Decreased Low Back Pain Intensity and Differential Gene Expression Following CalmareW: Results From a Double-Blinded Randomized Sham-Controlled Study
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Decreased Low Back Pain Intensity and
Differential Gene Expression Following
CalmareW: Results From a Double-Blinded
Randomized Sham-Controlled Study
Angela R. Starkweather, Patrick Coyne, Debra E. Lyon, R. K. Elswick, Jr., Kyungeh An,
Jamie Sturgill
Correspondence to Abstract: In this double-blinded, randomized controlled trial we evaluated the
Angela R. Starkweather effects of Calmare1, a non-invasive neurocutaneous electrical pain intervention, on
E-mail: astarkweathe@vcu.edu lower back pain intensity as measured by the “worst” pain score and on pain inter-
ference using the Brief Pain Inventory-Short Form, on measures of pain sensitivity
Angela R. Starkweather assessed by quantitative sensory testing, and on mRNA expression of pain sensitiv-
Associate Professor and Chair ity genes. Thirty participants were randomized to receive up to 10 sessions of Calm-
Department of Adult Health and Nursing are1 treatment (n ¼ 15) or a sham treatment (n ¼ 15) using the same device at a
Systems
non-therapeutic threshold. At 3 weeks after conclusion of treatment, compared with
Virginia Commonwealth University School
the sham group, the Calmare1 group reported a significant decrease in the “worst”
of Nursing
pain and interference scores. There were also significant differences in pain sensi-
1100 East Leigh Street
tivity and differential mRNA expression of 17 pain genes, suggesting that Calmare1
P.O. Box 980567
can be effective in reducing pain intensity and interference in individuals with persis-
Richmond, VA 23298-0567
tent low back pain by altering the mechanisms of enhanced pain sensitivity. Further
Patrick Coyne study of long-term pain outcomes, particularly functional status, analgesic use and
Clinical Director of Palliative Care health care utilization, is warranted. ! 2015 Wiley Periodicals, Inc.
Virginia Commonwealth University
Richmond, VA
Keywords: low back pain; chronic pain; Calmare1; scrambler; gene expression
Research in Nursing & Health, 2015, 38, 29–38
Debra E. Lyon
Executive Associate Dean Accepted 24 October 2014
Thomas M. and Irene B. Kirbo Endowed Chair DOI: 10.1002/nur.21632
University of Florida Published online in Wiley Online Library (wileyonlinelibrary.com).
Gainesville, FL
,
Note: Additional authors are listed on the last page.
Persistent low back pain is one of the nation's most expen- risk of complications and untoward side effects (Freburger
sive medical conditions and a leading cause of disability. et al., 2009). The identification of safe and effective pain
Of the $30 billion spent annually on direct care expendi- management strategies is a national priority and important
tures for low back pain (LBP), approximately 95% goes goal for individuals with persistent LBP, a condition that
toward the treatment of individuals who develop persistent can have a significant negative impact on quality of life and
LBP (Soni, 2011). Even with conventional treatments that health status (Institute of Medicine, 2011).
include psychobehavioral and pharmacological therapeutic Nurses play a critical role in the assessment of pain
options, over 80% of individuals who develop persistent and provision of symptom management strategies.
LBP will continue to have pain for >12 months (Institute of Although physical activity is a mainstay of persistent LBP
Medicine, 2011). It is the most common site of pain in treatment and important component of self-management,
young and middle-aged adults and one of the most fre- pain intensity is a major limiting factor for engaging in phys-
quent reasons for sick leave and long-term time out of ical activity (Chou & Huffman, 2007). Building an evidence
employment (Burgoyne, 2007). With a substantial increase base on alternative non-pharmacological modalities, such
in the prevalence of persistent LBP over the past decade, as the Calmare1 device tested in this study, can help guide
there has also been a rise in the use of epidural injections, the selection of therapeutic options for reducing pain inten-
surgery, and opioid medications, interventions that carry a sity and improving function. Moreover, simultaneously
"
C 2015 Wiley Periodicals, Inc.30 RESEARCH IN NURSING & HEALTH
investigating the effect of the intervention on underlying Calmare1 group to .7 (#91%) and the standard therapy
pain mechanisms could provide foundational knowledge for group to 5.8 (#28%). After 2 and 3 months, the Calmare1
advancing the delivery of personalized symptom manage- group mean VAS remained low at 1.4 and 2.0 respectively
ment for individuals with persistent LBP. while there was minimal change in the standard therapy
group. Similar findings on the effect of Calmare1 on pain
intensity have been reported for patients with chemotherapy-
induced peripheral neuropathy and postherpetic pain
Interrupting the Mechanisms of Persistent
(Coyne, Wan, Dodson, Swainey, & Smith, 2013; Ricci et al.,
Pain
2011; Smith, Coyne, Parker, Dodson, & Ramakrishnan,
Several lines of evidence support the premise that persistent 2010; Smith & Marineo, 2013).
LBP develops as a consequence of enhanced pain sensitiv- Although the results of these trials have been
ity, an altered state of pain processing that augments pain impressive, they have all been open-label and thereby
and impairs descending pain inhibition. Physiological provided limited information regarding placebo analgesic
changes that lead to enhanced pain sensitivity include sensi- effects, which can confound interpretation of the interven-
tization of nociceptors and neuronal circuits (Freburger tion's unique effectiveness. In addition, no investigators
et al., 2009; Giesecke et al., 2004) and modifications in the have examined the influence of Calmare1 on pain sensi-
expression of genes that encode pain signaling molecules tivity, a physiological mechanism involved in the refrac-
and their receptors, particularly genes associated with neu- tory nature of LBP (Clauw et al., 1999; Jankowski &
rotrophins (Jacobsen, Eriksen, Pedersen, & Gjerstad, 2010; Koerber, 2010; O’Neill, Manniche, Graven-Nielsen, &
Nicol & Vasko, 2007; Pezet & McMahon, 2006), inflamma- Arendt-Nielsen, 2007). Although the placebo effect can
tory mediators (Ren & Dubner, 2007) and catecholamines have a significant impact on subjective pain scores, one
(Emery, Young, Berrocoso, Chen, & McNaughton, 2011; would not expect to observe a change in pain sensitivity
Gold & Gebhart, 2010). Further elucidation of the molecular or mRNA expression of pain sensitivity genes with admin-
events leading to reduced LBP could help to guide the inte- istration of a sham intervention (Gracely, 2005). Previous
gration of non-pharmacological strategies for symptom studies in animal models exposed to nerve injury have
management. demonstrated decreased pain sensitivity in response to
Neurocutanous electrical stimulation may alter the neurocutaneous electrical stimulation (Cavalcante
release of pain-promoting molecules in the periphery and Miranda de Assis et al., 2014; Yang, Yang, & Gao,
thereby modulate peripheral nociceptive function (Hulse, 2010). However, the effect of electrical stimulation on
Donaldson, & Wynick, 2012). The Calmare1 device was peripheral mediators of pain sensitivity has not been pre-
designed to interrupt the mechanisms of persistent pain by viously examined.
transforming, or scrambling, the pain signaling messages Therefore, this study was designed as a double-
initiated by damaged/injured nerve fibers (Sabato, Marineo, blinded randomized sham-controlled trial in order to evalu-
& Gatti, 2005). Using biophysics-derived algorithms, the ate the effects of Calmare1 on pain intensity and intefer-
device transmits electrical waveforms that mimic endoge- ence, measures of pain sensitivity, and mRNA expression
nous action potentials that are recognized as non-pain of pain sensitivity genes in individuals with persistent LBP.
information by damaged nerve fibers. The ability to modify The primary aim was to compare the intensity of LBP and
action potentials of the affected nerve fibers into non-pain pain interference, measured by the Brief Pain Inventory-
sensory information is unique. In particular, the Calmare1 Short Form (BPI-SF), between participant groups random-
device generates nonlinear waveforms, as opposed to the ized to Calmare1 or sham over time. The secondary aims
linear waveforms of transcutaneous electrical nerve stimu- were to evaluate the effect of Calmare1 on pain sensitivity
lation (TENS). In addition, the waveforms are wide and in response to noxious stimuli and on mRNA expression of
therefore able to stimulate the C-fibers as well as A-beta candidate genes involved in the transduction, maintenance,
fibers and dynamically sequenced so that the nerve fibers and modulation of pain responses.
cannot adapt.
The safety and efficacy of Calmare1 was demon-
strated in a trial that included 226 patients with idiopathic
pain including LBP, trigeminal neuralgia and complex neu- Methods
ropathies (Sabato et al., 2005). Of these, 80% responded
Design and Setting
with >50% pain relief, 10% responded with pain relief from
25% to 49%, and 10% had no response. A subsequent trial The study used a parallel-group, simple randomization
included 52 patients with chronic neuropathic pain who were scheme with 1:1 ratio and was conceptualized as a superi-
randomized to Calmare1 or standard pharmacological treat- ority trial to examine whether Calmare1 provided more
ment (Marineo, Iorno, Gandini, Moschini, & Smith, 2012). pain relief than sham at 3 weeks after treatment comple-
The enrollment mean pain intensity score on visual analog tion. The trial took place at a large, urban academic health
scale (VAS) was 8.1 and decreased at 1 month in the care system in the mid-Atlantic region where an average of
Research in Nursing & HealthDECREASED LOW BACK PAIN INTENSITY/ STARKWEATHER ET AL. 31
10,657 patients with LBP is seen each year. The subjects allocation in a locked cabinet until the study was complete.
of the study were recruited from March to June 2013. The remaining study team members and participants were
blinded to the randomization scheme. There were no drop-
outs in either group. The progress of the participants through
the study is shown in Figure 1.
Participants
Power analysis. The primary endpoint was the
Individuals between the ages of 18–50 years of age who change in the “worst” pain score measured by the BPI-SF
were diagnosed with persistent nonspecific LBP were from baseline to 3 weeks post-intervention. Using an antici-
invited to participate through referrals from their primary pated effect size (Cohen's d) of 1.58 determined from a pre-
health care provider. For the purpose of the study, persis- vious study (Marineo et al., 2012), with a statistical power
tent nonspecific LBP was defined as pain without a specific level of .8 and probability level of .5, the minimum total sam-
cause or need for surgical intervention, located anywhere ple size for a two-tailed hypothesis is 16, with 8 participants
in the region of the low back bound superiorly by T12 and per group. Thus, the planned sample size of 30 participants
inferiorly by the buttock crease, which had been present for with 15 in each group was deemed appropriate.
$3 months duration for >4 days/week and was rated at an
intensity level of $4 on the numerical pain scale (from
1 ¼ no pain to 10 ¼ pain as bad as one can imagine).
Measures
Eligible participants were: (i) between 18 and
50 years of age; (ii) diagnosed with persistent nonspecific Demographics. Age, gender, race/ethnicity,
LBP; and (iii) able to read and speak English. The age employment, socioeconomic status, educational attain-
range was designed to provide a homogenous sample in ment, and lifestyle behaviors (smoking, exercise) were col-
terms of general health, work status, and contributing fac- lected at enrollment.
tors of persistent LBP. Pain intensity and interference. The BPI-SF
Patients were excluded for the following conditions consists of 15 questions that measure pain location, inten-
during the screening process: (i) chronic pain at another sity, pain treatment, treatment effectiveness, and functional
site or associated with a painful condition (e.g., fibromyal- interference from pain (Keller et al., 2004). The BPI-SF
gia, rheumatoid arthritis) due to possible confounding fac- assesses pain intensity at its “worst,” “least,” and “aver-
tors on the analysis of mRNA expression of pain age,” over the past week, as well as pain “now,” using a
sensitivity genes; (ii) pregnant and/or breastfeeding due numerical rating scale from 0 ¼ no pain to 10 ¼ worst possi-
to unknown potential effects on the fetus and breast milk; ble pain imaginable. A lower score on any of these items
(iii) latex allergies due to risk of skin hypersensitivity reac- reflects less pain. Pain interference is measured on the
tions with placement of the electrodes; (iv) skin conditions BPI-SF by asking how much pain has interfered with seven
such as open sores that would prevent proper application daily activities (general activity, walking, work, mood, enjoy-
of electrodes; (v) previous treatment with Calmare1 or ment of life, relations with others, and sleep). Pain interfer-
intolerance to transcutaneous electronic nerve stimula- ence for each daily activity is rated on a 0–10 scale and
tion. Due to potential interference of the electrical stimuli scored as the mean of the seven items; a lower score rep-
on physiological functioning of underlying organs and resents less interference. The BPI-SF has been validated
other implanted devices, the following exclusion criteria in individuals with low back pain, demonstrates sufficient
were also applied: (vi) severe arrhythmia or any form of reliability (coefficient alpha >.70) and sensitivity to change
equivalent heart disease; (vii) history of myocardial infarc- over time (Keller et al., 2004).
tion or ischemic heart disease within the past 6 months; Based on previous studies, our hypothesis was that
(viii) history of epilepsy, brain damage or use of anti-con- at the 3-week follow-up visit, the group randomized to
vulsants; (ix) prior celiac plexus block or other neurolytic Calmare1 would have significantly lower “worst” pain and
pain control treatment within 4 weeks; (x) active with- interference scores compared to the sham group. The
drawal from drugs and/or alcohol; (xi) implanted drug “worst” pain and interference scores of the BPI were used
delivery system (e.g., Medtronic SynchromedTM); and (xii) as the primary endpoint, as suggested by the IMMPACT
pacemakers, automatic defibrillator, aneurysm clips, vena recommendations for assessing pain in clinical trials (Dwor-
cava clips, or skull plates. kin et al., 2005). The “worst” pain score was selected a
Among the 67 people screened for the study, 30 met priori, as it has excellent test–retest reliability (a ¼ .93;
the inclusion criteria and agreed to participate. Using a com- Cleeland, 2009) and reflects temporal pain variability, a
puterized random number table, the participants were dimension of the pain experience that is heavily influenced
assigned to either the Calmare1 intervention group (n ¼ 15) by pain sensitivity.
or sham control group (n ¼ 15) by an intervention-designated Pain sensitivity. Pain sensitivity was measured
research assistant (IDRA) who did not perform data collec- using a standardized quantitative sensory testing (QST)
tion or have access to study data. The IDRA kept a running protocol in which study participants were asked to rate their
list of the participant number and randomization group level of pain in response to three types of noxious stimuli
Research in Nursing & Health32 RESEARCH IN NURSING & HEALTH
FIGURE 1. CONSORT participant flow diagram.
(Rolke et al., 2006). Test–retest and inter-rater reliability of recorded; a lower value is consistent with enhanced pain
the QST protocol has been reported in several clinical tri- sensitivity.
als, with each individual test achieving a CI of .87–.94 Candidate gene expression. At each data col-
(Chesterton, Sim, Wright, & Foster, 2007; Moss, Sluka, & lection visit, whole blood was collected by venipuncture into
Rice, 2007). Normalized age and gender-specific data one 5 ml EDTA vacutainer and one 10 ml cell preparation
acquired by our laboratory were used to assess the pres- tube with sodium citrate, labeled with a unique study identi-
ence of pain sensitivity. fication label, and transported directly to the laboratory for
First, heat pain threshold was assessed on the partic- processing. RNA isolation was performed using the Leuko-
ipant's forearm and painful area of the back, by applying a LOCKTM total RNA isolation system (Applied Biosystems,
thermode (Medoc Pathway SystemTM; Durham, NC) that Carlsbad, CA) according to the manufacturer's protocol and
increased in temperature at a rate of .5°C/second. Thresh- was reverse transcribed using SuperScript VILO cDNA
old was defined as the temperature at which pain was first synthesis kit (Invitrogen, Valencia, CA). The mRNA expres-
reported. A lower heat pain threshold is consistent with sion of 84 genes involved in the transduction, maintenance,
enhanced pain sensitivity. Next, rating of pain in response and modulation of pain responses was determined (Neuro-
to a single thermal stimulus of 48°C applied to the painful pathic & Inflammatory RT2 Profiler PCR Array; Sabio Sci-
area of the back was evaluated. A higher rating represents ences, Valencia, CA) using qPCR performed on the
a higher level of pain intensity and enhanced pain sensitiv- BioRad CFX961. After an initial incubation step, 35 cycles
ity. Finally, pressure pain thresholds in response to a hand- (95°C for 15 seconds and 1 minute at 60°C) of PCR were
held pressure algometer were assessed on the painful area performed. Expression levels were quantified using the
DD
of the back. Pressure threshold was recorded as the algo- Ct method, which normalizes data of the genes of inter-
meter loading (kPa) at which pain was first detected. Simi- est to b-actin (controls are included in array). The Bio-
lar to the heat pain threshold, the amount of stimulus RadCFX software was used to determine optimal baseline
(pressure) required to produce the first onset of pain was and threshold settings of the assay Ct values.
Research in Nursing & HealthDECREASED LOW BACK PAIN INTENSITY/ STARKWEATHER ET AL. 33
Procedures Statistical Analysis
Prior to the intervention, data collection took place in a Descriptive statistics were calculated for the demographic char-
private research suite, where the participant was asked acteristics of the participants and to assess the homogeneity of
to complete study questionnaires, have blood drawn, and both groups, using Chi-square for all categorical variables and
undergo sensory testing by a designated research assis- Student's t-test for continuous variables. To analyze the effec-
tant who was blinded to group assignment. All study tiveness of the intervention, a series of repeated-measures
questionnaires were self-administered. The laboratory analyses of variance (ANOVA) were performed, with the “worst”
personnel involved in processing of genetic assays were pain and interference scores as the dependent variables, and
blinded to the randomization of the study participants time (baseline, 1-, and 3-week follow-up visit), group (Calmare1
throughout the study and at the time their genetic meas- or sham), and group by time interaction terms as the indepen-
ures were quantified. dent variables. The repeated measures model accounts for the
Upon completion of baseline study measures, the correlations that might arise from observations of the same indi-
participant received a clinical pain examination, and the viduals over time. Data were analyzed using SPSS statistical
assigned intervention was initiated by the intervention-des- package (version 18.0 Chicago, IL), and the level of significance
ignated research assistant (IDRA), who was trained in was set at p < .05.
administering Calmare1. The IDRA followed a script to Secondary endpoints included heat and pressure
explain the study intervention and provide instructions to pain thresholds and mRNA expression levels of the 84 can-
each participant. During the clinical exam, the IDRA asked didate genes. For all housekeeping genes included in the
the participant to identify the most painful area of the back assay (ACTB, B2M, GAPDH, HPRT1, and RPLP0), the
and to point to the confines of the area of pain. mean and standard deviation of Cq values across all sam-
Electrode placement and device settings. ples was calculated. ACTB exhibited the lowest variance
The number of electrodes used and placement of the elec- and highest abundance and was therefore used as
trodes were dependent on the study group assignment. For the housekeeping gene for normalization. For the 84 candi-
participants randomized to Calmare1, two pairs of electro- date genes, the DCt values for each timepoint t were calcu-
des were placed in the same dermatome associated with lated as DCt ¼ CqGOI,t – CqATCB,t. Thereafter, for each
the most painful area, approximately 25 mm outside of the subject, the relative-fold change in expression at 3 weeks
outer confines of the most painful area. During each post-intervention with respect to baseline was calculated as
30 minutes session, the settings were increased on the 2#DDCt, where #DDCt ¼ DCt # DC1.
device by 10 U every 20 seconds, to a maximum of 70 U. For each of the 84 genes, a random coefficient model
The sham group had one set of electrodes placed in the including treatment group (Calmare1 vs. sham) and time (base-
dermatome above the most painful area. The settings were line vs. 3 weeks post-intervention) as fixed effects was fit. A
increased from 0 to 10 U and remained at 10 U for the likelihood ratio test was used to test the null hypothesis that the
duration of each session. treatment group effects were zero (Hedeker & Gibbons, 2006).
Ten 30-minute sessions were administered over 10 A p < .01 threshold was used to determine whether Calmare1
working days or until the participant reported no pain, in and sham expression profiles significantly differed.
which case the treatment ended and they were scheduled
for a 1 week follow-up visit. A daily log and schematic dia-
gram of electrode placement was maintained to ensure Results
consistent delivery of the intervention. Participants were
The demographic characteristics of the participants in each
scheduled for follow-up data collection at 1 and 3 weeks
group did not differ significantly, as shown in Table 1. Most
after their final study treatment sessions. The same proto-
participants were working part- or full-time, had a college-
col for administering study questionnaires, performing
level education, and reported LBP duration between 6 and
blood draws and QST was followed for each follow-up data
12 months. In both groups, 80% of participants reported
collection visit.
using non-steroidal anti-inflammatory drugs (NSAIDs) inter-
mittently for pain (4 times per week).
Ethical Considerations
At the 1- and 3-week follow-up visits, there was a
The study was approved by the Institutional Review Board statistically significant difference in the “worst” pain score
at a university before the study began, and the participants between the Calmare1 and sham groups (Table 2). Simi-
gave written informed consent in a face-to-face interview. larly, pain interference was significantly different between
Participant confidentiality was assured throughout the study groups at the 3-week follow-up visit, with significantly lower
period. Each participant was assessed for adverse events pain interference in the Calmare1 group. The “worst” pain
during and after each session and at each study visit. All and interference scores of the BPI showed a significant
participants were told that they had the right to withdraw decrease in the Calmare1 group from baseline to the
from the study at any time. 3-week follow-up visit, whereas the scores of the sham
Research in Nursing & Health34 RESEARCH IN NURSING & HEALTH treatment group did not change over time. In the Calmare1 line and 3 weeks post-intervention, while baseline mRNA lev- group, seven (47%) participants had a >50% reduction in els of the 84 candidate genes did not differ. Using a p-value the “worst” pain score from baseline to the 3-week follow- threshold of 1 year Current smoker .29 Yes 1 6 3 20 No 14 94 12 80 Research in Nursing & Health
DECREASED LOW BACK PAIN INTENSITY/ STARKWEATHER ET AL. 35
Table 2. Worst Pain and Interference Scores in CalmareW and Sham Treatment Groups Over Time
Calmare1 (n ¼ 15) Sham (n ¼ 15)
Assessment Time Mean SD Mean SD F pgroup % time
“Worst” pain Baseline 5.40 1.52 4.98 2.11 .56 .45
1 week follow-up 4.34 1.22 5.76 1.34 9.39 .01
3 weeks follow-up 3.23a 1.27 5.81 1.75 23.4236 RESEARCH IN NURSING & HEALTH
Table 4. Differential Gene Expression in the CalmareW pain scores, decreased function, and higher risk of radio-
Group at 3 Weeks Post-Treatment graphic progression of osteoarthritis. This approach has not
been used to examine pain phenotypes of LBP or response
Gene Fold Regulation pa
to interventions. However, in a recent study of gene expres-
BDKRB1 #2.468 .0069 sion across different tissue types, including blood, skin, dor-
CACNA1B #1.518 .0091 sal root ganglion, and slices of brain tissue, a consistent
CHRNA4 #1.924 .0053
level of methylation or expression changes was found, which
GDNF #2.141 .0036
GRM1 #1.715 .0033
may make using gene expression profiles of PBLs possible
NGF #2.599 .0040 in the future (Bell et al., 2014). Identifying the specific pain
NTRK1 #1.980 .0035 sensitivity genes that are most relevant to persistent LBP
OPRD1 #1.812 .0049 and those that contribute to pain relief will be a key factor in
PENK #1.850 .0042 translating this approach into practice.
PLA2G1B #1.816 .0020
Taken together, the results of the study demonstrate
a
Difference from sham treatment group. a significant reduction in pain intensity, pain interference,
and pain sensitivity at 3 weeks following the Calmare1
intervention in comparison with the sham group. As nurses
maintenance, and modulation of pain responses. At are heavily invested in the delivery of effective symptom
3 weeks post-intervention, the Calmare1 group had signifi- management interventions, it is important to identify non-
cantly lower pain sensitivity scores compared to the sham pharmacological strategies for reducing pain and improving
group, yet the differences from baseline to 3 weeks within function for individuals with persistent LBP. The present
the Calmare1 group did not reach a level of statistical sig- study demonstrates that Calmare1 may significantly
nificance, most likely due to the small sample size. In addi- reduce pain intensity while receiving the intervention and
tion, the Calmare1 group had significant downregulation of lessen variability of LBP intensity and interference with
17 pain genes at the 3 weeks follow-up visit, many of which activities over time. Because physical activity is important
code for proteins and receptors that mediate inflammation to prevent recurrent LBP and improve functional status, fur-
and nociceptive signaling. Increased peripheral expression ther investigation of Calmare1 as part of an intervention for
of nerve growth factor (NGF) and glial-derived neurotrophic persistent LBP that includes physical activity and long-term
factor (GDNF), can potentiate primary afferent nerves and functional outcomes will help to inform clinical practice.
lead to peripheral sensitization (Malin et al., 2006). Expres-
sion levels of both neurotrophin genes were significantly
lower in the Calmare1 group compared to sham 3 weeks Study Limitations
following the intervention.
Several limitations of this study are worth noting, in addition
In contrast, animal models exposed to nerve injury
to the small sample size. Although referrals to the study were
and then given electrical stimulation demonstrated an
made by clinicians who had previously diagnosed the partic-
immediate reduction in pain sensitivity along with downre-
ipants with nonspecific low back pain, we did not review
gulation of pain-promoting molecules in the spinal cord and
medical records or diagnostic imaging for confirmation. How-
brain (Fang, Liang, Du, & Fang, 2013; Yang et al., 2010).
ever, during the exam, particular attention was paid to detect-
However, nerve injury using animal models may not repli-
ing any red flags or signs of serious underlying pathology,
cate the mechanisms of pain sensitivity that contribute to
and none were noted in the participant sample. In addition,
persistent LBP in humans, specifically changes in the rate
the sham procedures of the protocol had not been previously
of healing (Cavalcante Miranda De Assis et al., 2014). In
evaluated. However, we did assess whether participants
addition, the differences in electrical frequency and dosage
believed they had received Calmare1 therapy (and not the
of the intervention may influence the physiological
sham treatment) after the three-week follow-up appointment,
response at the peripheral and central levels (Cavalcante
and similar responses were obtained from both groups. We
Miranda de Assis et al., Yang et al.).
used a candidate gene approach to assess differential gene
Although we cannot infer that the modification in
expression. The candidate gene approach has inherent limi-
expression levels of these genes was responsible for the
tations of potentially not accounting for other genes relevant
reduction in pain intensity, interference, and pain sensitivity,
to pain or interventions, and changes in gene expression do
the findings do present an intriguing approach for exploring
not necessarily result in modifications at the protein level.
the systemic gene expression signature of a selected pain
phenotype or, as in this case, response to treatment.
Recently, gene expression profiles of peripheral blood leuko-
Conclusions
cytes (PBLs) were evaluated in patients with symptomatic
knee osteoarthritis (Attur et al., 2011). In that study, patients The results of this study suggest that Calmare1 provides
with knee osteoarthritis who had increased expression of significantly more low back pain relief than sham at 3 weeks
interleukin (IL)-1b (>2-fold compared to controls) had higher post-intervention and can reduce pain intensity, interference,
Research in Nursing & HealthDECREASED LOW BACK PAIN INTENSITY/ STARKWEATHER ET AL. 37
and pain sensitivity in individuals with persistent low back rats. BMC Complementary and Alternative Medicine, 13, 134.
pain. The differential expression of pain genes between the doi: 10.1186/1472-6882-13-134
intervention and sham group suggests that Calmare1 may Freburger, J. K., Holmes, G. M., Agans, R. P., Jackman, A. M.,
exert an effect by downregulating pain receptors and pro- Darter, J. D., Wallace, A. …Carey, T. S. (2009). The rising preva-
teins involved in maintaining persistent pain. Further study is lence of chronic low back pain. Archives of Internal Medicine,
169, 251–258. doi: 10.1001/archinternmed.2008.543
warranted of long-term outcomes after Calmare1, including
functional status, analgesic use and health care utilization. Giesecke, T., Gracely, R. H., Grant, M. A. B., Nachemson, A.,
Petzke, F., Williams, D. A., & Clauw, D. J. (2004). Evidence of
augmented central pain processing in idiopathic chronic low
back pain. Arthritis and Rheumatism, 50, 613–623.
References
Gold, M. S., & Gebhart, G. F. (2010). Nociceptor sensitization in pain path-
Attur, M., Belitskaya-Levy, I., Oh, C., Krasnokutsky, S., Greenberg, ogenesis. Nature Medicine, 16, 1248–1257. doi: 10.1038/nm.2235
J., Samuels, J. …Abramson, S. B. (2011). Increased interleukin-
Gracely, R. H. (2005). Evaluation of pain sensations. In: H. Merskey,
1b gene expression in peripheral blood leukocytes is associated
J. D. Loeser, & R. Dubner (Eds.), The paths of pain. (pp. 271-
with increased pain and predicts risk of progression of symptom-
284). Seattle: International Association for the Study of Pain
atic knee osteoarthritis. Arthritis & Rheumatology, 63, 1908–1917.
Press.
doi: 10.1002/art.30360
Hedeker, D., & Gibbons, R. D. (2006). Longitudinal data analysis.
Bell, J. T., Loomis, A. K., Butcher, L. M., Gao, F., Zhang, B., Hyde,
Hoboken, NJ: John Wiley & Sons.
C. L. …Zondervan, L. (2014). Differential methylation of the
TRPA1 promoter in pain sensitivity. Nature Communications, 5, Hulse, R. P., Donaldson, L. F., & Wynick, D. (2012). Peripheral gala-
1–11. doi: 10.1038/ncomms3978 nin receptor 2 as a target for the modulation of pain. Pain
Research and Treatment, Article 545386. doi: http://dx.doi.org/
Benedetti, F. (2009). Placebo effects: Understanding the mecha-
10.1155/2012/545386 .
nisms in health and disease. New York: Oxford University Press.
Institute of Medicine. (2011). Relieving pain in America: A blueprint
Burgoyne, D. S. (2007). Prevalence and economic implications of
for transforming prevention, care, education and research. Wash-
chronic pain. Managed Care, 16, 2–4.
ington, DC: The National Academies Press.
Cavalcante Miranda de Assis, D., Martins Lima, E., Teixeira Goes,
Jacobsen, L. M., Eriksen, G. S., Pedersen, L. M., & Gjerstad, J.
B., Zugaib Cavalcanti, J., Barbosa Paixao, A., Vannier-Santos,
(2010). Catechol-O-methyltransferase (COMT) inhibition reduces
M. A. …Baptista, A. F. (2014). The parameters of trancutanous
spinal nociceptive activity. Neuroscience Letters, 473, 212–215.
electrical nerve stimulation are critical to its regenerative effects
doi: 10.1016/j.neulet.2010.02.049
when applied just after a sciatic crush lesion in mice. Biomedical
Research International, Article 572949, 1-8. Jankowski, M. P., & Koerber, R. (2010). Neurotrophic factors and
nociceptor sensitization. In: M. P. Jankowski & H. R. Koerber
Chesterton, L. S., Sim, J., Wright, C. C., & Foster, N. E. (2007). Interrater
(Eds.), Translational pain research: From mouse to man. (pp. 31-
reliability of algometry in measuring pressure pain thresholds in health
50). Boca Raton, FL: CRC Press.
humans using multiple raters. Clinical Journal of Pain, 23, 760–767.
Keller, S., Bann, C. M., Dodd, S. L., Schein, J., Mendoza, T. R., &
Chou, R., & Huffman, L. H. (2007). Guideline for the evaluation and
Cleeland, C. S. (2004). Validity of the Brief Pain Inventory for use
management of low back pain: Evidence review. Glenview, IL:
in documenting the outcomes of patients with noncancer pain.
American Pain Society.
Clinical Journal of Pain, 20, 309–318.
Clauw, D. J., Williams, D., Lauerman, W., Dahlman, M., Aslami, A.,
Malin, S. A., Molliver, D. C., Koerber, H. R., Cornuet, P., Frye, R.,
Nachemson, A. L. …Wiesel, S. W. (1999). Pain sensitivity as a cor-
Albers, K. M., & Davis, B. M. (2006). Glial cell line-derived neuro-
relate of clinical status in individuals with chronic low back pain.
trophic factor family members sensitize nociceptors in vitro and
Spine, 24, 2035–2041. doi: 10.1097/00007632-199910010-00013
produce thermal hyperalgesia in vivo. Journal of Neuroscience,
Cleeland, C.S. (2009). The Brief Pain Inventory user guide. (pp. 1-9). 26, 8588–8599.
Houston: M. D Anderson Cancer Center.
Marineo, G., Iorno, V., Gandini, C., Moschini, V., & Smith, T. J.
Coyne, P. J., Wan, W., Dodson, P., Swainey, C., & Smith, T. J. (2012). Scrambler therapy may relieve chronic neuropathic
(2013). A trial of scrambler therapy in the treatment of cancer pain more effectively than guideline-based drug management:
pain syndromes and chronic chemotherapy-induced peripheral Results of a pilot, randomized, controlled trial. Journal of Pain
neuropathy. Journal of Pain and Palliative Care Pharmacother- and Symptom Management, 43, 87–95. doi: 10.1016/j.
apy, 27, 359–364. doi: 10.3109/15360288.2013.847519 jpainsymman.2011.03.015
Dworkin, R. H., Turk, D. C., Farrar, J. T., Haythornthwaite, J. A., Jensen, Moss, P., Sluka, K., & Wright, A. (2007). The initial effects of knee
M. P., Katz, N. …Witter, J. (2005). Core outcome measures for chronic joint mobilization on osteoarthritic hyperalgesia. Manual Thera-
pain clinical trials: IMMPACT recommendations. Pain, 113, 9–19. pies, 12, 109–118. doi: 10.1016/j.math.2006.02.009
Emery, E. C., Young, G. T., Berrocoso, E. M., Chen, L., & McNaugh- Nicol, G. D., & Vasko, M. R. (2007). Unraveling the story of NGF-
ton, P. A. (2011). HCN2 ion channels play a central role in inflam- mediated sensitization of nociceptive sensory neurons: ON or
matory and neuropathic pain. Science, 333, 1462–1466. doi: OFF the Trks? Molecular Interventions, 7, 26–41.
10.1126/science.1206243
O’Neill, S., Manniche, C., Graven-Nielsen, T., & Arendt-Nielsen, L.
Fang, J. F., Liang, Y., Du, J. Y., & Fang, J. Q. (2013). Transcutane- (2007). Generalized deep tissue hyperalgesia in patients with
ous electrical nerve stimulation attenuates CFA-induced hyperal- chronic low back pain. European Journal of Pain, 11, 415–420.
gesia and inhibits spinal ERK1/2-COX-2 pathway activation in doi: 10.1016/j.ejpain.2006.05.009
Research in Nursing & Health38 RESEARCH IN NURSING & HEALTH
Pezet, S., & McMahon, S. B. (2006). Neurotrophins: Mediators and Symptom Management, 40, 883–891. doi: 10.1016/j.
modulators of pain. Annual Review of Neuroscience, 29, 507– jpainsymman.2010.03.022
538. doi: 10.1146/annurev.neuro.29.051605.112929
Smith, T. J., & Marineo, G. (2013). Treatment of postherpetic pain with
Ren, K., & Dubner, R. (2007). Pain facilitation and activity-dependent Calmare therapy, a patient-specific neurocutaneous electrical stimu-
plasticity in pain modulatory circuitry: Role of BDNF-TrkB signal- lation device. American Journal of Hospice and Palliative Care
ing and NMDA receptors. Molecular Neurobiology, 35, 224–235. (Advance online publication). doi: 10.1177/1049909113494002
doi: 10.1007/s12035-007-0028-8
Soni, A. (2011). Top 10 most costly conditions among men and
Ricci, M., Pirotti, S., Scarpi, E., Burgio, M., Maltoni, M., Sansoni, E., women 2008: Estimates for the U.S. civilian noninstitutionalized
& Amadori, D. (2011). Managing chronic pain: Results from an adult population, age 18 and older. Medical Expenditure Panel
open-label study using MC5-A Calmare device. Supportive Care Survey (MEPS) Statistical Brief #331. Rockville, MD: AHRQ.
in Cancer, 20, 405–412.
Weinkauf, B., Obreja, O., Schmelz, M., & Rukwied, R. (2014). Differ-
Rolke, R., Magerl, W., Campbell, A., Schalber, C., Caspari, S., Birklein, F., ential time course of NGF-induced hyperalgesia to heat versus
& Treed, R. D. (2006). Quantitative sensory testing: A comprehensive mechanical and electrical stimulation in human skin. European
protocol for clinical trials. European Journal of Pain, 10, 77–88. Journal of Pain (Advance online publication). doi: 10.1002/
ejp.603 [Online ahead of print].
Sabato, A. F., Marineo, G., & Gatti, A. (2005). Calmare therapy. Min-
verva Anestesiologica, 71, 479–482. Yang, L., Yang, L., & Gao, X. (2010). Transcutaneous electrical
nerve stimulation on Yongquan acupoint reduces CFA-induced
Smith, T. J., Coyne, P. J., Parker, G. L., Dodson, P., &
thermal hyperalgesia of rats via down-regulation of ERK2 phos-
Ramakrishnan, V. (2010). Pilot trial of a patient-specific cutane-
phorylation and c-fos expression. The Anatomical Record, 293,
ous electrostimulation device (MC5-A Calmare) for chemother-
1207–1213. doi: 10.1002/ar.21157
apy-induced peripheral neuropathy. Journal of Pain and
Authors continued from first page:
Jamie Sturgill
Assistant Professor
R. K. Elswick, Jr.
Director of the Center for Biobehavior Clinical Research
Professor and Director of Data Management
Virginia Commonwealth University School of Nursing Laboratory
Virginia Commonwealth University School of Nursing,
Richmond, VA
Richmond, VA
Kyungeh An
Associate Professor
Virginia Commonwealth University School of Nursing
Richmond, VA
ACKNOWLEDGMENTS
Components of this project were supported by the National Institute of Nursing Research through grant #P30 NR011403 (MJ
Grap, PI). Dr. Starkweather (R01 NR013932) and Dr. Lyon (R01 NR012667) are currently receiving grants from the National
Institute of Nursing Research, National Institutes of Health. The content of this publication is solely the responsibility of the
authors and does not represent the official views of the National Institute of Nursing Research or the National Institutes of
Health. The trial was registered on clinicaltrials.gov under NCT01896687.
Research in Nursing & HealthYou can also read
