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Pulsed Electromagnetic Fields for Postsurgical Pain Management in Women Undergoing Cesarean Section A Randomized, Double-Blind, Placebo-controlled Trial

Authors:
Pulsed Electromagnetic Fields for Postsurgical Pain
Management in Women Undergoing Cesarean Section
A Randomized, Double-Blind, Placebo-controlled Trial
Maryam Khooshideh, MD,*Seyedeh Sakineh Latifi Rostami, MD,*
MahdiSheikh,MD,PhD,
w
Batool Ghorbani Yekta, MD,
z
and Ali Shahriari, MD
y
Objectives: To evaluate the efficacy of pulsed electromagnetic field
(PEMF) in relation to reducing postoperative pain, analgesic use,
and wound healing in patients undergoing Cesarean section
(C-section).
Methods: This randomized, double-blind, placebo-controlled trial
evaluated 72 women who underwent elective C-section. Thirty-six
patients were assigned to the active-PEMF and 36 to the sham-
PEMF groups. The participants were asked to report their pain
intensity on a Visual Analog Scale (VAS) at 2, 4, 6, 12, and 24
hours and 2, 4, and 7 days after surgery. The amount of analgesics
used was recorded. The surgical site was evaluated to assess the
wound-healing process on the seventh postoperative day.
Results: Postoperative pain VAS scores were significantly lower in
the active-PEMF group in all the measured periods within the early
and the late postoperative periods. Fewer women in the active-
PEMF group experienced severe postoperative pain within 24
hours postoperatively (36% vs. 72%, P= 0.002). Analgesic use
during the first 24 hours after C-section was 1.9-times lower in the
active-PEMF group (1.6 ± 0.7 vs. 3.1 ± 1.2, P< 0.001). The total
analgesic use during the seventh postoperative days was 2.1-times
lower in the active-PEMF group than in the sham group (1.7 ±0.7
vs. 3.7± 1.1, P< 0.001). Seven days postoperatively, patients in
the active-PEMF group had better wound healing with no exudate,
erythema, or edema (P= 0.02).
Conclusions: PEMF treatment after C-section decreases post-
surgical pain, analgesic use, and surgical wound exudate and edema
significantly, and is associated with a high level of patient
satisfaction.
Key Words: electromagnetic therapy, healing, PEMF, post-
operative, wound
(Clin J Pain 2017;33:142–147)
Cesarean section (C-section) is a lifesaving surgical
procedure to deliver the baby. Most countries have
a C-section rate >15%, and approximately 18.5 million
C-sections are performed yearly throughout the world
according to the 2010 World Health Organization (WHO)
report.1
Postoperative pain management is an important issue
in clinical practice, especially in patients who undergo C-
section, because postoperative pain in these patients can
affect maternal and neonatal well-being adversely, and
might increase postsurgical complications.2–4 Postsurgical
pain can cause maternal immobility and further increase the
risk of thromboembolic events that has already increased
during pregnancy.2–4 Pain may also impair the mother’s
care for her neonate and may affect early mother-infant
interactions and effective breastfeeding adversely.2–4
Although different approaches have been described for
proper pain relief, these approaches are still inadequate and
unsatisfactory in many patients.2,3 In addition, due to lac-
tation, using systemic analgesics, especially opioids, which
are used commonly for post-C-section pain relief,3can
affect the mother and the infant negatively and increase
their morbidity.5,6 Therefore, finding a safe and effective
technique for post-C-section pain relief is an urgent need.
Pulsed electromagnetic field (PEMF) devices have
been cleared by the US Food and Drug Administration for
the relief of acute and chronic pain, the promotion of soft-
tissue healing, and the improvement of circulation.7–11
There is accumulating evidence that PEMF treatment can
have significant anti-inflammatory and tissue-healing
effects.7–10
Recently, several studies have shown promising results
using PEMF in plastic and oral surgeries.9–14 Two studies
evaluated PEMF treatment for the postsurgical pain con-
trol in breast surgeries; in these studies, PEMF treatment
reduced the pain and the use of analgesics significantly in
the postsurgical period.10,11 Improvement in soft-tissue
healing and pain management were also reported in
another study that used PEMF treatment after oral sur-
gery.9Several pathways have been proposed for the anti-
inflammatory and analgesic effects of PEMF treatment,
including the effects of PEMF signals on increasing anti-
inflammatory cytokines, endogenous analgesic agents, and
endogenous opioid precursor proteins, and decreasing
proinflammatory cytokines and endogenous hyperalgesic
agents.10,15
Given the promising results of PEMF treatment in
plastic and oral surgeries and the growing evidence of
safety, pain-relieving, anti-inflammatory, and tissue-healing
effects of PEMF devices, we postulate that these devices
Received for publication October 15, 2015; revised March 30,
2016; accepted March 7, 2016.
From the Departments of *Obstetrics and Gynecology, Arash Wom-
en’s Hospital; yAnesthesiology, Roozbeh Hospital; wMaternal,
Fetal and Neonatal Research Center, Tehran University of Medical
Sciences; and zDepartment of Physiology, Applied Physiology
Research Center, Tehran Medical Sciences Branch, Islamic Azad
University, Tehran, Iran.
Supported by the Research Deputy of the Tehran University of Med-
ical Sciences (Grant Number: 93D-940-130), Tehran, Iran. The
authors declare no conflict of interest.
Reprints: Mahdi Sheikh, MD, PhD, Maternal, Fetal and Neonatal
Research Center, Vali-asr Hospital, Imam Khomeini Hospital
Complexes, Keshavarz Blvd, Tehran 1419733141, Iran (e-mail:
mahdisheikh@gmail.com).
Copyright r2016 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/AJP.0000000000000376
ORIGINAL ARTICLE
142 |www.clinicalpain.com Clin J Pain Volume 33, Number 2, February 2017
Copyright r2017 Wolters Kluwer Health, Inc. All rights reserved.
could also be used in other kinds of surgeries, especially in
laparotomy and obstetrics surgeries, which are associated
with significant postoperative pain and opioid use. On
searching the literature, we could not find studies evaluating
the effect of PEMF treatment in surgeries involving deep
organs. It is still unknown whether PEMF treatment can
provide an acceptable pain relief and tissue healing in these
kinds of surgeries.
In view of this lack of information, we conducted this
study to evaluate the efficacy of PEMF treatment in
reducing postoperative pain and analgesic use in patients
undergoing a C-section. We also tried to evaluate the effect
of PEMF treatment on wound healing, return to daily liv-
ing activities, and participant satisfaction.
MATERIALS AND METHODS
Study Population and Study Design
This prospective, randomized, double-blinded, pla-
cebo-controlled trial was conducted on 72 pregnant women
who were admitted to Arash Women’s Hospital (a tertiary
referral center), of the Tehran University of Medical Sci-
ences, Tehran, Iran, for elective C-section delivery from
August 2014 through December 2014. Women were con-
sidered eligible if they met the following inclusion criteria:
20 to 35 years of age, singleton uncomplicated pregnancy, a
gestational age of 37 to 42 weeks, and not having a history
of >1 C-sections. Exclusion criteria were: having any
underlying medical disease, a history of any abdominal
surgery other than C-section, a history of any drug or
opium dependency, and refusing to give an informed con-
sent to participate in the study.
Randomization was performed before the surgery. A
computerized random number generator was used for
sequence generation, which was carried out by M.S. Simple
randomization with a 1:1 allocation ratio was used in this
study. We used consecutive opaque envelops for allocation
concealment, which was performed by S.S.L.R. The
envelops were opaque when held to the light, and were
opened sequentially only after the participant’s name and
other details were written on the appropriate envelop. The
implementation of assignments was carried out by M.K.
This study was double-blinded, with M.S. performing the
blinding. Health care providers, participants, and data
collectors were all blinded to the PEMF and sham-PEMF
groups until the end of the study.
The Intervention, Data, and Specimen Collection
After explaining the procedure and obtaining a written
informed consent from the participants, a standardized
questionnaire was completed for the mothers who enrolled
in the study through interviews and medical records. The
questionnaire contained demographic, medical, gyneco-
logical, obstetrical, and social history, as well as vital signs
obtained through physical examinations and the gestational
age that was calculated on the basis of ultrasound imaging.
The participants were allocated randomly into 2 groups: 36
were assigned to the intervention (PEMF treated) group
and 36 were allocated to the placebo (sham-PEMF treated)
group (Fig. 1).
A Visual Analog Scale (VAS) was used to determine
the pain intensity; VAS is a continuous scale comprised of a
horizontal line 100 mm in length. The scale ranges from 0
(no pain) to 100 (worst imaginable pain). The following
cutoff points on the pain VAS were used: no pain (0 to
4 mm), mild pain (5 to 44 mm), moderate pain (45 to
74 mm), and severe pain (75 to 100 mm). Patients were
educated on how to use and interpret the pain VAS; they
were also asked to place a cross-line on the unmarked
horizontal scale at the required times.
All participants underwent spinal anesthesia with
12.5 mg bupivacaine. Immediately after the C-section,
either an active-PEMF device (RecoveryRx; BioElectronics
Corp.) or a sham-PEMF device (an exactly similar device
without any electromagnetic activity that was made by the
same company) was placed on the surgical wound dressing
continuously for 7 days (Fig. 2). The PEMF devices used in
this study consisted of an elliptical coil that was 12 cm in
size and a radiofrequency energy generator powered by a
battery that had an emission frequency of 27.1 MHz, a
pulse rate of 1000 pulses per second, a 100-ms pulse dura-
tion, and a peak spatial power density of 75 mW/cm
2
. The
circuitry consisted of low-voltage (3 V) digital or analog
electronics controlling all of the timing functions to pro-
duce the therapeutic radiofrequency field with the antenna’s
field directly over the site to be treated. The devices applied
to patients in the placebo group were switched on in the
same way as the active devices, but without producing an
electromagnetic field.
Participants were asked to report their pain intensity
on the basis of the VAS, and the pain intensity was eval-
uated at 2, 4, 6, 12, and 24 hours after surgery. After dis-
charge, participants were asked to record their pain
intensity on the second, the fourth, and the seventh post-
operative days. The requirement for analgesics during the
hospital admission and the amount of analgesics used were
recorded. In our study, diclofenac 100 mg suppositories
were used as the postoperative analgesic. The surgical site
was evaluated for factors that could delay the wound-
healing process including infection, erythema, hematoma,
edema, and wound exudate on the seventh postoperative
day. For ethical reasons, on discharge, analgesics were
recommended for all patients (diclofenac 100 mg supposi-
tories, once a day) on an as-needed basis. Patients could
choose to discontinue or use none if they had no symptoms.
Participants were asked to record the amount of analgesics
used from the discharge day till the seventh postoperative
day. The duration needed to return to daily living activities
as reported by the mother and the patient satisfaction (not
satisfied, moderately satisfied, highly satisfied) from the
treatment received were also recorded at the end of the
study.
The primary outcome of our study was the post-
operative pain intensity as reported by the pain VAS during
the first 24 hours and 1 week postoperatively. Secondary
outcomes were the amount of analgesic use during the
postoperative period, the presence of edema, erythema,
hematoma, and exudate from the surgical wound on the
seventh postoperative day that could impair the wound-
healing process, the duration of return to daily living
activities, and overall participant satisfaction.
This study was approved by the Research Deputy and
the Ethics Committee of Tehran University of Medical
Sciences on July 17, 2014 (approval number: 93/D/940/130)
and is registered at the Iranian Registry of Clinical
Trials (http://www.irct.ir), which is a Primary Registry in
the WHO Registry Network (registration number =
IRCT2014070711020N3). The authors confirm that all
ongoing and related trials for this intervention are
registered.
Clin J Pain Volume 33, Number 2, February 2017 PEMF and Postsurgical Pain
Copyright r2016 Wolters Kluwer Health, Inc. All rights reserved. www.clinicalpain.com |143
Copyright r2017 Wolters Kluwer Health, Inc. All rights reserved.
Although the study was submitted to http://www.irct.
ir before the expected recruitment start date, the approval
process took a long time and the date of confirming the
registration passed the submitted starting date; therefore,
the registration timing appeared as registration while
recruiting. However, officially, recruiting the patients was
started after the registration approval on August 05, 2014
and was ended on the December 10, 2014, 1 month after the
expected end date.
Another change that was made to the registered pro-
tocol was that in the original protocol the time point was set
at 10 days after C-section; however, because significant
postsurgical pain usually does not last for >1 week, and
also because the first 7 days after surgery are the crucial
period for wound healing, the time point was changed to 7
days.
Statistical Analysis
The sample size was calculated for a power of 80%,
a= 0.05, b= 20%, and a standard effect size of 0.85. All
statistical analyses were performed using SPSS statistical
software (PASW version 18.0.0; SPSS Inc., Chicago, IL).
Data were displayed using mean, SD, and percentage.
Mean comparisons between 2 groups and variables were
performed using the ttest for independent samples. Pearson
correlation coefficient, w
2
analysis, Fisher exact test,
repeated measures analysis of variance (ANOVA), and the
Logistic Regression Model were also used. The level of
statistical significance was set at P-value <0.05.
FIGURE 2. The PEMF device attached to the surgical wound
dressing.
FIGURE 1. The flow diagram of the study showing patients’ randomization.
Khooshideh et al Clin J Pain Volume 33, Number 2, February 2017
144 |www.clinicalpain.com Copyright r2016 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r2017 Wolters Kluwer Health, Inc. All rights reserved.
RESULTS
Descriptive Statistics
This study included 72 women with a singleton
uncomplicated pregnancy with a gestational age >37 weeks
who were admitted for elective C-section. Thirty-six women
were assigned randomly in the intervention group to receive
active-PEMF therapy and 36 to the placebo group to
receive the sham-PEMF therapy, for 7 days post-
operatively. On enrollment, the mean ± SD of the partic-
ipants’ age was 26.1 ± 2.6 years, the gestational age was
39.2 ± 1.5 weeks, the body mass index before pregnancy
was 24.2 ± 3.9, and the body mass index upon admission
was 32.1 ± 2.7. About 36 participants (50%) had a pre-
vious history of C-section. The ttest for independent
samples and the w
2
analysis showed that there were no
significant differences in the demographics between the 2
study groups (Table 1).
The Effect of PEMF Therapy on Postoperative
Pain and Analgesic Use
Repeated measures ANOVA and the independent
samples ttest demonstrated that the postoperative pain
VAS scores were significantly lower in the active-PEMF
group than in the sham-PEMF group in all the measured
periods (Table 2 and Fig. 3). The w
2
analysis showed that
fewer women in the active-PEMF group experienced severe
postoperative pain (VAS score of 75 to 100 mm) within 24
hours after the C-section compared with the sham-PEMF
group (36% vs. 72%, P= 0.002).
According to the independent samples ttest, analgesic
use (mean suppository counts) during the first 24 hours
after C-section was 1.9-times lower in the active-PEMF
group than in the sham group (1.6 ± 0.7 vs. 3.1 ± 1.2,
P< 0.001). Total analgesic use during 7 postoperative days
was 2.1-times lower in the active-PEMF group compared
with the sham group (1.7 ± 0.7 vs. 3.7 ± 1.1, P< 0.001)
(Table 3 and Fig. 4).
The Effect of PEMF Therapy on Surgical-Site
Inflammation, Patient Satisfaction, and Return
to Daily Activities
We used the w
2
analysis and the Fisher exact test when
appropriate to compare secondary outcomes between the 2
study groups. Seven days after the C-section, mothers in the
sham-PEMF group had significantly higher rates of wound
exudate (13% vs. 0%, P= 0.02) and edema (11% vs. 0%,
P= 0.04) in the surgical site compared with the active-
PEMF group. No infection or erythema was observed in
any of the groups (Table 3). The satisfaction level was
significantly higher in the active-PEMF group (P= 0.001):
in the active-PEMF-treated group, 50% of the patients
reported a high and 50% had a moderate satisfaction level
with the treatment received, whereas in the sham group,
25% reported high and 44% had moderate satisfaction
levels, and 30% were not satisfied with the treatment
received (Table 3). Using the independent samples ttest, no
statistically significant differences were observed in the time
to return to daily activities between the 2 groups (the active-
PEMF group: 3.4 ± 0.7 d; the sham-PEMF group:
3.6 d ± 1.3, P= 0.58) (Table 3).
DISCUSSION
This was the first study to evaluate the applicability of
PEMF devices in surgeries involving deep organs and lap-
arotomy. PEMF therapy reduced postsurgical pain and the
use of analgesics effectively in the both the immediate and
the late postsurgical periods in women who underwent C-
section, and reproduced essential findings in studies with
other surgical procedures. In the studies of Heden and
Pilla11 and Rohde et al,10 PEMF treatment provided good
pain control and reduced narcotic use postoperatively in
breast augmentation and reduction surgeries. In addition,
in the Stocchero et al9study, PEMF treatment reduced the
pain after mandibular third-molar extraction significantly.
Several mechanisms involving inflammatory mediators
might contribute to the analgesic effects of PEMF treat-
ment. Studies have shown that PEMF signals increase the
anti-inflammatory cytokine interleukin (IL)-10 and
decrease the proinflammatory cytokine IL-1b,10,15 which is
a potent hyperalgesic agent and a stimulator of nociceptors
through direct and indirect pathways.16,17 Animal studies
suggest that IL-1bmight be a signaling molecule that can
excite nociceptive fibers in as little as 1 minute in sensory
transmission, and IL-1breceptors were found in many
sensory neurons.16–19 IL-1balso modulates neuronal
excitability through its effect on neuronal receptors such as
sodium channels, GABA receptors, NMDA receptors, and
through its effect on the release or the activation of noci-
ceptive molecules such as prostaglandins, IL-6, and sub-
stance-P.17,20,21
TABLE 1. Comparison of Demographics Between the
Intervention (Active-PEMF) and the Placebo (Sham-PEMF)
Groups
Demographics
PEMF Group
(N = 36)
Placebo Group
(N = 36) P
Participants age (y)
(mean ± SD)
26.4 ± 2.3 25.9 ± 2.9 0.43 (NS)
Gestational age (wk)
(mean ± SD)
39.4 ± 1.6 39.1 ± 1.4 0.8 (NS)
BMI before
pregnancy
(mean ± SD)
23.8 ± 3.4 24.5 ± 4.4 0.46 (NS)
BMI upon admission
(mean ± SD)
32.3 ± 2.8 31.8 ± 2.6 0.52 (NS)
History of previous
C/S (n [%])
18 (50) 18 (50) 1 (NS)
BMI indicates body mass index; C/S, Cesarean section; NS, non-
significant; PEMF, pulsed electromagnetic field.
TABLE 2. Comparison of Pain VAS Scores and Analgesic Use
Between the Active-PEMF and the Sham-PEMF Groups in the
Measured Times
Mean ± SD of Pain VAS Scores
Postoperative
Time
PEMF
Group
Placebo
Group P
2 h 53 ± 18 63 ± 16 0.01
4 h 41 ± 13 59 ± 8 < 0.001
6 h 37 ± 13 51 ± 8 < 0.001
12 h 30 ± 5 38 ± 10 < 0.001
24 h 23 ± 4 36 ± 12 < 0.001
2 d 18 ± 10 26 ± 4 < 0.001
4 d 6 ± 4 16 ± 4 < 0.001
7 d 0.8 ± 2 3 ± 4 0.01
PEMF indicates pulsed electromagnetic field; VAS, Visual Analog Scale.
Clin J Pain Volume 33, Number 2, February 2017 PEMF and Postsurgical Pain
Copyright r2016 Wolters Kluwer Health, Inc. All rights reserved. www.clinicalpain.com |145
Copyright r2017 Wolters Kluwer Health, Inc. All rights reserved.
PEMF may also produce analgesic effects by affecting
nitric oxide (NO) synthesis; NO exhibits analgesic effects in
the periphery in early stages of inflammation, and pain
intensity has been shown to correlate negatively with NO
levels.22 PEMF increases NO synthesis through a cascade
that involves calcium, calmodulin, and cGMP produc-
tion.23,24 Another proposed mechanism is the effect of
PEMF on endogenous opioids. PEMF was shown to
increase endogenous opioid precursor proteins including
proenkephalin, proopiomelanocortin, and prodynorphin.15
In the study of Ventura et al,25 direct exposure of isolated
myocyte nuclei to PEMF enhanced prodynorphin gene
transcription markedly.
In our study, PEMF was associated with a better
wound-healing response at 7 days postoperatively, without
any exudate, edema, or erythema at the incision site. Other
studies that used PEMF in oral and plastic surgeries also
reported that PEMF therapy accelerated wound healing
and tissue repair.9–11 PEMF signals modulate Ca
2+
bind-
ing to calmodulin and calmodulin-dependent enzymes and
NO production.24,26 Evidence from animal and human
studies indicate that NO plays a key role in wound repair,
which is attributable to its functional influences on angio-
genesis, inflammation, cell proliferation, and matrix depo-
sition and remodeling.27 Moffett and colleagues evaluated
the effect of PEMF on cultured human keratinocyte and
fibroblast cells; they found that mRNA levels of many
factors that are involved in tissue repair and remodeling
were upregulated after PEMF exposure. PEMF treatment
resulted in the increased expression of integrins and cell
surface receptors that interact with components of the
extracellular matrix.28 During wound healing, integrins
play important roles in reepithelialization, angiogenesis,
and wound contraction. Transcript levels of multiple
cyclins and DNA replication factors that regulate cell
division were also upregulated after PEMF treatment in
both cell types.28
In this study, postoperative PEMF therapy was safe
and easily applicable, and the mothers were highly satisfied
with using this device in the postsurgical period. The
FIGURE 3. Mean pain Visual Analog Scale (VAS) scores between
the pulsed electromagnetic field (PEMF)-treated (thick line) and
the placebo-treated (thin line) groups during the 7 postoperative
days.
TABLE 3. Comparison of the Outcomes Between the Active-
PEMF and Sham-PEMF Groups
Outcomes
PEMF
Group
(N = 36)
Placebo
Group
(N = 36) P
Experiencing severe pain
within 24 h PO (n [%])
13 (36) 26 (72) 0.002*
Analgesic use within 24 h PO
(mean ± SD [sum of
suppository count])w
1.6 ± 0.7
(61)
3.1 ± 1.2
(112)
< 0.001*
Analgesic use within 7 d PO
(mean ± SD [sum of
suppository count])w
1.7 ± 0.7
(64)
3.7 ± 1.1
(135)
< 0.001*
Duration to return to daily
activities (mean ± SD) (d)
3.4 ± 0.7 3.6 ± 1.3 0.58
Satisfaction levels (n [%]) 0.001*
High 18 (50) 9 (25)
Moderate 18 (50) 16 (44)
Low 0 11 (30)
Surgical wound infection
(n [%])
00
Surgical wound exudate at
10 d PO (n [%])
0 5 (13) 0.02*
Surgical wound edema at
10 d PO (n [%])
0 4 (11) 0.04*
*Statistically significant P-value (< 0.05).
wDiclofenac 100 mg suppositories.
PEMF indicates pulsed electromagnetic field; PO, postoperation.
FIGURE 4. The number of Diclofenac suppositories used within
24 hours and 7 days postoperatively in the treatment versus the
placebo group.
Khooshideh et al Clin J Pain Volume 33, Number 2, February 2017
146 |www.clinicalpain.com Copyright r2016 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r2017 Wolters Kluwer Health, Inc. All rights reserved.
available literature supports the safety of PEMF devices in
long-term applications.8These promising results show that
PEMF therapy can be used as an effective and safe
modality for postoperative pain management, with positive
effects on wound healing that is associated with high
maternal satisfaction in the postoperative period. In addi-
tion, by decreasing maternal requirement for systemic
analgesics and opioids during the postoperative period, and
subsequently decreasing neonatal exposure to these drugs,
PEMF therapy could also have potential benefits to the
neonates. However, effects of PEMF therapy on lactation,
neonatal wellbeing, and mother-infant interaction requires
investigation in future studies.
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Clin J Pain Volume 33, Number 2, February 2017 PEMF and Postsurgical Pain
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Article
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This study shows that a non-thermal pulse-modulated RF signal (PRF), configured to modulate calmodulin (CaM) activation via acceleration of Ca(2+) binding kinetics, produced an immediate nearly 3-fold increase in nitric oxide (NO) from dopaminergic MN9D cultures (P<0.001). NO was measured electrochemically in real-time using a NO selective membrane electrode, which showed the PRF effect occurred within the first seconds after lipopolysaccharide (LPS) challenge. Further support that the site of action of PRF involves CaM is provided in human fibroblast cultures challenged with low serum and exposed for 15min to the identical PRF signal. In this case a CaM antagonist W-7 could be added to the culture 3h prior to PRF exposure. Those results showed the PRF signal produced nearly a two-fold increase in NO, which could be blocked by W-7 (P<0.001). To the authors' knowledge this is the first report of a real-time effect of non-thermal electromagnetic fields (EMF) on NO release from challenged cells. The results provide mechanistic support for the many reported bioeffects of EMF in which NO plays a role. Thus, in a typical clinical application for acute post operative pain, or chronic pain from, e.g., osteoarthritis, EMF therapy could be employed to modulate the dynamics of NO via Ca/CaM-dependent constitutive nitric oxide synthase (cNOS) in the target tissue. This, in turn, would modulate the dynamics of the signaling pathways the body uses in response to the various phases of healing after physical or chemical insult or injury.
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The transduction mechanism for non-thermal electromagnetic field (EMF) bioeffects has not been fully elucidated. This study proposes that an EMF can act as a first messenger in the calmodulin-dependent signaling pathways that orchestrate the release of cytokines and growth factors in normal cellular responses to physical and/or chemical insults. Given knowledge of Ca(2+) binding kinetics to calmodulin (CaM), an EMF signal having pulse duration or carrier period shorter than bound Ca(2+) lifetime may be configured to accelerate binding, and be detectable above thermal noise. New EMF signals were configured to modulate calmodulin-dependent signaling and assessed for efficacy in cellular studies. Configured EMF signals modulated CaM-dependent enzyme kinetics, produced several-fold increases in key second messengers to include nitric oxide and cyclic guanosine monophosphate in chondrocyte and endothelial cultures and cyclic adenosine monophosphate in neuronal cultures. Calmodulin antagonists and downstream blockers annihilated these effects, providing strong support for the proposed mechanism. Knowledge of the kinetics of Ca(2+) binding to CaM, or for any ion binding specific to any signaling cascade, allows the use of an electrochemical model by which the ability of any EMF signal to modulate CaM-dependent signaling can be assessed a priori or a posteriori. Results are consistent with the proposed mechanism, and strongly support the Ca/CaM/NO pathway as a primary EMF transduction pathway. The predictions of the proposed model open a host of significant possibilities for configuration of non-thermal EMF signals for clinical and wellness applications that can reach far beyond fracture repair and wound healing.