889

The F-ratio value is 93.51448. The p-value is < 0.00001. The result is significant at p < 0.01.

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X. Sofra, N. Lampe

5. Discussion
This randomized double blind longitudinal clinical trial that was conducted in
the absence of any pain medication, indicated a significant lasting improvement
in pain analgesia and the symptomatology of neuropathy after six half-hour
treatments on each leg with ultra-low energies nanotechnology, supporting
our hypothesis. Interestingly, age was not a factor since older subjects reported
greater pain analgesia and neuropathic symptomatology relief than younger
subjects on all measures. Although we included a symptomatology checklist, a
clinical interview and physical examination along with the self-report measures,
it should be noted that subjective reports are usually prone to distortion based
on the individual experience and personal perspective. We made an inference
that our results were due to a significant reduction of oxidative stress subse-
quently decreasing inflammation, on the basis of previously mentioned research
associating oxidative stress to inflammation [21] [22] [23], and mathematical
evidence that electrons control the cells’ ion gates at energies below thermal
noise [27]. The nanotechnology’s electron generation and flow through the ion
channels and into the cells interiors presumably repair the uneven number of
electrons in free radicals, thus transforming them into stable molecules. The
unobstructed flow of electrons though ion sodium, potassium and calcium
channels at discrete times based on the mathematical calculations of tunneling
electrons controlling the timing of circadian rhythms [27], may also energize
age-inactivated molecular mechanisms, invigorate blood circulation, trigger cel-
lular detoxification, ultimately decreasing inflammation and initiating a bottom
up reparative process.
Our clinical study fell short in terms of examining oxidative damage in the
subjects’ blood, or exploring inflammation markers such as the C-reactive pro-
tein (CRP) for example, that increase when there is an inflammatory condition.
Overall, additional measures to test for oxidative damage, inflammation mark-
ers, hyperglycemia, and level of endothelial dysfunction in diabetic subjects with
neuropathy is necessary to further validate and substantiate our results.

6. Conclusion
Our sample was small, and the study’s outcome was entirely based on subjective
assessments and short self-report questionnaires that are usually prone to idio-
syncratic distortion, exaggerations or understatements, in the absence of addi-
tional measures to test for oxidative damage, inflammation markers or hyper-
glycemia. However, the results of the self-report questionnaires, symptomatolo-
gy checklist, clinical interviews and physical examinations were consistent in
reiterating a long-term reduction of inflammation, neuropathic pain and overall
symptomatology, following treatment with ultra-low energy nanotechnology.
Results were statistically significant suggesting an alternative solution to adverse
consequences such an amputated limp or lengthy expensive hospitalizations, by
decreasing inflammation, and offering long-term analgesia and relief from neu-

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 X. Sofra, N. Lampe

ropathic symptomatology.

Acknowledgements
The authors would like to thank William Stewart for his electronic research on
this new ultra-low energy technology.

Funding Sources
This project was not been funded by an outside source or institution.

Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this pa-
per.

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