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Research Article
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Chronic pain intervention using pulsed shortwave therapy: the relationship between pain demographics and central sensitization inventory
Sree N Koneru1, Richard Staelin2 & Ian M Rawe*,1
1 Clinical Research Division, BioElectronics Corporation, Frederick, MD 13905, USA
2Fuqua School of Business, Duke University, Durham, NC 27708, USA
*Author for correspondence: Tel.: [phone]; Fax: [phone]; [e-mail]
Practice points
• Inthisstudy,themajorityofchronicpainsufferersreportedmildtoextremecentralsensitizationwhenevaluated using the central sensitization inventory (CSI).
• WomanreporthigherCSIscorescomparedwithmen,evenafteradjustingforanydifferencesinbaselinepain scores.
• PaindurationappearstodrivehigherCSIscores.
• Paindurationhasadirecteffectonthenumberofreporteddiagnosedcentralsensitizationsyndromes,whichisa
subpart of the CSI.
• BaselinepainlevelsareuncorrelatedwithCSIscores,exceptforveryhighCSIscores(extremecentral
sensitization).
• ActiPatch?R pulsed shortwave therapy provided an effective (≥2 visual analog scale reduction) chronic pain
therapy for nearly 70% of subjects, reducing their pain levels by an average of over 50%, regardless of baseline CSI scores.
Aim: The central sensitization inventory (CSI) is a validated, patient-reported questionnaire that quantifies symptoms of hypersensitivity disorders such as chronic pain, for which central sensitization (CS) may be the etiology. Objective: To investigate the analgesic effectiveness of ActiPatch and analyze the relationship between baseline CSI scores and demographics of chronic pain sufferers. Methods: Upon completing a 7-day ActiPatch trial, baseline CSI scores along with other assessment measures were obtained via e-mail from 174 chronic pain sufferers. Conclusion: CSI scores were positively correlated with gender (higher for women), baseline visual analog scale scores and pain duration. ActiPatch was found to be effective in reducing baseline pain for all subjects by an average of 4.3 visual analog scale points.
First draft submitted: 22 May 2018; Accepted for publication: 22 November 2018; Published online: 29 May 2019
Keywords: central sensitization • central sensitization inventory • chronic pain • pain duration • pain relief • PSWT • pulsed shortwave therapy
Central sensitization (CS) is now understood to play a critical role in the development of many types of chronic pain [1,2]. Sustained acute pain leads to persistent C-fiber activation and can induce a state of spinal hypersensitivity, known as CS [3]. Therefore, CS manifests as increased activity of pain facilitation pathways, coupled with mal- functioning descending pain inhibitory pathways which result in dysfunctional endogenous analgesic control [4]. These faulty pathways result in enhanced pain response to noxious stimuli (hyperalgesia) and importantly allowing low-threshold sensory inputs to activate the pain circuits (allodynia), both of which are challenging to treat through pharmacotherapy [5].
The pathophysiology of many unrelated clinical disorders that involve both pain- and non-pain-related condi- tions has been linked to CS. These including osteoarthritis [6–8], rheumatoid arthritis [9,10], chronic lower back pain [11], fibromyalgia [12–15], primary dysmenorrhea [16], endometriosis [17,18], chronic prostatitis [19], whiplash
10.2217/pmt-2018-0032?C 2019BioElectronicsCorporation PainManag.(Epubaheadofprint) ISSN1758-1869

Research Article
Koneru, Staelin & Rawe
Green light illuminates when device is on
The electronics and battery are in this module
Therapeutic area is inside loop
Figure 1. The ActiPatch?R (BioElectronics Corporation, MD, USA) is a commercially available, over-the-counter medical device used for treating chronic pain. The wearable device uses sensation-free electromagnetic fields that are pulsed 1000 times a second (pulsed shortwave therapy) to regulate the activity of afferent nerves.
Taken with permission from BioElectronics Corporation.
neck injury [20,21], overactive bladder [22], shoulder pain [23], TMJ [24], migraine [25,26], tennis elbow [27,28], chronic fatigue syndrome [9] and post-traumatic stress disorder [29]. Additionally, sleep quality has been found to play a significant role in the relationship between CS and pain [30–32].
Reynolds et al. [3] note that while there are no direct methods to assess CS, psychosocial laboratory techniques such as quantitative sensory testing (QST) can be useful [33]. QST allows for quantifying sensory perception in an individual in response to externally applied thermal or mechanical stimuli [33,34]. Essentially this type of testing determines sensation and pain thresholds in an individual by, for example, quantifying the level of applied pressure that is required to evoke a pain response. Perhaps the most popular use of QST with regards to CS is in quantifying the extent of temporal summation, which is an increase in pain perception in response to repetitive, noxious stimuli. Additionally, QST methods have been used to assess both pain facilitation and inhibition pathways reliably. Although invaluable as a laboratory technique in quantifying the level of CS with regards to chronic pain, employing QST as a diagnostic tool for CS can be time consuming and expensive. Guidelines have now been developed to allow for the use of psychometric tools that evaluate symptoms linked to the onset of CS. The central sensitization inventory (CSI) is a validated patient-reported questionnaire that was developed as a component of this classification system [35–40]. The CSI seeks to quantify central sensitization symptoms using a series of 25 questions, each with five possible answers and a 5-point temporal Likert scale where the available responses are: never (0), rarely (1), sometimes (2), often (3) and always (4). Thus, CSI scores can range from 0 to 100 and fall into 1 of 5 clinical categories that indicate the severity of CS: 0–29 (sub-clinical), 30–39 (mild), 40–49 (moderate), 50–59 (severe) and 60–100 (extreme) [40]. The CSI has a second section (part B), the goal of which is to obtain information on previously diagnosed central sensitization syndromes (DCSSs) [37].
In this paper, a registry of responses from 174 chronic pain sufferers was used to explore how CSI is related to several population demographics such as gender, age, duration and intensity of pain. In addition, we explored if the effectiveness of a specific over-the-counter (OTC) neuromodulation device, ActiPatch (Figure 1), is a function of baseline CSI levels. This medical device uses sensation-free pulsed shortwave therapy (PSWT) [41] and has previously been reported to provide relief from chronic pain [42–45]. When placed over the area of pain and worn continuously it can provide pain relief in as quickly as 2–3 h, although other cases reported relief after 3–4 days. It is currently available for OTC use in many countries including the EU, Canada and USA. Randomized, double-blind, placebo controlled studies that utilized the ActiPatch reported clinically significant decreases in pain, along with a decrease in the use of analgesic medication [42,46,47]. One of these studies looked at knee osteoarthritis, which is a classic CS syndrome, since the level of pain is often not correlated to the level of joint degeneration [8]. In this knee osteoarthritis study [42], pain pressure threshold testing indicated that subjects who used active ActiPatch devices reported a significant increase in pain tolerance both locally and distally, when compared with the placebo
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Pulsed shortwave therapy, chronic pain and central sensitization
Research Article
group. Since pain pressure threshold testing is a form of QST, this indicated that PSWT treatment may induce changes in central pain processing, thereby increasing pain threshold levels. This clinical evidence is supplemented by evidence from two registry studies, which concluded that ActiPatch provided significant pain relief in a wide variety of chronic pain conditions [44,45].
This current registry study examines the effectiveness of ActiPatch in reducing pain of chronic pain sufferers across a wide range of CSI scores, supplementing existing clinical evidence.
Methods
The data for this registry study were collected as part of a general assessment of UK residents who ordered a 7-day trial sample of the ActiPatch musculoskeletal pain therapy device (ActiPatch, BioElectronics Corporation, MD, USA), thereby indicating prior interest in finding a solution that provides them pain relief. The package for this device included directions for use which indicated how and where to place the device, turn it on and the duration of treatment (24 h per day for 7 days). E-mail addresses of these residents were acquired via the product ordering process. Based on the ordering date, a trial completion date was estimated for each customer, following which an assessment questionnaire was sent using Constant Contact (Constant Contact, MA, USA) e-mail marketing software. A second reminder e-mail, requesting completion of the assessment, was sent 4 days after the first e-mail. Data collection was completed in 8 days of the first e-mail. In all, 1800 subjects were contacted, of whom 174 agreed to participate. Participation in the e-mail assessment was voluntary, and no other method or incentive was used to collect the data.
The self-reported assessment was designed to collect data on gender, age, pain duration, pain levels before and after using the ActiPatch 7-day trial (using an 11-point visual analog scale [VAS] pain score) and finally, the CSI. The CSI (which is further discussed in section 3.2) consisted of 25 standardized questions [37] of which all, but three, were related to factors other than pain levels or frequency. As such, the CSI primarily taps into nonpainful symptoms related to CS.
ActiPatch
ActiPatch is a low power (Figure 1), PSWT shortwave therapy device that is classified as an OTC, class II(a) medical device in the EU and used for and marketed as an adjunct therapy for chronic pain. The device operates at a carrier frequency of 27.12 MHz and pulses 1000 times per second, each sustained for a duration of 100 µs. The peak incident power on tissue, as measured into a 50 ?? load is 73 µW/cm2.
Data handling
Data obtained from the general assessment described above were exported into a comma-delimited (CSV) file, and analyzed using Microsoft Excel (Microsoft Corporation, WA, USA). Statistical analysis of differences between means was performed using the student’s t-test, where p < 0.05 was considered statistically significant. Multiple regression analyses were conducted to determine the strength of relationships between CSI, duration of pain and reduction in pain with variables such as gender, duration of pain and intensity of pain, using RegressIt, an add-on package to Microsoft Excel.
Results
Population demographics
The data acquisition process yielded 174 responses, all of which were used for data analysis. The distributions for gender, age and pain duration are shown in Table 1. The sample population consisted mainly of women (82%), having a mean age of approximately 53 years, reporting chronic pain lasting more than 3 months (mean duration of approximately 7.7 years) and a mean pain level of 7.82 ± 0.14 VAS points. In addition, this population reported a mean CSI of 42.4 ± 1.29 and an average of 1.43 ± 0.15 DCSSs, in other words, syndromes associated with a clinical diagnosis of central sensitization. Thus, the sample is composed of a heterogeneous group of chronic musculoskeletal pain sufferers with high levels of baseline pain, who also indicated high levels of central sensitization, were diagnosed with CS syndromes, and who were seeking alternative modalities for treating their pain.
The basic components of CSI
The CSI is composed of 25 questions concerning specific CS symptoms. These questions have previously been categorized into four groups using factor analysis; these components being: physical, emotional, headache and jaw,
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Research Article Koneru, Staelin & Rawe
Table1. Subjectdemographicsincludinggender,age,durationofpain,meanbaselinevisualanalogscalescoreand
central sensitization inventory.
Characteristic
Age
N = 174
8–24 1
25–34 6
35–44 34
45–54 48
55–64 56
65 plus 29
Prefer not to answer 0
Pain duration
0–6 months 17
6 m–1 year 19
1–2 years 23
2–5 years 26
5–10 years 39
10–20 years 32
20 years plus 18
Gender (N[%])
Men 32 (18.4%)
Women 142 (81.6%)
Baseline pain 7.82 ± 0.14
Baseline CSI 42.52 ± 1.29
Baseline DCSS 1.43 ± 0.15
CSI: Central sensitization inventory; DCSS: Diagnosed central sensitization syndrome.
and urological [40]. The mean scores for these four components (calculated as the mean of scores of all questions grouped under that component) for the sample is shown below in Figure 2. The eight questions associated with physical symptoms had the highest mean response score (2.29 or between the responses ‘sometimes’ and ‘often’ but closer to ‘sometimes’). The next highest was the seven emotional distress symptoms, averaging a score of 1.62 (approximately equally spaced between ‘rarely’ and ‘sometimes’), followed by means of 1.1 for the other two groups of symptoms. Four of the eight questions classified as physical symptoms (‘muscle stiff/achy’, ‘don’t sleep well’, ‘easily tire with physical activity’, ‘low energy’) were scored 2 or greater in 75% of the sample indicating that these subjects at least ‘sometimes’ suffered from a non-pain specific symptom. Thus, these chronic pain sufferers not only reported having high levels of pain, but were also likely to report one or more non-pain physical symptoms and possibly exhibit other CS-related syndromes.
CSI by gender, age, baseline VAS & duration of pain
Table 2 categorizes the CSI scores into five subgroups classifying how likely a subject has CS, these subgroups being: 0–29 (subclinical) 30–39 (mild), 40–49 (moderate), 50–59 (severe), and 60–100 (extreme). This table displays the general relationship between the different subgroups of CSI and the subgroup means for the different population characteristics. To test the significance of these relationships, multiple regressions were used where the dependent variable was the person’s CSI score and the independent variables were gender, age (the mean for the person’s age category), duration of pain (the mean of the person’s duration category) and baseline VAS. The coefficient for age was found to be insignificant (p = 0.176), while the coefficients for gender, duration of pain and baseline were significant (p = 0.006, p = 0.0005 and p = 0.024, respectively).
Men and women in the sample population reported statistically insignificant differences in baseline pain (7.31 vs 7.93 VAS; p = 0.14) (Table 3). However, women reported higher CSI and DCSS baseline scores than men (34.16 vs 43.94 for CSI) and (0.84 vs 1.44 for DCSS), both of which were significantly different (p = 0.003 and p = 0.05,
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Pulsed shortwave therapy, chronic pain and central sensitization Research Article
2.50
2.00
1.50
1.00
0.50
0.00
2.29
1.62
1.11 1.10
Physical
Emotional
Headache & jaw
Urological
Components of CSI
Figure 2. Subjects reported the highest mean score on the physical component of CSI. This is to be expected, since the subjects under consideration are chronic musculoskeletal pain sufferers. Positive mean scores on other components indicate that subjects’ chronic pain could also be linked to other components of central sensitization. CSI: Central sensitization inventory.
Table2. Outcomemeasuresofthesamplepopulation,categorizedintofivecentralsensitizationinventorygroups (mean ± SE).
Outcome measure CSI 0–29 (n = 41)
subclinical
% of population 24%
CSI 30–39 (n = 35) mild
19%
CSI 40–49 (n = 46) moderate
27%
CSI 50–59 (n = 23) severe
13%
CSI 60–100 (n = 29) extreme
18%
Women/men 29/12 27/6 40/7 17/5 29/1
Age 55.60 ± 1.67 54.07 ± 1.94 52.98 ± 1.51 54.28 ± 2.07 48.52 ± 2.38
Pain duration 4.24 ± 0.83 6.50 ± 1.17 8.11 ± 1.09 11.36 ± 1.71 10.00 ± 1.18
Mean CSI 20.78 ± 1.10 34.60 ± 0.50 44.28 ± 0.45 54.00 ± 0.58 68.66 ± 1.27
DCSS† 0.32 ± 0.08 0.77 ± 0.18 1.20 ± 0.18 1.73 ± 0.28 3.41 ± 0.35
Baseline VAS 7.61 ± 0.29 7.49 ± 0.35 7.46 ± 0.31 7.91 ± 0.26 9.00 ± 0.23
Treatment VAS 4.39 ± 0.40 3.49 ± 0.47 4.13 ± 0.35 5.26 ± 0.50 5.97 ± 0.55
Percentage decrease 42% 53% 45% 34% 34%
†Diagnosed central sensitization syndromes (Part B of CSI).
CSI: Central sensitization inventory; DCSS: Diagnosed central sensitization syndrome; SE: Standard error of the mean; VAS: Visual analog scale.
Table3. Outcomemeasuresforthesamplepopulation,menandwomen(mean±SE).
Pain metric
Baseline VAS
Population (n = 174)
7.82 ± 0.1
Men (n = 32)
7.31 ± 0.42
Women (n = 142)
7.93 ± 0.15
Treatment VAS 4.52 ± 0.2 4.94 ± 0.50 4.42 ± 0.22
Percentage improvement 42% 32% 44%
Mean CSI 42.14 ± 1.27 34.16 ± 2.84 43.94 ± 1.38
Mean DCSS† 1.43 ± 0.15 0.84 ± 0.22 1.44 ± 0.14
†DCSSs (Part B of CSI).
CSI: Central sensitization inventory; DCSS: Diagnosed central sensitization syndrome; SE: Standard error of the mean; VAS: Visual analog scale.
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Mean score of components

Research Article
Koneru, Staelin & Rawe
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0
0–29 30–39 40–49 50–59
Baseline CSI score
60–100
Figure 3. Baseline mean VAS scores by CSI subgroup along with graphic representation of ± standard error of the means for each displayed mean. The last CSI subgroup (60–100) reported significantly higher baseline pain, when compared with the other subgroups (p = 0.002).
CSI: Central sensitization inventory; VAS: Visual analog scale.
respectively). In addition, the proportion of women to men was higher in groups that reported higher CSI scores (Table 2).
CSI & baseline VAS
The relationship between reported initial pain levels and CSI is shown in Figure 3. The first three categories of CSI scores appear to be uncorrelated with the mean baseline VAS scores within those subgroups. However, for subjects who reported CSI scores of 50 or greater, there is an increase in mean baseline pain levels resulting in significantly higher baseline pain for those reporting CSI scores 60 or above (p = 0.002).
Pain duration & population characteristics
Pain duration was organized into seven subgroups, 0–6 months, 6 months to 1 year, 1–2 years, 2–5 years, 5–10 years, 10–20 years and 20 years plus. The subgroup means for the different outcome measures for the different pain duration subgroups are shown in Table 4. Using multiple regression analysis, we find that the proportion of women to men showed no correlation with pain duration (p = 0.638), nor did the mean age (p = 0.888). However, from Figure 4 it can be seen that baseline measures of CSI, DCSS and VAS scores in general increased with pain duration. The reported mean baseline pain of subjects that reported durations of less than 2 years was significantly different compared with those with pain durations of five or more years (p = 0.002). In contrast, there were no significant differences in the mean post-treatment VAS scores across the different duration of pain levels (p = 0.19). The number of individuals with a given pain duration who reported a specific DCSS is shown in Figure 5 (multiple chemical sensitivities are not shown and were reported by just three subjects). In general, the likelihood of reporting one or more DCSS increases with pain duration (Figure 4B & Figure 5) reaching a peak in the 10–20-year pain duration category. The 0–6 month group reported a higher mean DCSS than other groups until the 5–10 year group; however, it was not significantly different from the 6 month to 1 year group. Figure 5 indicates that DCSS occurrence increases with pain duration. The syndromes of restless leg and irritable bowel tended to be the most
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Baseline VAS pain

Pulsed shortwave therapy, chronic pain and central sensitization Research Article
Table4. Outcomemeasuresofthesamplepopulation,categorizedbythedurationofreportedpainreportedinmonths and years (mean ± SE).
Outcome measure 0–6 months 6 m to 1 years 1–2 years 2–5 years 5–10 years 10–20 years 20+ years
Sample size 17 19 23 26 39 32 18
Women/men 15/2 14/5 19/4 22/4 32/7 25/7 15/3
Age 51.85 ± 2.19 57.39 ± 2.37 52.98 ± 2.23 53.73 ± 2.09 51.85 ± 1.91 51.69 ± 2.19 55.61 ± 2.57
CSI 30.24 ± 4.01 36.47 ± 3.39 34.91 ± 2.41 40.42 ± 3.50 47.28 ± 2.86 48.16 ± 2.55 49.28 ± 3.41
DCSS† 1.29 ± 0.40 0.79 ± 0.79 0.96 ± 0.27 1.15 ± 0.21 1.49 ± 0.33 1.75 ± 0.31 1.61 ± 0.40
Baseline VAS 6.94 ± 0.60 6.84 ± 0.63 7.00 ± 0.31 7.88 ± 0.32 8.28 ± 0.29 8.66 ± 0.18 8.11 ± 0.25
Treatment VAS 4.71 ± 0.63 4.00 ± 0.70 4.26 ± 0.60 4.92 ± 0.32 3.82 ± 0.37 5.50 ± 0.47 4.39 ± 0.56
% VAS decrease 32.1% 41.5% 39.1% 37.6% 53.9% 36.5% 45.9%
†DCSSs (Part B of CSI).
CSI: Central sensitization inventory; DCSS: Diagnosed central sensitization syndrome; SE: Standard error of the mean; VAS: Visual analog scale.
100 10 90 9 80 8 70 7 60 6 50 5 40 4 30 3 20 2 10 1
2.1 1.9 1.7 1.5 1.3 1.1 0.9 0.7
Mean baseline CSI Mean baseline VAS
0 00.5 0–6m 6m– 1–2 yrs 2–5 yrs 5–10 10–20 20 yrs
1 yr yrs yrs +
Pain duration
0–6m 6m–1yr 1–2 yrs 2–5 yrs 5–10 10–20 20 yrs yrs yrs +
Pain duration
Figure 4. Correlations between pain duration and baseline measures. (A) Baseline measures of CSI and VAS along with graphic representation of ± standard error of mean, as a function of pain duration. (B) Baseline DCSS along with graphic representation of ± standard error of mean as a function of pain duration. The trend lines in both figures indicate that pain duration is positively correlated with baseline measures of CSI, DCSS and VAS.
CSI: Central sensitization inventory; DCSS: Diagnosed central sensitization syndrome; VAS: Visual analog scale.
commonly reported syndromes across all pain duration groups (Figure 5). In contrast, fibromyalgia, depression and anxiety, and panic attacks were most likely to occur in individuals who suffered with chronic pain for longer periods of time.
ActiPatch treatment effectiveness as a function of CSI
The mean percentage decrease in pain for the total sample of chronic pain sufferers that occurred after the 7-day trial of ActiPatch is shown in Tables 2 and 4 for the five CSI subgroups and the seven pain duration subgroups, respectively. These tables indicate that pain was reduced by a mean of 45% for subjects reporting CSI scores below 50, compared with 34% for scores above 50. In contrast, there does not seem to be any discernible trend in absolute mean pain reduction across the different subgroups of pain duration (Table 4 & Figure 6). These data indicate that
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CSI score (0–100)
VAS score (0–10) DCSS

Research Article Koneru, Staelin & Rawe
50
45
40
35
30
25
20
15
10
5 0
0–6 m
6 m – 1 yr
1–2 yr
2–5 yr
Pain duration
5–10 yr
10–20 yr
20+ yr
Restless leg syndrome Fibromyalgia
Migraine or tension headaches Neck injury (including whiplash) Depression
Chronic fatigue syndrome TMJ
Irritable bowel syndrome Anxiety or panic attacks
Figure 5. The expression of diagnosed central sensitization syndromes in the pain duration subgroups increases with increasing pain duration. Nine of the ten syndromes are shown.
TMJ: Temporomandibular joint disorder.
irrespective of baseline pain level or duration, pain levels were reduced by a mean of 4.3 VAS points.
In the literature, pain reduction has been determined to be clinically meaningful only if VAS pain scores were reduced by more than 2 VAS points [48]. In this study, there were 118 individuals (68% of the sample) who reported a VAS pain score reduction >2 points. Labeled ‘responders’, a quantitative analysis was conducted on outcome measuresforthissubgrouponall fiveCSIsubgroups(Table5).Thepercentageofsubjectsclassifiedas‘responders’ gradually increases with the CSI scores, reaching a peak at the CSI 40–49 group. Effectiveness declines in the two higher subgroups with the lowest effectiveness rate reported at 55% in the CSI 60–100 group. However, the percentage reduction in pain for all the groups, which averaged about 59%, is stable over the total range of CSI scores. Thus, conditional on getting effective pain relief, all the CSI groups reported similar reductions in pain, albeit from different baseline VAS scores and thus different post-treatment VAS scores. Outcome measures (mean
± SE) for subjects (n = 118), and by gender, reporting treatment effectiveness (≥2 VAS reduction).
Discussion
The results from this Registry study pertaining to baseline pain, treatment outcome and pain duration were consistent with two prior published Registry studies. Baseline pain in the current sample population was 7.82 (standard deviation [SD]: 1.87), compared with 8.02 (SD: 1.55) in the 5000 subject study [44], and 8.04 (SD: 1.46) in the 1394 subject chronic back pain Registry study [45]. Additionally, treatment VAS scores were consistent across the three studies with 43% pain reduction in the current study and 37% [44], 40% [45] in the two prior
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% of subjects reporting syndrome

Pulsed shortwave therapy, chronic pain and central sensitization Research Article
10
9
8
7
6
5
4
3
2
1
0
Baseline VAS Treatment VAS Difference
0–6 months
6 months – 1 year
1–2 years
2–5 years
5–10 years
10–20 years
20 years plus
Figure 6. VAS point reduction was found to be consistent across all pain duration groups, indicating that ActiPatch is an effective intervention, irrespective of reported pain duration. This indicates that ActiPatch could be providing pain relief by reducing nerve hypersensitivity associated with central sensitization.
VAS: Visual analog scale.
Table5. Outcomemeasures(mean±SE)forsubjects(n=118),andbygender,reportingtreatmenteffectiveness(≥2 VAS reduction).
Outcome measures CSI 0–29 (n = 28)
subclinical
Effectiveness rate 68%
CSI 30–39 (n = 24) mild
73%
CSI 40–49 (n = 34) moderate
74%
CSI 50–59 (n = 14) severe
64%
CSI 60–100 (n = 17) extreme
55%
Women/men 23/5 20/4 32/3 11/3 16/1
Women/men 79%/42% 74%/67% 80%/43% 65%/60% 55%/100% effectiveness
Age 56.05 ± 1.63 53.79 ± 2.03 53.79 ± 1.70 51.64 ± 2.61 53.88 ± 2.34
Pain duration 4.03 ± 0.71 7.49 ± 1.24 7.70 ± 1.28 12.39 ± 2.10 10.83 ± 1.46
Mean CSI 21.03 ± 1.08 34.21 ± 0.50 44.29 ± 0.52 53.79 ± 0.76 68.38 ± 1.84
DCSS 0.31 ± 0.08 0.89 ± 0.19 0.91 ± 0.19 1.79 ± 0.45 3.75 ± 0.46
Baseline VAS 7.70 ± 1.50 7.57 ± 0.39 7.74 ± 0.25 8.14 ± 0.23 9.31 ± 0.23
Treatment VAS 3.21 ± 0.30 2.39 ± 0.49 3.14 ± 0.27 3.79 ± 0.35 4.00 ± 0.52
% VAS decrease 58.3% 68.4% 59.4% 53.4% 57%
The first two CSI score groups reported higher VAS percentage decreases than the last CSI score group. However, the last CSI score group reported the highest decrease in VAS points. CSI: Central sensitization inventory; DCSS: Diagnosed central sensitization syndrome; SE: Standard error of the mean; VAS: Visual analog scale.
Registry studies. These pain reductions were also consistent with outcomes from two randomized controlled trials that investigated the analgesic efficacy of the ActiPatch device for plantar fasciitis and osteoarthritis of the knee. In the former study, the reported mean morning (am) VAS score reduction, considered to be a more accurate measure for plantar fasciitis, was 40% [46], while in the latter study the reported mean VAS score reduction was 25% [42].
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Visual analogue pain

Research Article
Koneru, Staelin & Rawe
This study investigated the inter-relationship between patient characteristics such as age, gender, pain duration, VAS pain level and the relationship of these measures with CS as measured by the CSI. Age was not found to be significantly related to CSI, but gender, baseline VAS scores and pain duration were all found to be positively and significantly related to CSI. The relationship between CSI and the two pain measures, in other words, intensity and duration is of particular interest since the CSI primarily quantifies symptoms other than pain, for example, depression, difficulty performing daily tasks, low energy – etc. This data do not allow for an attribution of cause and effect, but indicate that these long-term chronic pain sufferers were displaying multiple symptoms associated with CS.
Women reported higher CSI scores, although their mean baseline VAS scores were not significantly higher than males. Baseline VAS scores were significantly higher for subjects who reported extreme CSI scores (60 or greater). Subjects who reported pain duration of 2 years or more, reported a mean CSI score of 40 or more. Thus, these subjects presented the possibility for a clinical diagnosis of ‘moderate’, ‘severe’ or ‘extreme’ CS. A study on bladder pain which utilized CSI, reported similar findings where higher CSI scores positively correlated with pain duration [49]. There also appears to be a positive correlation between pain duration and mean number of individual DCSSs, indicating that the duration of pain experienced may be a driving force behind the expression of these syndromes. One such example is fibromyalgia, which was reported as a DCSS by 21 subjects. More than 90% of these cases occurred in individuals who were suffering with chronic pain for more than 5 years (it is acknowledged that difficulties in diagnosing fibromyalgia may play a role). Depression, which is also a DCSS, was reported by 52 individuals, the vast majority of whom also reported longer pain durations. Thus, 60% of these individuals who reported depression had pain durations of 5 years or more, and 79% reported pain durations of 2 years or more. Thus, not only did individuals who suffer with pain for long periods of time report higher baseline pain levels, but also higher CSI scores and more diagnosed CS syndromes. Finally, although mean baseline pain levels were found to be similar among individuals who reported pain durations of 2 years or less, subjects reporting longer pain durations, especially 5 years or more, reported, higher baseline VAS scores by about 15% (VAS 7 vs VAS 8) compared with those with durations of 2 years or less.
Given that CSI and DCSS both measure the manifestation of CS, it is not surprising that the mean number of DCSS is positively correlated with CSI scores. However, this relationship appears to be nonlinear, with a doubling in the number of syndromes, from 1.71 syndromes in the group reporting a CSI score 50–59, to 3.41 in the group reporting a CSI score 60–100. However, even those with lower CSI scores reported DCSS. For example, the lowest group, in other words, with CSI scores <29, reported one or more diagnosed CS syndromes 22% of the time. To put this in context, consider a CSI score of 21, which is the mean score for the group reporting a CSI score of 0–29. Such a score might be obtained in a large number of ways. One such way would be for the respondent to indicate on the CSI that he/she was suffering ‘often’ from seven different CS-related symptoms (e.g., seven symptoms with a score of three). Another way would have the respondent indicating suffering ‘sometimes’ from nine different CS-related symptoms (2 x 9 = 18) and ‘often’ suffering from a tenth symptom (increasing the score by three). These examples indicate that even though individuals in the CSI group 0–29 would be considered as having ‘subclinical’ CS, these chronic pain sufferers show many of the symptoms associated with CS. Interestingly, the mean pain level for this group of pain sufferers is not statistically different from the next two subgroups. In fact, the first three subgroups have mean pain levels that are only marginally significantly lower than the 50–59 CSI subgroup. However, the first three CSI subgroups have baseline pain levels that are significantly less than that of the group having CSI scores 60 or greater (p < 0.001).
In this study, the neuromodulation medical device, ActiPatch, was found to relieve pain across all pain duration groups (as witnessed by the approximately equal reduction in absolute mean VAS). This finding has been previously demonstrated by Rawe et al. [44] in a 6-month duration registry study of subjects who had previously indicated that they positively responded to the first 7-day treatment. Specifically they reported the ActiPatch provided an effective long-term intervention, irrespective of the duration of chronic pain; a factor that this current study shows is positively related to CS. Similarly, data from Figure 6 indicate that irrespective of baseline pain level or duration, upon using ActiPatch for 7 days, pain is consistently reduced by about 4.3 VAS points. In addition, data from Table 5, which look only at positive responders show that the mean percentage improvement across all CSI score subgroups for these positive responders is just less than 60%. These data are compatible with the premise that ActiPatch treatment provides pain relief by mitigating afferent nerve hypersensitivity associated with CS. If true, then ActiPatch provides pain relief by improving pain tolerance thresholds, a key indicator of the presence of CS. In
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this way, it reduces CS. Bagnato et al. [42] have already shown through QST, which is a gold standard of evaluating the extent of CS [3,22], that ActiPatch improves pain tolerance thresholds.
Although we found ActiPatch reduced pain regardless of the CSI score, the effectiveness was lower for subjects who reported CSI scores of 50 or above. This was due primarily to the fact that there were less positive responders (i.e., subject who indicated at least a 2 VAS reduction over the 7 days) for the higher CSI groups. Thus, subjects with CSI scores less than 50 were positive responders about 75% of the time resulting in reported overall mean pain reductions for these subgroups of about 45%. In contrast, those subjects with CSI scores 50 or above were positive responders less than 60% of the time and thus reported an overall mean pain reduction of about 34%.
Our data does not allow us to determine why ActiPatch was found to be less effective for subjects with CSI scores in the severe (50–59) and extreme (60–100) range. However, we note that this treatment was only for 7 days and respondents with higher levels of CSI scores also reported many more syndromes and much longer duration of pain, both of which could impede quick pain relief. Perhaps longer application of this modality of treatment for these high CSI pain sufferers would produce treatment effectiveness comparable to subjects reporting CSI scores of less than 50. With this noted, a preliminary regression with the reduction in pain as the dependent variable and gender, age, duration, DCSS and CSI score as the independent variables, showed that only CSI score and gender are significantly related to pain reduction. Women, even after adjusting for their CSI score, report pain reduction about one VAS point greater than men (comparing Tables 2 & 5 also indicates that women are more likely to be responders when compared with men, i.e., 71/53%). These regression results indicated that the CSI score captures the effects of duration and DCSS, since the marginal effects for these two observed factors were insignificant. Thus, while pain duration may be the primary indicator for both baseline VAS and CSI scores, the latter is most useful in predicting the level of VAS reduction that can be achieved with ActiPatch use for these chronic pain sufferers.
Putting all these observations together, there are several insights that could be valuable to the practicing pain specialist. First, obtaining CSI scores for patients is a low-cost method of assessing the degree to which the chronic pain sufferer is also incurring other CS symptoms. Second most of these symptoms will probably be physical and thus affect the person’s quality of life. Third, CSI scores seem to be strongly related to pain intensity levels, duration of pain and gender, with women indicating a significantly higher level of CS-related symptoms when compared with men, all else equal. Fourth, ActiPatch provided effective (≥2 VAS reduction) pain relief within 7 days to nearly 70% of this chronic pain population, with the largest percentage reduction occurring in subjects with mild-moderate levels of CS as determined by their CSI scores. Fifth, although the percentage reduction in pain is a function of CSI, the absolute level of reduction in VAS points is not. Finally, duration of pain seems to be an important driver of baseline pain levels and the number of DCSSs. However, knowing a patient’s baseline CSI score appears to be a better indicator of the amount of pain relief to expect by using ActiPatch. Thus, effectiveness is less a function of the duration of pain than the CSI score and gender. Importantly, women seem to respond more positively to this treatment modality than men. At this time, we have no strong opinions on why, although other studies have shown similar results [50–52].
Limitations
This study had several limitations. First, it relied on self-reported data, and required respondents to recall prior (baseline) pain levels. However, this data are consistent with two other larger registry studies collecting similar measures. Second, it was based on a convenience sample of self-identified chronic pain sufferers looking for a possible solution to their (high) level of pain. Still, there was little reason to believe this selection would modify any observed relationships between CSI and the population measures. Third, there was no control group to help assess the possible placebo effect of the observed reduction in pain. Thus, it is impossible to directly attribute improvement in pain levels to modifying CS. This is further compromised since the study did not take post- treatment CSI measures and thus could not directly address whether the medical device reduced CS.
Conclusion & future perspective
The degree of CS appears to be driven by pain duration, the level of reported pain, gender and the manifestation of DCSSs. The results of this study suggest that ActiPatch could be an effective pain therapy for individuals over all levels of central sensitization, as measured by the CSI. Most of the questions (22/25) in the current CSI questionnaire are related to factors other than pain. However, recent literature indicates that a short-form version of the CSI, consisting of nine questions may be more suited to quantify CS for chronic pain patients [53]. Further
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Koneru, Staelin & Rawe
studies are needed to determine whether neuromodulation therapies such as ActiPatch can not only provide pain relief, but also mitigate other symptoms associated with CS (and thus reduce CSI scores).
Financial & competing interests disclosure
S Koneru and I Rawe are paid employees of BioElectronics Corporation. R Staelin is an investor in BioElectronics Corporation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.
The authors state that they have obtained verbal and written informed consent from the patient/patients for the inclusion of their medical and treatment history within this case report.
Open access statement
This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
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