ATHM 5359_final_PNI

Ross—Effects of EMF on Inflammatory Pain Mechanisms34 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3
Electromagnetic Field Devices and Their
Effects on Nociception and Peripheral
Inflammatory Pain Mechanisms
Christina L. Ross, PhD; Thaleia Teli, PhD; Benjamin S. Harrison, PhD
REVIEW ARTICLE
ABSTRACT
Context • During cell-communication processes,
endogenous and exogenous signaling affects normal and
pathological developmental conditions. Exogenous
influences, such as extra-low-frequency (ELF)
electromagnetic fields (EMFs) have been shown to affect
pain and inflammation by modulating G-protein
coupling receptors (GPCRs), downregulating
cyclooxygenase-2 (Cox-2) activity, and downregulating
inflammatory modulators, such as tumor necrosis factor
alpha (TNF-α) and interleukin 1 beta (IL-1β) as well as
the transcription factor nuclear factor kappa B (NF-κB).
EMF devices could help clinicians who seek an alternative
or complementary treatment for relief of patients chronic
pain and disability.
Objective • The research team intended to review the
literature on the effects of EMFs on inflammatory pain
mechanisms.
Design • We used a literature search of articles published
in PubMed using the following key words: low-frequency
electromagnetic field therapy, inflammatory pain markers,
cyclic adenosine monophosphate (cAMP), cyclic guanosine
monophosphate (cGMP), opioid receptors, G-protein
coupling receptors, and enzymes.
Setting • The study took place at the Wake Forest School
of Medicine in Winston-Salem, NC, USA.
Results • The mechanistic pathway most often considered
for the biological effects of EMF is the plasma membrane,
across which the EMF signal induces a voltage change.
Oscillating EMF exerts forces on free ions that are present
on both sides of the plasma membrane and that move
across the cell surface through transmembrane proteins.
The ions create a forced intracellular vibration that is
responsible for phenomena such as the influx of
extracellular calcium (Ca2+
) and the binding affinity of
calmodulin (CaM), which is the primary transduction
pathway to the secondary messengers, cAMP and cGMP,
which have been found to influence inflammatory pain.
Conclusions • An emerging body of evidence indicates
the existence of a frequency-dependent interaction
between the mechanical interventions of EMF and cell
signaling along the peripheral inflammatory pain pathway.
(Altern Ther Health Med. 2016;22(3):##-##.)
Christina L. Ross, PhD, is a research fellow at the Wake
Forest Institute for Regenerative Medicine (WFIRM) and a
research fellow at Wake Forest Center for Integrative
Medicine, Wake Forest School of Medicine, in Winston-
Salem, North Carolina. Thaleia Teli, PhD, is a research
fellow at WFIRM. Benjamin S. Harrison, PhD, is an
associate professor at WFIRM.
Corresponding author: Christina L. Ross, PhD
E-mail address: chrross@wakehealth.edu
I
n humans, electromagnetic-field (EMF) therapy has
proven to be a safe, noninvasive, easy-to-use method to
treat the site of pain and inflammation.1
Research has
shown that therapeutic applications at extra-low-frequency
(ELF) levels (ie, 1-100 Hz) of EMF stimulate the immune
system by suppressing inflammatory responses at the cell
membrane level.2
Double-blind, placebo-controlled clinical
trials have reported that EMF passes through the skin into
the body’s conductive tissue,3-5
reducing pain and delaying
the onset of edema shortly after trauma.6,7
In a randomized,
double-blind, sham-controlled clinical study, low-frequency
(LF), pulsed EMF (PEMF) at 0.1 to 64 Hz was reported to
improve mobility and decrease pain and fatigue in patients
with fibromyalgia (FM).8
Both clinical and in vitro studies have reported that
EMF is effective in the treatment of osteoarthritis (OA).9,10
Although many drugs have been used recently for the
treatment of OA, the majority of them relieve pain and
increasefunctionbutdonotmodifythecomplexmechanisms
that occur in the pathology.11
PEMF has a number of well-
documented physiological effects on cells and tissues,
including the expression of the transforming growth factor
beta (TGF-β) super family, an increase in the levels of
glycosaminoglycan, and an anti-inflammatory action.12
Due

Ross—Effects of EMF on Inflammatory Pain Mechanisms ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 35
to those discoveries, a strong rationale exists for supporting
the use of biophysical stimulation with PEMF for the
treatment of inflammatory pain that is related to diseases
such as OA, FM, and migraine headache. Although the
treatment may be a promising therapy, investigators have
reported conflicting outcomes, with obvious differences in
their measuring techniques. Some studies do not report the
frequency and intensity (ie, the field strength) of their
treatment device; therefore, it is difficult to compare the
parameters being used toward specific outcomes.
For this review, the authors performed a literature
search of articles published in PubMed using the following
key words: low-frequency electromagnetic field therapy,
inflammatory pain markers, cyclic adenosine monophosphate
(cAMP), cyclic guanosine monophosphate (cGMP), opioid
receptors, G-protein coupling receptors, and enzymes. The
literature search was conducted from October of 2014 to
May of 2015.
EMF NOMENCLATURE
When discussing cellular influences by either
endogenous or exogenous fields, it is important to define the
nomenclature. The term EMF is used to summarize the
whole field, which includes electric, magnetic, and combined
electromagnetic effects.
An electric field (EF) involves a current that can be
either direct (DC) or alternating (AC). Units of electrical
current are measured in amperes (A), and differences in
electrical potential are measured in volts (V). Units of
magnetic-flux density (ie, intensity) are measured in either
Gauss (G) or Tesla (T), which is 10000 Gauss.
Faraday’s Law of Induction and Maxwell’s equations
explain how an EMF is generated. A static electric field is
generated by a static charged particle (q). The electric field or
“E” component of an EMF exists whenever a charge (Q) is
present. Its strength is measured in volts per meter (V/m)
and is expressed as intensity for field strength. An electric
field of 1 V/m is represented by a potential difference of
1 volt existing between 2 points that are 1 m apart.
A magnetic field (MF), or the “M” component of an
EMF, arises from current flow. The Tesla or Gauss is used
mainly to express the flux density or field strength produced
by the MF. Both EFs and MFs are generated if a charged
particle moves at a constant velocity. Combined, they
generate an EMF when the charged particle is accelerated.
Most often, the acceleration takes place in the form of an
oscillation; therefore, electric and magnetic fields often
oscillate. A change in the EF creates an MF, and any change
in the MF creates an EF. That interaction suggests that the
higher the frequency of the oscillation is, the more the
electric and magnetic fields are mutually coupled.
EMFs can affect biochemical reactions and the behavior
of charged molecules near cell membranes. The magnetic
aspect can influence cell behavior by (1) exerting a force on
moving charge carriers, such as ions; (2) generating electric
fields in conductive substances; (3) changing the rate of
diffusion across membranes13
; and (4) distorting bond angles,
which affects protein-structure binding and, therefore,
macromolecule synthesis.14
Unlike EFs, which are shielded by the highly dielectric
properties of the cell membrane, magnetic gradients penetrate
deeper through layers of living tissue,15
acting directly on cell
organelles. Pulsing the EMF causes a rise and fall in ion fluxes,
whereby changes in the membrane potential cause an inward
current flow, resulting in hyperpolarization of its potential.16
Depending on the parameters involved in the EMF treatment
and the biological process in question, either stimulation or
inhibition can occur. In contrast to the membrane, the
cytoplasm or fluids in extracellular spaces contain no free
electrons to carry a charge; the current is carried by charged
ions, such as sodium (Na+
), potassium (K+
), chloride (Cl-
),
and extracellular calcium (Ca2+
).
TYPES OF EMF DEVICES
EMF devices exhibit varying parameters that include
(1) frequency—the number of cycles per time unit (Hz);
(2) amplitude—the intensity or magnetic-field strength; and
(3) exposure—the time duration.17,18
The objective of the
devices is the production of a uniform EMF to expose cells
or tissue to a consistent set of dosing parameters. For
therapeutic purposes, the devices include the transcutaneous
electrical nerve stimulation (TENS) and transcranial direct
current stimulation (tDCS) devices, the solenoid, and the
Helmholtz coil (Figure 1).
Figure 1. EMF Devices
Abbreviations: EMF, electromagnetic field;
TENS, transcutaneous electrical nerve stimulation.
(A) TENS
(C) Helmholtz Coil
(B) Solenoid
Wire Coil
Magnetic
Field

Transcranial Direct Current Stimulation
TENS has been used to treat a variety of conditions with
battery-generated electric current that stimulates nerves to
reduce inflammatory pain. The device is connected to the
skin via 2 or more electrodes that modulate pulse width,
frequency, and intensity. Although typically used at the site
of an injury, it is possible that an application outside the
injured site can be effective.
Ainsworth et al have confirmed that hypothesis by
showing that application of TENS to the contralateral hind
limb of rats reduces the hyperalgesia of an inflamed limb.19,20
The study presented the results for each animal by showing
the differences in pressure between the measurements
performed on the right hind paw, which had been injected
with carrageenan, and those performed on the left hind paw,
which had been injected with saline. A reduction in
thresholds was interpreted as hyperalgesia; however, it must
be taken into consideration that the analgesic effects of TENS
might have been stress induced. Greater hyperalgesia
stemming from the inflammatory process that had been
induced by the carrageenan in the right paw would have
required less pressure to provoke the removal of the paw
from the algesimeter, thereby leading to a more negative
value when comparing the inflamed and noninflamed paw.
Exposure applications in those 2 studies were either (1) an
HF of >50 Hz), with an intensity below motor contraction
(ie, sensory intensity) or (2) an LF of <10 Hz, with an intensity
that produced motor contraction (ie, 20-40 pulses per
second).21,22
It is generally thought that TENS produces
analgesia by activation of cutaneous afferent fibers at the site of
application; however, other reports have shown the importance
of deep-tissue afferents in analgesia produced by TENS.23
Various theories have been proposed to explain the
analgesic mechanism of TENS. Recent in vivo studies have
demonstrated that part of the analgesia is mediated through
neurotransmitters acting at peripheral sites. Sabino et al24
have interpreted TENS effects to be mediated by many
neurotransmitters, including opioids, serotonin,
acetylcholine, norepinephrine, and gamma-aminobutyric
acid. In that study, LF but not HF TENS was shown to
involve the mu-opioid 5-HT2 and 5-HT3 receptors.
HF but not LF TENS has been reported to involve delta-
opioid receptors and to reduce aspartate and glutamate levels
in the spinal cord. Santos et al have reported the effects of an
LF at 10 Hz and an HF at 130 Hz of TENS on hyperalgesia
and edema when applied before serotonin (5-HT) was
administered to rats’ paws.25
In that study, both LF and HF
TENS were applied to the right paw for 20 minutes, and
5-HT was administered immediately after the TENS.
Santos et al used the Hargreaves method26
to measure
nociception, and a hydroplethysmometer was used to
measure edema. That method measures the level of cutaneous
hyperalgesia from thermal stimulation in carrageenan-
induced inflammation in rats’ paws, showing greater bioassay
sensitivity and providing measurements of other behavioral
parameters in addition to paw withdrawal, as well as
supplying a measurement of the nociceptive threshold. In the
Santos et al study, neither the LF nor the HF TENS inhibited
5-HT-induced edema; however, the LF TENS, but not the
HF, significantly reduced 5-HT-induced hyperalgesia.
SomersandClemente27
havereportedthatadministration
of HF or a combination of HF and LF TENS daily can reduce
mechanical, but not thermal, allodynia in the right hind paw
of rats with right-sided chronic construction injury (CCI).
Daily HF TENS appeared to elevate the dorsal horn’s
synaptosomal content of gamma-aminobutyric acid (GABA)
bilaterally, and a combination of HF and LF TENS elevated
the dorsal horn’s content of aspartate, glutamate, and glycine
bilaterally over that seen in untreated CCI rats.
Fang et al28
have shown in an in vivo study that TENS
may be an effective therapy in controlling inflammatory pain
by inhibiting the activation of the spinal extracellular signal-
regulated kinase (ERK) 1/2-cyclooxygenase (COX)-2
pathway. Those researchers induced inflammatory pain in
rats using carrageenan. Treatment was applied using TENS at
an LF of 2 Hz and an HF of 100 Hz, with intensities ranging
from 1 to 2 mA at 5 hours and 24 hours after the injection,
with each treatment lasting 30 minutes. Although the
outcome related to control of peripheral inflammation was
found to be independent of anti-inflammatory activity, the
analgesic effects of TENS on the inhibition of the ERK1/2-
COX-2 pathway was statistically significant at 2 Hz, but not
at 100 Hz. Those trials suggest that adequate dosing,
particularly the correct frequency, is critical to obtaining
pain relief with TENS. Basic scientific studies using animal
models of inflammation also report changes in the peripheral
nervous system as well as in the spinal cord and descending
inhibitory pathway in response to TENS.22
Transcranial Direct Current Stimulation
In clinical trials, tDCS devices have also been reported
to be effective in the treatment of migraine headache. Those
devices look very similar to the TENS device, with electrodes
placed on the patient’s forehead. In randomized, double-
blind, controlled study, Rocha et al29
studied 23 adults,
11 with and 12 without an aura, and compared them with
11 healthy patients to test the effects of 12 sessions of tDCS
treatment on the visual cortex during a 90-day period. The
phosphene threshold (PT) induced by the tDCS was recorded
to measure the excitability of the visual cortex before and
after each session. The measurements at baseline showed a
higher level of cortical excitability in patients with migraines
when compared with healthy volunteers. After the tDCS
application, a significant decrease was observed in the
number of migraine attacks, frequency of painkiller intake,
and duration of each attack in the intervention group. PT
analysis indicated that no differences existed in cortical
excitability after treatment. The clinical improvements of the
patients after tDCS treatment were not correlated with
changes in cortical excitability.
Laste et al30
has reported that tDCS can induce changes
in cortical excitability in rats (N=18, with 9 in the treatment

group and 9 in the sham group) and in humans, which lasted
beyond the duration of the stimulation. To evaluate the
effects of eight 20-minute treatments with tDCS for chronic
inflammatory pain, the rats were injected with complete
Freund’s adjuvant (CFA) in the right footpad to induce
inflammation. Both the intervention and sham groups were
exposed to a hot plate; then, Von Frey tests were applied
immediately and at 24 hours after the last tDCS session of
500 µA. The results showed significant, lasting, neuroplastic
effects related to the analgesic effects of tDCS on a chronic-
pain model of peripheral inflammation.
To study the analgesic effects of tDCS on postprocedural
pain in healthy patients with abdominal pain after endoscopic
retrogradecholangiopancreatography(ERCP),arandomized,
sham-controlled study was conducted involving 21 patients
who were exposed to 20 minutes of 2-mA treatment with
tDCS immediately after the ERCP procedure.31
As outcome
measures, the study used a visual analog scale, the McGill
Pain Questionnaire, and a brief pain inventory and also
documented the patient-controlled use of analgesics and
adverse events. In the intervention group, 22% less
hydromorphone was used by patients versus the sham group.
The tDCS patients also reported significantly less interference
with sleep because of pain, with t17
= 3.70 and P = .002, and
less throbbing pain as well, with t16
= 2.37 and P = .03. The
visual-analog pain scale and mood scores at 4 hours post-
ERCP showed no significant differences, despite
hydromorphone use. The side effects of the tDCS treatment
were limited to mild tingling, itching, and stinging under the
site of the electrode placement.
As to the frequency-specific effects of tDCS, Khadka et al32
tested a range of 3 signals—39 and 76 µA at 1, 10, and
100 Hz—in an in vitro test creating electrode-failure
modes. Both the DC and AC components of the voltages
across the electrodes were compared, and participants were
asked to rate subjective pain. The researchers’ results
showed that average voltage and pain scores were not
significantly different across the test-current intensities and
frequencies.
Solenoids
A solenoid consists of a thin loop of coiled wire that
produces a uniform MF when an electric current passes
through it. The device is used by exposing the painful or
inflamed area to the field for a prescribed amount of time.
The EMF produced by solenoids has been used to affect the
inflammatory biomarkers that are associated with oxidative-
stress plasma fibrinogen, nitric oxide (NO), L-citrulline,
carbonyl groups, and superoxide dismutase (SOD) in rats
with experimental myopathy.
Vignola et al33
have compared an EMF treatment with a
sham treatment at a 50-Hz frequency and a 20-mT intensity,
for 30 minutes per day per rat. The researchers’ results
showed that the EMF decreased the levels of fibrinogen,
L-citrulline, NO, SOD, and carbonyl groups, with significant
muscle recovery.
Sanserverino et al34
have reported that a solenoid at
50 Hz, which emitted field intensities between 3 mT and
6 mT, had relieved pain and improved joint mobility with
15 sessions at 15 to 40 minutes daily. Subsequently, an
82% improvement was observed when single-joint disease
was considered as compared to a 66% improvement for
multiple-joint disease (polyarthrosis). The absence of side
effects also proved to be an added benefit. The researchers’
hypothesis for the mechanisms of action included
transmembrane ionic activity.
Helmholtz Coils
The Helmholtz coil consists of 2 identical, circular,
magnetic coils (ie, solenoids), which are placed symmetrically
along a common axis, 1 on each side of the experimental area
and separated by a distance that is equal to the radius of the
coil. Each coil carries an equal amount of electric current
flowing in the same direction, producing a uniform MF via
Faraday’s law.
Helmholtz coils have been used as the intervention in
various studies (eg, animal models of arthritis, cell-culture
systems, and clinical trials). In a review of these studies,
Ganesan et. al35
indicated that EMF not only alleviated the
pain of arthritic conditions, but also afforded chondrocyte
protection, exerted anti-inflammatory action, and helped
bone remodeling. Although clinical trials have reported
beneficial effects with PEMF therapy, Ganesan et. al35
stated the results were not consistent, reporting little
evidence was available showing PEMF is more effective
than placebo.
Li et al9
have assessed both the beneficial and harmful
effects of EMF for the treatment of OA as compared with
placebo or sham. Evaluating controlled trials using EMF for
OA with 4 or more weeks of treatment duration, the
researchers found 9 studies of 636 patients in the Cochrane
Database of Systemic Reviews that found EMF treatment
provides a moderate benefit for OA sufferers in terms of pain
relief. The researchers, however, suggested that further
studies are required to confirm whether the treatment can
provide clinical benefits in terms of physical function and
quality of life.
In 2014, Adravanti et al36
reported as much as one
year after total knee arthroplasty (TKA), a significant
percentage of 33 patients had not attained complete
recovery and indicated the patients’ long-term pain
outcomes were unfavorable. Patients were treated 4 hours
per day for 60 days and assessed before surgery at 1, 2, and
6 months postopertatively, using international scores. One
month after TKA, the pain level of knee swelling and
functional scores were significantly better in the treatment
group as compared with the control group. Pain was
significantly lower in the treatment group at the 6 month
follow-up. Three years after surgery, severe pain and
occasional walking limitations were reported in a
significantly lower number of patients in the treatment
group.

Studies conducted by Qin et al37
have reported that a
low-intensity, LF EMF from a Helmholtz coil provided
substantial relief to rats with various types of chronic pain
that triggered the activity of the thoracic spinal neurons in
response to noxious visceral stimuli. In their study, the
researchers recorded the T3-T4 spinal neurons in male rats
that had been anesthetized with pentobarbital and
administered with noxious chemicals producing cardiac
stimulation. Noxious esophageal distention was also
produced via inflation of a latex balloon. EMF frequencies of
<1 Hz and <0.05 µG were applied to both sides of the rats’
chests.
The study’s results showed a 75% decrease in excitatory
neuronal responses to intrapericardial chemicals for the
intervention group. The inhibitory effect on the spinal
neurons occurred at 10 to 20 minutes after EMF application,
and the effects continued 1 to 2 hours after termination of the
application. Seven of the 18 excitatory-response neurons
related to esophageal distention (39%) were inhibited; 5 were
excited (28%); and 6 were not affected by the treatment
(33%). The authors concluded that application of EMF could
reduce the nociceptive responses of the spinal neurons to
noxious, cardiac chemical stimuli, whereas the treatment was
not effective for nociceptive responses to esophageal
mechanical stimulation.
Regarding responses to thermal stimuli in animal
studies, Schaible38
exposed rats (n = 24) to EMF using a
Helmholtz coil, either sham or frequency-modulated, at
2 mT for 30 minutes on 2 consecutive days. The rats exhibited
strong analgesic effects to thermal stimulation applied to
footpads immediately after treatment, and up to 30 minutes
later. Schaible’s generalized speculations as to the mechanisms
of action included an EMF modulation of ion flux.
MECHANISMS AT MOLECULAR LEVEL
Tissue trauma, immune reactivity, and nerve injury are
frequently associated with an inflammatory pain response.
Within peripherally damaged tissue, such as skin, muscles,
joints, and viscera, the primary afferent neurons transduce
noxious mechanical, chemical, and/or thermal mechanisms
to activate specific receptors and ion channels in peripheral
nerve endings.40
Those events result in the initiation of action
potentials that propagate along the axons of primary, afferent
pain fibers to synaptic sites in the spinal cord’s dorsal horn.
Peripheral sensory neurons express opioid receptors and
opioid peptides, and the function of those neurons can be
modulated by endogenous opioids derived from immune
cells that seek to affect the mechanisms of inflammatory pain
and its inhibition.
Peripheral sensitization contributes to the pain
hypersensitivity found in inflammation and at the site of
tissue damage. Peripheral inflammation in primary sensory
neurons consists of changes in their neurochemical character
due to alterations in transcription and translation. The
electrical activity of primary afferent neurons is primarily
governed by the expression and function of ion channels that
define the resting membrane potential, action-potential
initiation, depolarization and repolarization, and transmitter
release from terminals in the dorsal horn.39
LF EMF passes unobstructed through living tissue40,41
and has been shown to modulate ion flux along the cell
membrane, thereby achieving opioid-mediated analgesia.42,43
Because EMF can alter ion flux, it can influence subsequent
cellular events in the signal-transduction cascade.44,45
The
effects of EMF on pain, nociception, and opiate-mediated
analgesia have a number of potential cellular targets that are
closely related (ie, Ca2+
ion fluxes, kinases, NO, and GPCRs),
establishing a chain of events leading to an increase in
analgesic affects.
Although the basic transduction mechanisms of EMF
are still being investigated, a substantial body of theoretical
work has focused on ion/ligand binding as a possible factor
for the biomechanical interaction of exogenous EMF with
the cell membrane. The application of any mechanical
stimulus, such as fluid-shear stress or exogenously applied
EMF, to the cell surface can activate mechanically sensitive
ion channels, G-protein kinases, and other membrane-
associated signal-transduction molecules, which trigger
downstream signaling cascades that can lead to force-
dependent changes in gene expression.46
It is now known that mechanical action at a distance
occurs in living cells,47-50
and that a unique form of mechanical
signaling provides a more rapid and efficient way to convey
information over long distances during cell communication
than does diffusion-based chemical signaling.
Panagopoulos et al proposed a simple hypothesis that an
oscillating, external EMF can exert an oscillating force on each
of the free ions that exist on both sides of the plasma
membrane and that the force can move across the membrane
via transmembrane proteins.51
The researchers have theorized
that the external oscillating force can produce a forced
vibration on each free ion, and when the amplitude of the ions’
force-vibration transcends some critical value, the oscillating
ions can give a false signal to gating channels that are
electrically sensitive, or even mechanically sensitive, thereby
interrupting the electrochemical balance of the membrane
and, therefore, of the entire cell function (Figure 2).
The types of channels include (1) voltage-gated channels
(ie, voltage-sensitive channels); (2) mechanically gated
channels (ie, channels gated by ion pressure); and (3) ligand-
gated channels (ie, chemically sensitive channels).52
Mechanical stimulation of the channels may help to explain
how mitochondria located far from the cell surface can sense
and respond to mechanical stressors by releasing reactive
oxygen species (ROS) and activating signaling molecules,
such as the GPCRs, that contribute to pain as well as nuclear
factorkappaΒ(NF-κΒ),atranscriptionfactorthatcontributes
to the inflammatory response.53
Voltage-dependent Ca2+
channels play a significant role in the cell-differentiation
process by triggering intracellular events, such as the
activation of enzymes that catalyze modulators of
inflammatory pain.54,55

One common theme in those studies is the biomechanics
of Ca2+
and its ability to alter the cell membrane to play a
significant role in the effects that EMF has on inflammatory
pain mechanisms.56
For an effect to occur in ligand-gated ion
channels, the interacting system must contain a Ca2+
molecular structure.57
For the EMF activation of the opioid
receptors against inflammation of peripheral tissue, for the
increased functionality of opioid receptors on peripheral
sensory neurons, and for the local production of endogenous
opioid peptides that have been observed in lymphocytes,
Ca2+
appears to be the principal cellular component affected
by the EMF exposure.58
And the Ca2+
/calmodulin (CaM)-
dependent signaling to intracellular enzyme systems appears
to act specifically as a primary transduction mechanism for
EMF treatment. As for cytokines and chemokines, the NO
activation of voltage-sensitive Ca2+
channels responds to
EMF exposure through Ca2+
/CaM stimulation of NO
synthesis. Beneficial responses may be largely a result of the
stimulation of the NO-cGMP-protein-kinase-G pathway.59
It has been reported that opiates induce analgesia by
diminishing the cellular-Ca2+
flux,60,61
and EMF has the
capability to reduce that flux to induce the same effect.42,62
It
has also been documented that Ca2+
channel blockers can
potentiate the effects of opiates by diminishing the inward
Ca2+
flux, and that action has been reported to occur in snails
and mice exposed to EMF.63,64
The Ca2+
channel agonists have
been investigated, with the researchers observing the
attenuating effects of opiates through enhancement of the
inward Ca2+
flux and potentiation of the effects of EMF.58,65,66
The mechanisms through which the EMF exchanges
informationbetweencellsandthewaysinwhichtheconversion
of that biomechanical signaling is translated have been
researched for decades. It has been reported that EMF can
permeate both the plasma and nuclear membranes of cells,
thereby affecting different types of tissues.67-69
The concept that
the extended membrane regions may be sensitive to EMF was
first proposed by Adey in 1974.70
Liboff has suggested that the
transport of calcium ions through channels of the cell
membrane involves a resonance-type response to the applied
EMF, which is the mechanism that activates ion flux, receptors,
kinases, and even transcription factors.71
Ursu et al72
found a strong correlation between the
kinetics of calcium flux and transient receptor potential
vanilloid 1 (TRPV1), the ligand-gated ion channel expressed
predominantly in nociceptive primary afferents that plays a
key role in pain processing. In that study, current-clamp
recordings were performed in the neurons of rats’ dorsal root
ganglia (DRG) to assess the consequences of TRPV1 activation
on neuronal excitability. The researchers reported that the Ca2+
ion flux and the TRPV1 influenced the trigger-of-action
potentials in sensory neurons. Due to that phenomenon, the
electrical-potential gradient that exists across the cells exposed
to the EMF can increase the activation of voltage-gated, Ca2+
ion channels on either side of the cell membrane, giving rise to
a gradient of intracellular Ca2+
that alters cell morphology.
That effect modulates the changes by intracellular actin
filaments in levels of cytosolic calcium73
and also produces a
significant decrease in the production of cyclic adenosine
triphosphate (ATP), which is a known master regulator of the
functioning of innate immune cells and of the generation of
inflammatory mediators.74,75
EFFECTS OF EMF
Effects on Ion-ligand Binding
Another focus of EMF biomechanics involves the ligand-
gated ion channels, which are a group of transmembrane,
ion-channel proteins that open to allow ions such a Ca2+
,
Na+
, Cl-
, and K+
to pass through the cell membrane in
Figure 2. Hypothesis for Mechanism of EMF
Note: The figure shows (A) a voltage-gated ion channel that controls intra- and extracellular ion flux due to a positive surface
charge, prior to application of EMF; and (B) a voltage-gated ion channel that can attenuate the opening and closing of the
ion channels, after application of EF or EMF, to trigger intracellular events due to a negative charge (-Q) that depolarizes the
plasma membrane.

Abbreviations: electromagnetic field (EMF); EF, electric field.
Polarized
Membrane
Ca2+
Ions
EMF
(A)
Depolarized
Membrane
Ca2+
Ions
Nonconductive
Medium=~3 nm
Insulating Membrane
(B)

response to the binding of an electrical or chemical
messenger.76-80
Ion fluxes such as those moving through
voltage-gated sodium and calcium channels are widely used
to treat inflammatory pain. In particular, voltage-gated
calcium channels (VGCCs) are the main source of
depolarization-induced calcium entry into neurons.81
Primary afferent neurons express multiple types of
VGCCs, with specific, subcellular, expression patterns and
functions. Those channels are clinically validated drug
targets for pain, and their roles in pain transmission have
been extensively reviewed.82
On peripheral nociceptors, they
arecriticalfornociceptivetransmissionbeyondtheperipheral
transducers and are responsive to exogenous stimuli, such as
waveform patterns emitted by EMFs.83
Although ion channels have a pervasive distribution,
recent studies have identified a number of channels, in
particular those of sodium and calcium, that appear to have
a more selective role in nociception.84
Many cationic channels
are responsible for the excitation of sensory neurons, and the
activation of those channels in sensory neurons is critical to
the generation of nociceptive signals. The main channels
responsible for inward membrane currents in nociceptors are
voltage-activated sodium and calcium channels, whereas
outward current is carried mainly by potassium ions.85
In
addition, the activation of nonselective cation channels is
also responsible for the excitation of sensory neurons. Thus,
the excitability of neurons can be controlled by regulating the
expression of or by modulating the activity of those channels.
It is well known that large numbers of free ions, such as
Ca2+
, Na+
, and K+
, reside on both sides of every cell membrane
and play an important role in signal transduction. Ion fluxes
throughcellmembranesareelucidatedbytheionconcentration
and voltage gradients between the 2 sides of the membrane.
Those ion fluxes affect primary afferent nociceptors that are
the initial part of the pain pathway86,87
and the accumulation of
ions creates an intense electric field on either side.18
Radhakrishnan and Sluka88
investigated cutaneous vs
knee-joint afferents and the antihyperalgesia that was
produced by TENS. The research showed differentially
blocked, primary afferents on use of local anesthetics. In the
study, hyperalgesia was induced by kaolin-carrageenan and
assessed by measuring a rat’s paw-withdrawal latency to heat.
Both HF and LF TENS were applied. Control experiments
were conducted using vehicles. Both frequencies completely
reversed hyperalgesia, and an injection of lidocaine into the
knee joint prevented the antihyperalgesia that would have
been produced by the HF or LF TENS. Application of an
anesthetic cream was shown to reduce the amplitude of the
cord-dorsum potential by 40% to 70% for both HF and LF
TENS, confirming the loss of large-diameter, primary-
afferent input. Therefore, the activation of joint afferents, but
not cutaneous afferents, prevented the antihyperalgesia
effects of the TENS. The researchers concluded that large-
diameter primary-afferent fibers from deep tissue are
required and that activation of cutaneous afferents is not
sufficient for TENS-induced antihyperalgesia.
Effects on G-protein Coupled Receptors
EMF has also been reported to affect inflammatory pain
by modulating GPCRs, which are 7-transmembrane domain
receptors that sense molecules outside the cell and activate
inside signal-transduction pathways.89
When the molecules
bind to a GPCR, that action is followed by a series of
conformational changes in the activated receptors, which are
capable of signaling to downstream molecules. When it
comes to the peripheral-pain pathway, inflammatory cells,
such as polymorphonuclear leukocytes (PMN), monocytes,
and macrophages, express a large number of GPCRs for
chemoattractants and chemokines.90
GPCRs are critical to
the migration of those phagocytes and their accumulation at
sites of inflammation, where they not only can exacerbate
inflammation but also can contribute to its resolution.
It has been hypothesized that the activation of GPCRs is
affected by voltage,91,92
due to reports that nonactivated
GPCRs do not appear to show any voltage-dependent
activity.93
That effect is in line with the hypothesis that the
binding of a charged agonist within an EMF that is present
on a cell membrane, is a major mechanism for the voltage
dependence of GPCR activation, indicating a definite voltage-
dependent activation of GPCRs at the receptor level. The
existence of voltage gradients on the cell surface and the ways
in which the gradients respond to EMF is of great importance
to inflammatory pain mechanisms.
Because endogenous EFs are generated by polarized ion
transport and conductive extracellular pathways, polarized ion
transport, which leads to the movement of a charge, can create
electrical-potential differences across immune cells.93
In that
process, the ion transport is dependent on the amount of
energy per unit of charge that is needed to move the ion across
the membrane. That amount is a measure of voltage potential.
Voltage potentials, such as those measured on lymphocyte
membranes, can reach +50 mV,94
due to the net positive charge
coming out of the cell by ions such as Na+
, K+
, and Ca2+
.
The idea that the immune system can communicate with
peripheral sensory neurons to modulate pain is based mainly
on reported interactions between opioid receptors and their
environments.95-97
One of the main aspects of inflammatory
pain pathways is the presence of opioid receptors that are
expressed on peripheral sensory nerve endings, cutaneous
cells, and immune cells, such as granulocytes, monocytes,
macrophages, and lymphocytes. During an inflammatory
response, those cells can produce the opioid peptides of
3 different receptors (ie, µ, δ, and к), which on activation, can
cause the dissociation of the GPCR subunits that inhibit
cyclic adenosine monophosphate (cAMP) production
and/or can interact with a membrane’s ion channels.98,99
Inflammation of peripheral tissue leads to the increased
functionality of opioid receptors on peripheral sensory
neurons and to local production of endogenous opioid
peptides. Opioid receptors are widely expressed in the
central and peripheral nervous systems as well as in numerous
nonneuronal tissues. Both animal models and human clinical
data support the involvement of peripheral opioid receptors

in analgesia, particularly in inflammation, where both the
opioid-receptor expression and efficacy are increased.100
EMF has been reported to reduce hyperalgesia and pain
through the release of endogenous opioids into the central
nervous system (CNS)101-106
; specifically, LF EMF at <10 Hz
can activate mu-opioid receptors, and HF at >50 Hz can
activate delta-opioid receptors in the spinal and rostral
ventral medulla (RVM).107
Different frequencies used under the same conditions
affect different opioid receptors. Experimental evidence has
shown that using the same time exposure and field strength of
EMF at ELFs <100 Hz, such as 4 Hz, will cause a spinal blockade
of mu-opioid receptors, preventing hyperalgesia, while the same
parameters used for EMF exposure at 100 Hz will prevent
hyperalgesia in delta-opioid receptors but not in mu-opioid
receptors.106,108
That frequency-dependent effect has been
reported at 60 Hz and 141 µT, with a 15-minute exposure, in
both mice109
and land snails.110
A 2-hour exposure of EMF at
1 Hz and a 20- to 27-µT field strength decreased the mu-opioid
receptors concentration in the brain of pigeons,111
with similar
outcomes at 50 Hz and 100 µT for 8 hours in rats.112
Studies have shown that exposure to a LF TENS device
produces endogenous opioids in both humans113
and rats.114
According to the investigators in those studies, the activation of
both the mu-opioid receptors and delta-opioid receptors
induced a reduction of hyperalgesia and pain. It is important to
note that animal studies tend to rely on reflex-based pain
assessments, which are increasingly recognized as being a poor
model of the pain experienced in humans compared to operant
assays.115
That statement is especially true in studies pertaining
to the effects of EMF on pain sensation in land snails.
Effects on Cytokines and Chemokines
Cytokines and chemokines are the mediators of
inflammation from within minutes to hours after injury
during the activation of inflammatory pain. They serve as
signals to engulf damaged tissue, destroy infectious agents,
and clear the wound bed for healing.116
Damaged cells
respond by activating stress-signaling pathways which
produce trauma-associated molecular patterns that activate
cue and chemotactic factors for other immune cells in the
area.117,118
The mechanistic effects of EMF on protein
molecules focus on the effects of gradients dependent on ion
flux on cytokines, such as tumor necrosis factor alpha (TNF-
α), interleukin 1 (IL-1), and interleukin 6 (IL-6), and
chemokines, such as interleukin 8 (IL-8) and regulated on
activation, normal T-cell expressed and secreted (RANTES).
In vitro studies have demonstrated the effects of EMF on
NF-κΒ, a downstream signal-transduction molecule,119
whereby researchers have reported that results can depend
on frequency, indicating that 8-µL/mL concentrations of
lipopolysaccharide (LPS)-challenged macrophages exposed
toEMFwithaHelmholtzcoilemittedatarangeoffrequencies
between 0 and 30 Hz. Those results showed a significant
downregulation of both TNF-α and NF-κΒ at 5 Hz but not at
10, 15, 25, or 30 Hz.120
A selective inhibition of NF-kB by ELF EMF may also be
involved in the decrease of chemokine production as reported
by Vianale et al,121
where the ELF-EMF exposure modulated
NF-kB activation as well as the proinflammatory cytokines
TNF-α and interleukin 1 beta (IL-1Β), growth factors, and
viruses known to cause infections.
In OA fibroblasts in the presence of EMF under
24-hour exposure at 75 Hz and 1.5 mT, other investigators
have reported that adenosine receptors downregulated the
proinflammatory cytokine IL-6 and the chemokine IL-8
while stimulating the release of interleukin 10 (IL-10), an
anti-inflammatory cytokine.122
At 50 Hz and 2.5 mT, EMF
exposure was reported to increase IL-1β in mouse
macrophages that had been activated with LPS after
24 hours but to decrease IL-1β in human fibroblasts when
using the same parameters. Under those same conditions,
EMF decreased IL-6 in LPS-activated human fibroblasts,
and TNF-α decreased when the researchers used the same
50 Hz with a 2.5 mT field on human fibroblasts activated
with LPS.
Other in vitro studies have shown that human
keratinocytes decrease IL-8 at an exposure to an EMF of 50
Hz and 1 mT for 4 hours, although they also have been
shown to decrease RANTES in the same cell line under the
same conditions.123
Mouse macrophages stimulated with LPS
and exposed to a time-varying EMF at 30 Hz and 400 Gauss,
were also reported to downregulate IL-6 and TNF-α after a
1-hour exposure.124
A range of EMF frequencies between
0and100Hzappeartoaffectvariousproteinsininflammatory
processes when studied in vitro.
In vivo studies have reported that a 27.12-MHz
radio frequency emitted from a solenoid device, with
3-ms bursts repeating at 2 Hz, can suppress significantly the
proinflammatory cytokine IL-1β, an early responder to injury
in rats with traumatic brain injury.125
That same frequency has
also been reported to cause a significant reduction in IL-1β
cytokines in wound exudate of human patients who had been
exposed to EMF for 20-minute treatments every 4 hours for the
first 3 days postoperatively and then every 8 hours for the next
3 days.60,61
EMF modulation of both cytokines and chemokines
may contribute to an increase in the NO that is involved in
the regulation of inflammatory pain modulators, such as
CaM, which in turn leads to the activation of endothelial NO
synthase (eNOS), increasing NO, and, thereby, modulating
cytokine expression through adenosine receptors and an early
decrease in the activity of NF-κΒ.
Effects on Enzymes
COX enzymes control the initial steps of the
inflammation process.126
Among the proteins mediating that
effect are dynorphin, an endogenous opioid that increases
neuronal excitability, and COX-2, the enzyme that produces
prostaglandin E2
(PGE2
). PGE2
is a known lipid mediator that
contributes to inflammatory pain.127
PGE2
increases the
phosphorylation of NO production through the activation of
cAMP-dependent protein kinase A (PKA).

In vitro studies have shown that adenosine receptors
modulate PGE2 in OA fibroblasts after 24 hours of exposure
to EMF at 75 Hz and 1.5 mT.122
EMF at 15 Hz and 0.6 mT for
72 hours has also been shown to affect that same analgesic
process by acting on PGE2
and PKA, initiating the release of
NO from osteoblasts and, thereby, increasing NO synthesis.128
NO appears early in biochemical cascades that are involved
in the inflammatory phase of tissue repair and has been
reported to be involved in the mechanism by which EMF
devices achieve pain relief.129
At 15 Hz and 0.6 mT, no significant differences have
been reported between unstimulated human monocytes that
either had been exposed or had not been exposed to EMF;
however, inducible NO synthase (iNOS) activity was
significantly reduced in LPS-stimulated human monocytes
that had been exposed to EMF at 15 Hz when compared to
LPS-stimulated cells that had not been exposed. That reduced
enzyme activity has been reported to be related to the
reduction of iNOS mRNA and immunoreactive iNOS
proteins that has been observed in rats induced with
experimental myopathy.33
Evidence linking EMF exposure to protein kinase C
(PKC) activity and analgesia provides an example of calcium-
activated, phospholipid-dependent PKC that plays an
important role in relaying transmembrane signaling inside
diverse, calcium-dependent, cellular processes during an
inflammatory pain response.130-132
Although the activation of
endorphins is a recurring theme in the process, compelling
evidence has indicated that EMFs can modulate opioid gene
expression.
Ventura et al133
found that the expression of opioid genes
was significantly increased following the exposure of
myocardialPKCinhibitorsthatsuppressedthetranscriptional
effects of cells exposed to an EMF at 50 Hz and 1.74 mT. The
researchers found that EMF-enhanced, myocardial, opioid
gene expression and a direct exposure of isolated myocyte
nuclei to EMF markedly enhanced prodynorphin gene
transcription in the intact cell. That EMF action was mediated
by nuclear PKC activation but occurred independently from
changes in PKC-isozyme expression and enzyme
translocation, suggesting the involvement of a nuclear
endorphinergicsystemintheregulationofgenetranscription.
DISCUSSION
EMF, when used to affect inflammatory pain, has been
shown to produce noninvasive outcomes while involving the
application of different frequencies, field strengths
(intensities), and time points that can affect nociception and
analgesia.134,135
Several parameters, including the doses,
frequencies, and phases of EMF devices are decisive as to
whether or not the cells respond, and if they do respond, in
what manner. For use of a TENS device, an application at
4 Hz and 10 to 18 mA for 20 minutes appears to activate the
mu-opioid receptor best, whereas an application at 100 Hz
and 10 to 18 mA for 20 minutes appears to activate the delta-
opioid receptors. Thermal analgesic affects have been
reported for applications at 20 Hz and 0.03 µT for 30 minutes
in rats; however, a debate still exists as to whether the
analgesic affect was stress induced.
Because various parameters of frequency, intensity, and
time of exposure are used for humans, animals, and cells, the
consistency of outcomes is difficult to ascertain. For example,
in a human keratinocyte model, Patruno et al have reported
a healing effect that is related to the effects on enzymes of an
EMF using an ELF of <100 Hz,136
and McKay et al have
reported that the EMF waveform is what generates the
effects. On the other hand, Kalra et al and Fleming et al have
suggested that the effects occur in the opioid receptors when
using a 4 Hz or a 1 µT field, respectively.43,137
What Fleming
does not explain is how an EMF would affect the receptor.
Table 1 identifies the different EMF frequencies, field
strengths, and exposure times and how the proposed
mechanisms along the peripheral inflammatory pain
pathways are affected.
As shown in Table 1, the parameters of time and
frequency can remain constant, but a change in field strength
will elicit a different outcome. Martin et al has reported that
the thermal analgesic effects were amplitude-(intensity-)
dependent in producing analgesia more quickly in male
rats.135
In that study, solenoids were used to emit an EMF,
with burst-firing configurations at once every 4 seconds for
30 minutes. Using a maximum strength of exposure at
0.25 µT, the researchers reported an analgesic response that
was significantly greater than the normal sham-field
responses, whereas the exposure at 0.30 µT did not produce
responses that differed significantly from the sham; the
standard error of the mean (SEM) for sham exposure was
2.2 and for EMF exposure was 0.4.135
Fleming et al138
reported that the whole-body exposure
of rats to a burst-firing EMF with intensities of 1 µT once
every 4 seconds for 20 minutes, displayed the minimum
intensity of stimulation needed to trigger the signal from
the axon to the spinal cord. When the electric current was
delivered to the rats’ footpads, its analgesic effect was still
apparent at 20 minutes after the removal of EMF and was
equivalent to the analgesia produced by 4 mg/kg of
morphine.
Kalra et al106
reported that hyperalgesia and pain were
attenuated in rats using 100 ms of exposure with a
10- to 18-mA field strength for 20 minutes; at 4 Hz, the
outcome was due to the activation of the mu-opioid receptor,
and at 100 Hz, the EMF activated the delta-opioid receptor.
The time of exposure appears to make a difference in the
outcome, as shown by Kavaliers et al,63
who reported for
snails that an application of EMF at 60 Hz and 100 µT altered
the Ca2+
flux, and the channels associated with opioid
receptors were dependent on the time of exposure. A
significant reduction in the analgesic effects of mu- and
kappa-opioid agonists occurred at 2 hours and 12 hours, but
at 48 to 120 hours showed no more effects than the 12-hour
application, and the 0.5-hour exposure had similar outcome
to that of the controls.

Patruno et al139
reported that EMF at a 50-Hz frequency
and a 1-mT field strength, with overnight exposure, enhanced
the re-epithelialization of keratinocytes by decreasing the
COX-2 expression and the downstream, intermediate PGE2
in vitro.
In conditions such as OA, controlling chondrocyte
degradation and inflammation is currently the most important
target. Some evidence has shown that PEMF can counteract
late-stage OA progression at 2 different frequencies, 37 Hz and
75 Hz, in 21-month-old guinea pigs. After 3 months of
stimulation with EMF for 6 hours per day, both histological and
histomorphometric analyses of the guinea pigs’ knees were
performed. In comparison to the nontreated sham group, at
both frequencies the EMF significantly reduced (1) the
histological cartilage score, which measures the severity of
cartilage pathology140
; (2) the Fibrillation index (FI), which
measures the pathological characteristic of fibrillation in OA;
(3) the subchondral bone thickness, which reflects the fact that
the damage in the cartilage matrix increases as the load duration
increases; and (3) the trabecular numbers. The EMF also
increased the trabecular thickness and separation (trabecular
spacing), which basic bone research has shown are key measures
characterizingthe3-dimensionalstructureofcancellousbone.141
EMF at 75 Hz produced significantly more beneficial effects on
the histological score and the FI than did EMF at 37 Hz. At
75 Hz, EMF counteracted cartilage thinning, as demonstrated
by significantly higher cartilage thickness values than either the
sham or the group treated at 37 Hz. In cases of severe OA, both
EMF frequencies were able to limit OA progression, but the
75-Hz stimulation achieved better results.
During clinical trials, certain frequencies and field
strengths have produced different outcomes depending on
the condition. In a randomized, double-blind, sham-
controlled clinical trial, a total of 50 patients with either
chronic generalized pain from FM or chronic localized
musculoskeletal or inflammatory pain were exposed to
extremely weak pulses of EMF at 400 µT and 1000 Hz or less
for 800 mT per second, using a portable solenoid device that
fitted to patients’ heads during the twice-daily, 40-minute
treatments for 7 days.142
The outcomes were recorded using a
visual analog scale. A differential effect of EMF over sham
treatment was noted in patients with FM that approached
statistical significance at P=.06 for n=17 but was not evident
in those treated who did not have FM (ie, had musculoskeletal
or inflammatory pain), P=.93 for n=15.
In a double-blind, placebo-controlled clinical trial,
22 patients were assigned to treatment (n=28) or sham (n=26)
groups to test the analgesic and antinociceptive effects of
low-intensity (ie, 8 Hz) EMF on FM patients.143
Pressure pain
thresholds before and after treatment were determined using
an algometer during the 8 consecutive, weekly sessions. Also,
blood serotonin levels were measured and patients completed
questionnaires to monitor symptoms. Repeated-measures
analysis of variance (ANOVA) indicated a statistically
significant improvement in the treatment group compared
with the controls with respect to somatosensory pain
thresholds, ability to perform daily activities, perceived
chronic pain, and sleep quality. Although improvement in
pain thresholds was apparent after the first session,
improvement in the other 3 measures occurred after week 6
Table 1. Conditions, Treatment Parameters, Mechanisms of Action, and Results
Inflammatory
Pain Condition Hz
Field
Strengths
Time
Courses Molecular Mechanisms Outcomes
Inflamed knee-
joint pain54
4 100 ms
10-18 mA
20 min Activation of mu-opioid
receptor was frequency-
dependent.
The treatment produced antihyperalgesia by activation of
mu-opioid receptors in the rostral ventral medulla of rats.
Inflamed knee-
joint pain54
100 100 ms
10-18 mA
20 min Activation of delta-opioid
receptor was frequency
dependent.
The treatment produced antihyperalgesia by activation of
delta-opioid receptors in the rostral ventral medulla of rats.
Thermal analgesic
effects73
20 0.03, 0.3,
3 µT
30 min Analgesic effects were EMF
intensity dependent.
The 0.03-µT field strength exhibited an analgesic response
(rat-paw reflex) that was significantly greater than that of the
sham treatment.
Effect on
endogenous
opioid systems in
burns56
60 100 µT 30 min, 2 h,
12 h, 48 h,
120 h
Alterations in the Ca2+
flux and
channels associated with opioid
receptors were time-dependent.
The treatment produced a significantly attenuated,
morphine-induced analgesia and reduced basal nociceptive
responses in snails via the reduced analgesic effects of the
mu- and kappa-opiate agonists. The 0.5-h time course
showed no significant effects. The 2-h and 12-h time courses
showed significant effects. The 48-h and 120-h time courses
showed effects that were more significant than the 12-h
course.
Effect on
endogenous
opioid systems in
burns130
60 100 µT 30 min, 1 h,
2 h
Alterations in the Ca2+
flux and
channels associated with opioid
receptors were time-dependent.
The 2-h time course had greater inhibitory effect than the
0.5-h course, with the 1-h course having an intermediate
effect in land snails for aversive thermal (nociceptive)
responses and morphine-induced analgesia.
Abbreviation: EMF, electromagnetic field.

of treatment. No significant differences were reported in
depression, fatigue, severity of headaches, or serotonin levels,
and no adverse side effects were reported. EMF is usually
more effective at less than 3 mT, with frequencies lower than
100 Hz.
Various research studies have given different outcomes,
either beneficial or with no effects, due to a lack of
standardization in the dosing parameters. Although most
therapeutic dosages are <100 Hz and in the micro- and milli-
Tesla and Ampere ranges, times of exposure have varied
greatly. If the mechanism of action does indeed occur at the
plasma membrane, and as is suggested by many investigators,
if it is driven by ion flux, then hours of exposure would not
be necessary to obtain results. Ion diffusion and transport
occur in seconds to minutes57
; therefore, fewer sessions of
shorter periods would prove to be far more beneficial than
1 or 2 sessions of long duration.
Of high importance is the lack of standardized
nomenclature and experimental protocols when it comes to
running trials. Like pharmaceuticals, where dosages vary
from patient to patient, EMF treatments also are dose and
tissue dependent.144-146
It has been suggested that the following
dosing parameters should be required for all practitioners
using EMF therapies147
: (1) the type of tissue that the EMF is
targeting; (2) the specific site of EMF application;
(3) the distance between the EMF field and tissue;
(4) the frequency of the EMF field; (5) the EMF field
strength; (6) the exact composition of the EMF device; and
(7) the exact time of exposure. Otherwise, it is difficult to
compare results.
CONCLUSION
When it comes to modulating inflammatory pain
mechanisms, numerous experimental findings have
reported that EMF affects cell function through mechanical
action on both the intracellular and plasma membrane
levels, which includes ion channels, receptors, cytokines,
and enzymes. Various EMF dosing parameters—frequency,
intensity and duration of exposure—all contribute to
different outcomes; however, frequencies of less than
100 Hz and intensities in the mT or mA range are reported
to be most effective in the downregulation of peripheral
inflammatory pain modulators.
From a clinical standpoint, the tDCS device appears to
be the most beneficial for migraine headache, using dosing
parameters of 100 Hz or less and intensities of 1 mA or less
for twelve 90-minute sessions. For postprocedural abdominal
pain in patients after endoscopy, treatment with a tDCS
device set at 0.2 mA for 20 minutes is reported to be most
beneficial. In conditions such as OA, controlling chondrocyte
degradation and inflammation is optimized at 75 Hz and a
1.5-mT field strength, with treatment for 15 minutes twice
daily for up to 42 days. The same parameters have been
shown to be beneficial after arthroplasty. For FM, treatment
at 8 Hz and 1 mA is reported to be beneficial if applied for
40 minutes twice daily for 7 days.
Although a multitude of research articles investigating
the effects of EMF on inflammatory pain mechanisms exist,
the methods for gathering the data have included an
overwhelming array of experimental models, EMF devices,
waveforms, and clinical applications. Therefore, a consensus
of standardized methods for experimentation is greatly
needed to determine which responses directly result from
the EMF exposure. Because various parameters of treatment
produce similar results, a report cross-referencing the
frequencies, field strengths, and times of exposure of EMF
treatments on inflammatory responses would be beneficial to
both researchers and clinicians working in the field.
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