Clinical Trial/Experimental Study Medicine ® OPEN Effects of neuro-adaptive electrostimulation therapy on pain and disability in fibromyalgia A prospective, randomized, double-blind study ∗ Carlos Udina-Cortés, PhDa, Josué Fernández-Carnero, PhDb,c,d, , Alberto Arribas Romano, MScb, ∗ s Castro-Marrero, PhDg, , Juan Nicolás Cuenca-Zaldívar, MSce, Jorge Hugo Villafañe, PhDf, Jesu Isabel Maria Alguacil-Diego, PhDb Abstract Background: To evaluate the effectiveness of non-invasive neuro-adaptive electrostimulation (NAE) therapy for treating chronic pain and disability in patients with fibromyalgia. Method/design: A prospective, randomized, sham-controlled study was conducted in 37 women with fibromyalgia. Participants were randomly assigned to receive either active NAE (n = 20) or stimulation with a sham device (n = 17). Participants in the experimental arm received eight 30-minute sessions over 4 weeks (2 sessions per week). The sham group received eight 30-minute sessions of sham stimulation. Therapeutic effects on pain relief, disability, and quality of life were evaluated using outcome measures at baseline, at 4 weeks, and after 3 months’ follow-up. Results: The findings indicated a significant reduction of pain in the active NAE group compared with the sham group immediately post-intervention, with a difference on the Visual Analog Scale (VAS) of 3 points (P = .001), and at 3 months’ follow-up (P = .02). There were significant intragroup differences between the groups (P < .05) at post-intervention. After the intervention, both groups presented significant reductions on the Fibromyalgia Impact Questionnaire (FIQ) with respect to baseline (P = .004), but not at the 3- month follow-up. In the conditioned pain modulation (CPM) in thumb variable we found significant differences between the groups at the 3-month follow-up (P = .02). No additional benefits for conditioned pain modulation and disability were observed between groups at the 3-month follow-up. Furthermore, anxiety/depression and catastrophizing improved in both groups, but no differences between groups were found. Conclusions: In this fibromyalgia cohort, NAE therapy significantly improved pain and quality of life at 4 weeks, but not at 3-month follow-up, compared with the sham stimulation group. Future investigations are needed in larger populations to confirm these findings. Abbreviations: ACR = American College of Rheumatology, BDI = Beck Depression Inventory, CPM = conditioned pain modulation, FIQ = Fibromyalgia Impact Questionnaire, FM = fibromyalgia, IMMPACT = Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials, JSS = Jenkins Sleep Scale, NAE = neuro-adaptive electrostimulation, PCS = Pain Catastrophizing Scale, PPT = pressure pain threshold, SCENAR = self-controlled energo neuroadaptive regulator, SF-36 = the 36-item Short-Form Health Survey, STAI = State Trait Anxiety Inventory, tDCS = transcranial direct current stimulation, TENS = transcutaneous electrical nerve stimulation, TS = temporal summation, TSK = Tampa Scale of Kinesiophobia, VAS = Visual Analog Scale. Keywords: electrostimulation, fibromyalgia, pain, rehabilitation Editor: Luis Manuel Castillo. J-FC and J-CM contributed equally to this work and share senior authorship. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors have no conflicts of interest to disclose. The datasets generated that support the findings of this study are available from the corresponding author upon reasonable request. a Institute Neurolife, b Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, University Rey Juan Carlos, c La Paz Hospital Institute for Health Research (IdiPAZ), d Motion in Brains Research Group, Institute of Neuroscience and Movement Sciences, Centro Superior de Estudios Universitarios La Salle, Universidad Autonoma de Madrid, e School of Health Sciences, University Francisco de Vitoria, Madrid, Spain, f IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy, g Vall d’Hebron Hospital Research Institute, Division of Rheumatology, Universitat Autònoma de Barcelona, Barcelona, Spain. ∗ Correspondence: Jesu s Castro-Marrero, Vall d’Hebron Hospital Research Institute, Division of Rheumatology, Universitat Autònoma de Barcelona, Passeig de la Vall d’Hebron 119-129, 08035 – Barcelona, Spain (e-mail: jesus.castro@vhir.org); Josué Fernández-Carnero, Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, University Rey Juan Carlos, 28933 – Madrid, Spain (e-mail: josue.fernandez@urjc.es). Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. How to cite this article: Udina-Cortés C, Fernández-Carnero J, Romano AA, Cuenca-Zaldívar JN, Villafañe JH, Castro-Marrero J, Alguacil-Diego IM. Effects of neuro- adaptive electrostimulation therapy on pain and disability in fibromyalgia: A prospective, randomized, double-blind study. Medicine 2020;99:51(e23785). Received: 9 July 2020 / Received in final form: 9 October 2020 / Accepted: 12 November 2020 http://dx.doi.org/10.1097/MD.0000000000023785 1 Udina-Cortés et al. Medicine (2020) 99:51 Medicine 1. Introduction effectiveness of NAE therapy in reducing pain and in improving Fibromyalgia (FM) is a chronic complex syndrome characterized disability in individuals with FM. above all by generalized musculoskeletal pain, and by other frequent symptoms such as fatigue, sleep disorders, anxiety/ 2. Materials and methods depression, and cognitive impairments.[1] FM directly affects performance of daily life activities and reduces health-related 2.1. Study design quality of life in these patients.[2] It affects approximately 2% of the A unicenter, prospective, randomized sham-controlled trial study general population in both sexes, with rates of 3.4% among was conducted in a cohort of FM patients. All participants read and women and 0.5% among men.[3] Despite the high prevalence, its signed an informed consent form prior to enrollment. The study diagnosis and management remains a challenge for patients and protocol was approved by the local Ethical Committee (University healthcare professionals. The pathophysiology of pain in FM is not Rey Juan Carlos, Madrid, Spain; reference number: 03/2019) and yet clear, but the latest research points to an alteration in pain conducted in accordance with the 1964 Helsinki declaration and processing and transmission, produced by neuroplasticity changes its later amendments or comparable ethical standards. The study is and dysfunction in the pain nociceptive pathways of the central registered at clinicaltrails.gov (NCT# 03882567). nervous system.[4] This translates into phenomena such as hyperalgesia, allodynia, increased temporal summation due to hyper-excitability in the posterior horn of the cord, and a decrease 2.2. Participants in the activation of descending inhibitory pain pathways.[5] Forty-four potentially eligible patients were recruited from local The current treatment of FM patients is aimed at improving FM associations from June 2018 through October 2019. All their symptoms and thus raising their quality of life. Non- participants were of Caucasian descent and from the same pharmacological treatments using physical therapies have been geographical area. Inclusion criteria for this study were: female applied for decades for the treatment of cardinal symptoms in FM sex, age between 18 and 65 years, previous diagnosis of FM by a such as pain, joint stiffness, and muscle fatigue.[6] Electrotherapy rheumatologist following the 2010 American College of is one of the techniques used in FM patients, since transcutaneous Rheumatology (ACR) case criteria.[1] The exclusion criteria electrical nerve stimulation (TENS) is able to modulate pain by were: inflammatory rheumatic condition; planned elective activating descending central inhibitory mechanisms and reduc- surgery during the study period; ongoing unresolved disability ing the excitatory signals of the posterior horn of the cord.[7] A claims; and symptoms of bipolar disorder, major depressive recent systematic review of the efficacy of this technique in FM disorder, panic disorder, and/or psychosis. patients found it to be effective in pain relief in 7 of the 8 studies included; however, the sample sizes were small and the power of the studies was low.[8] Transcranial direct current stimulation 2.3. Randomization and blinding (tDCS) is another electrotherapy technique that is being studied The sample size was calculated using G∗Power software v3.1. A for the treatment of FM, due to its direct effect on the CNS, blinded researcher performed the randomization of subjects, although the current evidence is limited. Anodic tDCS in the left using the statistical program GraphPad version 8.0 (GraphPad primary motor cortex has demonstrated its efficacy in improving software, Inc. La Jolla, CA). The sample was divided into 2 pain and sleep quality in people with FM.[9] groups (NAE group and sham-controlled group). Only the In our study, we use neuro-adaptive electrostimulation (NAE), therapist had access to the allocation schedule, and patients and a relatively new form of electrotherapy which has not been widely evaluators were blinded to the treatment allocation. studied to date. The NAE device is able to administer doses of impulses according to the electrical impedance responses it receives from the skin. The device used is capable of detecting 2.4. Procedures and interventions areas of altered sympathetic response such as activation zones or To apply NAE, we used the self-controlled energo neuroadaptive passage zones of nerve branches, which in many cases are regulator (SCENAR) 1NT-02.2C device, marketed under the subjected to electrostimulation. In addition, the beneficial effects commercial name SCENAR Physio (Ritm OKB ZAO, Taganrog, of NAE also seem to be related to its ability to stimulate nerve Russia; http://www.scenar.com.ru) (Fig. 1). SCENAR is a fibers which are not commonly activated by other types of transdermal neuro-stimulator destined for non-invasive treat- electrotherapy, and to generate afferent information and ment of physiological systems of the body related to pain. subsequently promote efferent reactions. External electrodes for paravertebral and facial localizations The effectiveness of NAE therapy has been studied in acute optimize access and application with a max supply current not conditions such as lateral ankle sprain, post-operative treatment greater than 650 mA. SCENAR provides two-phase stimuli of femur and ankle fracture, total knee replacement surgery, and without a DC-component with a waveform depending on the chronic diseases such as knee osteoarthritis, neck pain, and skin impedance under the electrode, generated at a fixed chronic plantar fasciitis.[10,11] In a study performed in patients frequency that can be controlled within 15 to 350 Hz. The with whiplash comparing the efficacy of NAE and TENS, NAE duration of the first phase ranges 4 ± 2 to 500 ± 50 mseconds, and showed better outcomes in both neck pain and disability the amplitude of the first pulse of the second stimulus phase varies compared with the TENS group.[26] However, the evidence from 1.7–2.5 V to 100–150 V. The protocol, specifically oriented regarding this type of therapy is extremely scarce and its to anatomical areas involved in sensitization and impairment of effectiveness in patients with FM has not been evaluated to date. nociceptive pathways, is applied for 30 min in 8 twice-weekly Therefore, we considered that NAE may be an effective add-on sessions. During the procedure, soft, comfortable transdermal treatment for pain in FM due to its ability to influence nociceptive stimulation is applied while the patient is in prone or supine pain processing pathways. The aim of this study is to evaluate the position (depending on the pathways to be treated). The placebo 2 Udina-Cortés et al. Medicine (2020) 99:51 www.md-journal.com Figure 1. NAE device. group underwent the same procedure for readings of conductivity 2.5.3. Fibromyalgia Impact Questionnaire. The validated skin reaction (time-impedance-type values) and the therapy Spanish version of the Fibromyalgia Impact Questionnaire stimulation phase with the sham device. Treatments were always (FIQ) was used to assess functional disability and the physical carried out at the same times by a therapist with experience in impact of the disease in FM patients. The FIQ comprises 10 items handling the SCENAR device (Transdermal Electrostimulator that measure physical disability and the degree of specific SCENAR class IIa, CE-2265 Operating Manual. Version 7.2–02, symptoms such as pain, rigidity, fatigue, depression and anxiety, May 2018). disability, and general well-being during the last week. Each symptom is measured on a response scale of 0 (absence of 2.5. Measures symptoms) to 10 (very severe symptoms) using visual analogue scales. The overall FIQ score ranges from 0 to 100, where higher All eligible participants were asked to fill out validated self- scores indicate a greater negative impact of FM on functioning, reported outcome measures to serve as symptom assessment tools classified into the following 3 categories: low impact (<50 under the supervision of a trained investigator (CU-C) who points), moderate (50–75 points), and severe (>75 points). The oversaw participant compliance. The measures used are listed FIQ has demonstrated good psychometric properties and an here: internal consistency of 0.93 in the Spanish FM population.[17] 2.5.1. Pain intensity. Pain intensity was assessed on a visual 2.5.4. Short form 36-item health-related quality of life. The analog scale ranging from 0 to 10 (Visual Analog Scale (VAS) = 0; Spanish version of the Short Form 36-item Health Survey (SF-36) is no pain, and VAS = 10; maximum pain).[12] one of the most widely used scales to evaluate generic health- 2.5.2. Pressure pain threshold. Pressure pain threshold (PPT) related quality of life, measuring physical and mental functioning is a quantitative sensory test of tissue sensitivity and it is defined within the context of an individual’s health status.[18] It comprises as the minimal amount of pressure at which a sense of pressure 36 questions which explore 8 dimensions of the state of health: changes to pain.[13] PPTs near the pathological site are thought to physical functioning (limitation of physical activities of daily life), represent the degree of peripheral nociception, whereas low PPTs physical role functioning (interference at work), bodily pain, distal to the pathology are markers of central nervous system general health perception, vitality, social functioning (interference hyper-excitability.[14] Recordings were collected over the thumb in habitual social life), emotional role (interference in work due to and the midpoint of the trapezius muscle between the emotional problems), and mental health (depression, anxiety, self- acromioclavicular joint and spinal procesus of the C7.[15] A control, and general well-being). The SF-36 produces 2 summary pressure algometer (Force Dial FDK/FDN 100 model, Wagner components, 1 physical and 1 mental, each one generated by Instruments, Greenwich CT) was used (kg/cm2). A mean score of combining the scores of each dimension. SF-36 scores range from 0 3 measurements was calculated. Temporal summation (TS) to 100, with scores below 50 indicating a more disabling effect of quantifies the state of neuronal excitability in the dorsal horn. It the individual’s health on his/her functioning. was measured using the protocol of 2009 Cathcart et al, causing 2.5.5. Jenkins sleep scale. The Jenkins Sleep Scale (JSS) is a 10 noxious mechanical stimuli in the PPT in the distal phalanx of brief questionnaire which has demonstrated good psychometric the third finger and in the upper trapezius.[16] Conditioned pain properties in FM and in improving pain symptoms.[19] It contains modulation (CPM) measures the disturbance of the descending 4 items that evaluate the frequency and intensity of sleep pain inhibitory system, which was also assessed by Cathcart problems, with values ranging from 1 to 5. Higher scores indicate et al’s protocol.[16] To this end, the occlusion cuff was used as a more acute sleep difficulties. conditioning stimulus and the pressure algometry as a test stimulus. Test stimuli were applied over distal phalanx of the 2.5.6. Pain catastrophizing scale. Catastrophizing about pain third finger and in the upper trapezius. was assessed with the Pain Catastrophizing Scale (PCS) in its 3 Udina-Cortés et al. Medicine (2020) 99:51 Medicine validated Spanish version. The PCS comprises 13 self-adminis- Haenszel test. The effect size on quantitative variables was tered items divided into 3 subscales that assess rumination (4 defined with h2 as 0.01 to 0.06 (small), 0.06 to 0.14 (medium), items), magnification (3), and helplessness (6). Items are rated in and >0.14 (large), or with the Kendall W, being defined as <0.1 relation to the frequency of respondents’ feelings and thoughts (small), 0.1 to 0.3 (medium), and >0.3 (large). In the qualitative related to pain, and are valued on a 5-point Likert scale from 0 variables, the effect size was defined between pairs with (never) to 4 (all the time). The 3 subscales are added together and significant differences using Cramer’s V, defined as 0.071 to the total score ranges from 0 to 52, with higher scores 0.212 (small), 0.212 to 0.354 (medium), and >0.354 (large). The corresponding to a greater frequency and intensity of negative level of significance was set at P < .05. thoughts and feelings regarding pain. The Spanish version of the PCS has demonstrated good psychometric properties in patients 3. Results with FM, with a Cronbach’s alpha of 0.87.[20] 3.1. Participants’ demographic and clinical data 2.5.7. State trait anxiety inventory. The Spanish version of the State Trait Anxiety Inventory (STAI) was used to measure trait Forty-four consecutive patients were screened, and 37 patients and state anxiety in the study population. It has 20 items for with FM (mean age ± SD: 52 ± 8 years) were potentially eligible to assessing trait anxiety and 20 for state anxiety. All items are rated participate. Figure 2 shows the recruitment and retention of the on a 4-point scale (e.g., from “almost never” to “almost study patients through the trial. Baseline demographic and always”). The STAI assesses trait anxiety (STAI-T), which refers clinical characteristics of the patients in each group are presented to relatively stable individual differences in anxiety proneness: in Table 1. that is, to interpersonal differences in the tendency to perceive stressful situations as dangerous or threatening, and to respond to 3.2. Response to treatment such situations with more intense state anxiety (STAI-S) 3.2.1. Pain intensity. There was a significant time factor (F = reactions. Higher scores indicate greater anxiety.[21] 11.161; P = .001) but no significant group  time interaction (F = 2.728; P = .07) for pain intensity assessed by the VAS. Post-hoc 2.5.8. Beck depression inventory. The Spanish version of the analysis indicated that patients with FM receiving NAE had Beck Depression Inventory (BDI) contains a 21-item self-report significant reductions in pain post-intervention (experimental rating inventory that measures symptom intensity in depression. group mean, 3.4; 95% CI: 2.6–4.3; control group mean, 5.3; The cut-off point for defining depressed and non-depressed 95% CI: 4.4–6.3, P < .001; significant difference between groups individuals is set at a value of 18. The BDI has demonstrated high 1.9; 95% CI: 3.2 to 0.6, P = .005), as well as at the 3-month internal consistency, with alpha coefficients of 0.88 and 0.81 for follow-up (experimental group mean, 4.7; 95% CI: 3.5–5.8, fibromyalgia populations.[22] P = .005; control group mean, 5.6; 95% CI: 4.3–6.9; difference 2.5.9. Tampa scale of kinesiophobia. The original 17-item between groups 0.9; 95% CI: 2.6 to 0.8, P > .05) period version of the Tampa Scale of Kinesiophobia (TSK) was used. (Table 2). Between-groups effect sizes were large (d = 1.95) after The TSK is a self-completed questionnaire used to assess the the intervention and small (d = 0.35) at the 3-month follow-up subjective rating of Kinesiophobia, or fear of movement. The period. TS in the thumb and trapezius muscle presented a non- total score ranges from 17 to 68 with higher scores indicating a significant time factor (F = 0.115–1.457, all P > .3) and a non- higher degree of Kinesiophobia. Several studies have demon- significant group  time interaction (F = 0.779; 1.853, P = .2). strated the validity and reliability of the scale as a psychometric The CPM in the thumb variable presented significant differences measure.[23] Outcomes were collected pre-, post-intervention, in the group factor (F = 6.328, P = .02). The post-hoc test showed and after 3 months’ follow-up by an evaluator blinded to significant differences between the groups at 3 months (P = .02) treatment allocation. with a medium effect size (r = 0.43, 95% CI: 0.3 to 0.4) in favor of the intervention group. No differences in CPM over the trapezius were found between the 2 groups during treatment 2.6. Statistical analysis sessions or in the time and group factor (P > .05). For the statistical analysis, the program R (version 5.3.1, Austria) 3.2.2. Disability. The ANOVA indicated a significant time factor was used. The Shapiro–Wilk test was then applied to detect (F = 16.489; P = .001) but no significant group  time interaction significant deviations from normality (P < .05) for the FIQ, JSS, (F = 2.343; P = .10) for FIQ. The post-hoc analysis revealed SF-36, PPT, TS, and CPM questionnaires. The Shapiro–Wilk test significant decreases in FIQ in both groups at post-intervention was applied to the baseline quantitative variables of both groups. compared with baseline data (all, P < .004), but not at 3-month All were normal, with the exception of the variable “duration of follow-up. There was also a statistically significant difference illness” in the intervention group. Qualitative variables were between the active versus sham groups (P = .04) post-intervention described in absolute values and frequencies, and quantitative (Table 3). variables with mean and standard deviation or with medians and interquartile range (IQR) depending on whether they were 3.2.3. Quality of life. For the physical, mental, and total scores normally distributed. For the variables other than “duration of on the SF-36, the ANOVA did not reveal a significant time factor illness” (VAS, PCS, and TSK) the distribution was normal, and (F = 0.312–1.958, all P > .20) or a significant group  time so parametric tests were applied. Quantitative variables were interaction (F = 0.198–0.374, all P > .60) (Table 3). JSS presented analyzed using a two-factor repeated measures ANOVA a significant time factor (F = 6.858; P = .002) but not a significant (between–within) or its robust equivalent using pseudostatistics group  time interaction (F = 1.576; P = .20). We found signifi- such as Wald and ANOVA, bootstrap, and averages truncated to cant differences in the experimental group (P = .001), but not in 20% depending on the fulfilment of the assumption of normality. the control group at post-intervention. There was a significant Qualitative variables were analyzed using the Cochran–Mantel– difference between the 2 groups (P = .01) post-intervention. 4 Udina-Cortés et al. Medicine (2020) 99:51 www.md-journal.com Assessed for eligibility (n=44) ENROLLMENT Excluded (n=2) • Other excluding pathologies (n= 1) • Participant in another study (n= 1) ALLOCATION Randomized (n=42) Neuro-Adaptive Sham group Electrostimulation (NAE) (n=19) group (n=23) Lost to Follow-up (n=3) Lost to Follow-up (n=2) FOLLOW-UP - Did not perform the - Did not perform the sessions established in the sessions established in the protocol (n=2) protocol (n=3) ANALYSIS Analyzed (n=20) Analyzed (n=17) Excluded from analysis Excluded from analysis (n=0) (n=0) Figure 2. Consort flow chart of the study population. Between-groups effect sizes were large (d = 6.8) after the TSK, did not present significant differences for time (F = 0.216; intervention and small (d = 0.1) after 3 months’ follow-up P = .8, partial eta = .051), or the group  time interaction (F = (Table 3). 1.158, all P = .30). For catastrophizing, significant differences were found in the main time factor (F = 13.983, P < .001, Mauchly’s 3.2.4. Psychological parameters. The ANOVA revealed a test = .219); the post-hoc test showed significant differences significant effect of time (F = 13.984; P = .001) but not for the between the pre–post treatment and pre-treatment sessions – 3 group  time interaction (F = 1.242; P = .30) on the PCS. The post- months (P < .001) with a medium and significant effect size (h2 = hoc analysis revealed significant differences at post-intervention in 0.096, 95% CI: 0.074–0.326) (Table 4). The variables STAI-S (F = both groups (all, P < .04) as well as at 3 months’ follow-up 0.742, P = .009, Mauchly’s test < .001), STAI-T (F = 0.841, (P = .005) for the control group. Between-groups effect sizes were P = .027, Mauchly’s test = .013), PCS (F = 13.983, P < .001, small (d = 0.4) after the intervention and (d = 0.4) at 3 months’ Mauchly’s test = .219), and BDI (F = 8.136, P < .001, Mauchly’s follow-up period (Table 4). Kinesiophobia, as measured by the test = .057) presented significant differences in the time factor. 5 Udina-Cortés et al. Medicine (2020) 99:51 Medicine Table 1 Clinical Trials (IMMPACT) group investigating the effects of Demographic and clinical characteristics among study partici- pain on individuals with whiplash.[24] In that study, twenty 20- pants at baseline. minute sessions were applied over 4 weeks with follow-up at 4, 8, 12, and 16 weeks. An improvement in pain intensity was found in Active (n = 20) Sham (n = 17) Pa the intervention group, amounting to 4.2 points on the VAS: that Age (yr) 52 (9) 52 (8) .92 is, an improvement of 67.7%, which the authors describe as a Time from diagnosis (yr) 1.6 (0.1) 2.0 (1.7) .83 clinically important change.[24] In our study, we found a change VAS 6.4 (1.7) 6.3 (1.0) .91 of 2 points (46.7%) immediately after the intervention, PPT thumb 3.9 (2.1) 3.9 (2.6) .89 PPT trapezius 2.3 (1.2) 1.9 (1.3) .82 representing a clinically relevant improvement; at 12 weeks; TS thumb 2.0 (1.7) 1.9 (1.6) .96 however, the score had fallen slightly to 1.7 points. TS trapezius 1.6 (1.8) 1.7 (1.3) .88 In a recent Cochrane systematic review[8] analyzing the effects CPM thumb 0.38 (1.6) 0.15 (1.4) .49 of a low frequency current similar to the therapy we used, the CPM trapezius 0.63 (1.7) 0.41 (1.1) .62 authors found a reduction in pain after the application of TENS FIQ 57.3 (14.6) 55.4 (13.2) .81 in FM patients but with a very low level of evidence; the Global SF-36 66.0 (4.0) 66.9 (2.6) .84 improvement in pain only exceeded 30% when TENS was JSS 14.0 (4.2) 15.9 (4.1) .75 combined with exercise. In our study we found that patients PCS 22.2 (12.8) 18.7 (8.1) .68 surpassed that degree of improvement, but only immediately STAI 26.2 (9.9) 27.8 (10.9) .93 after the intervention; at 3-month follow-up it was no longer BDI 17.5 (8.2) 15.9 (9.3) .87 TSK 29.3 (5.7) 32.8 (4.6) .79 observed. We attribute this to the fact that we applied only 8 sessions, compared with an average of 20 sessions that were Values are shown as mean (standard deviation). BDI = Beck Depression Inventory, CPM = conditioned conducted in the studies included in the review. In a pilot study, pain modulation, FIQ = Fibromyalgia Impact Questionnaire, JSS = Jenkins Sleep Scale, PCS = Pain Dailey et al[25] found a 30% increase in hypoalgesia in FM Catastrophizing Scale, PPT = pressure pain threshold; SF-36 = Medical Outcome Study 36-item Short Form Health Survey, STAI = State Trait Anxiety Inventory, TS = temporal summation, TSK = Tampa patients when TENS was applied in the cervical region compared Scale of Kinesiophobia, VAS = Visual Analog Scale. with placebo. These results are at odds with ours, since we found a Data were analyzed using Student’s t test for independent samples, and the Mann–Whitney U non- an increase of 23.9% in the NAE group, although there were no parametric test when appropriate. differences with regard to the sham (placebo) group. Perhaps the discrepancies between the studies are due to the fact that Dailey However, no significant differences were found in the group factor et al team performed only 1 session while we performed 8 and group–time interaction in any of the variables (P > .05). Effect sessions. No other studies have evaluated mechanical hyper- size was small in all the variables analyzed: STAI-S (h2 = 0.037, algesia in FM. 95% CI: 0.011–0.206), STAI-T (h2 = 0.015, 95% CI: 0.001– TS did not decrease in our study. To our knowledge, there are 0.169), PCS (h2 = 0.096, 95% CI: 0.074–0.326), and BDI (h2 = no studies that have measured TS in FM patients when applying 0.055, 95% CI: 0.027–0.244) (Table 4). physical therapy. The only study which applied an interferential current at 1 or 4 kHz compared with placebo in patients with low back pain found statistically significant changes in patients who 4. Discussion received interferential current vs the placebo group; these This is the first proof-of-concept study of NAE therapy in differences may have been due to their use of medium frequency individuals with FM. Our results showed that neuro-adaptive and that fact that the patients underwent more sessions.[21] No therapy showed a significant improvement over sham placebo at previous studies have assessed CPM with NAE. Dailey et al[25] 3 months in conditioned pain modulation. There was also a evaluated the effects of a single session of TENS in patients with significant improvement in pain intensity and sleep quality, but FM and found a rate of improvement in the CPM about 30%. In only immediately after the end of the session. No differences our study the change at 3 months’ follow-up was 97.4%, higher between groups in terms of disability were shown. than in previous studies. The difference may be attributed to the These results challenge those of a previous study by the differences in the number of sessions carried out in the 2 Initiative on Methods, Measurement, and Pain Assessment in studies.[25] Table 2 Pain intensity. Mean (SD) for outcomes at all study visits for each group, mean (SD) difference within groups, and mean (95% CI) difference between groups. Groups Difference within groups Difference between groups Baseline 4-wk Follow-up Post minus Pre FU minus Pre Post FU Active Active Active Sham Active Sham Active Sham Active Sham Active Sham minus Sham minus Sham Outcomes (n = 20) (n = 17) (n = 20) (n = 17) (n = 20) (n = 17) (n = 20) (n = 17) (n = 20) (n = 17) (n = 37) (n = 37) ∗ ∗ VAS 6.4 (1.7) 6.3 (1.0) 3.4 (2.1) 5.3 (1.5) 4.7 (2.6) 5.6 (2.3) 3.0 (0.5) 1.0 (0.5) 1.8 (0.6) 0.8 (0.7) 1.9#( 3.2 to 0.6) 0.9 ( 2.6 to 0.8) Thumb PPT (kg/cm2) 3.9 (2.1) 3.9 (2.6) 3.4 (1.2) 3.7 (2.5) 3.7 (1.4) 4.5 (2.3) 0.5 (0.3) 0.2 (0.4) 0.2 (0.6) 0.6 (0.6) 0.3 ( 1.5 to 1.0) 0.8 ( 1.9 to 0.5) 2 Trapezius PPT (kg/cm ) 2.3 (1.2) 1.9 (1.3) 1.8 (0.8) 2.0 (1.9) 1.9 (0.7) 2.1 (1.0) 0.4 (0.2) 0.1 (0.2) 0.3 (0.2) 0.2 (0.3) 0.2 ( 1.1 to 0.8) 0.2 ( 0.7 to 0.4) 2 Thumb TS (kg/cm ) 2.0 (1.7) 1.9 (1.6) 2.0 (2.2) 2.2 (1.2) 2.6 (2.1) 1.7 (1.1) 0.0 (0.5) 0.3 (0.4) 0.6 (0.5) 0.2 (0.5) 0.2 ( 1.4 to 1.0) 0.9 ( 0.2 to 2.1) Trapezius TS (kg/cm2) 1.6 (1.8) 1.7 (1.3) 1.9 (1.7) 1.4 (1.7) 2.7∗(2.3) 1.6 (1.4) 0.3 (0.4) 0.3 (0.5) 1.1 (0.5) 0.1 (0.5) 0.5 ( 0.6 to 1.7) 1.1 ( 0.2 to 2.4) Thumb CPM (kg/cm ) 2 0.38 (1.6) 0.15 (1.4) 0.03 (2.4) 0.29 (1.2) 0.4 (4.6) 0.56 (0.8) 0.35 (0.6) 0.15 (0.6) 0.78 (0.4) 0.41 (0.5) 0.27 ( 1.0 to 1.6) 0.96#(0.1 to 1.8) 2 Trapezius CPM (kg/cm ) 0.63 (1.7) 0.41 (1.1) 0.43 (1.8) 0.09 (1.9) 0.28 (1.2) 0.59 (1.1) 0.20 (0.5) 0.50 (0.5) 0.35 (0.4) 0.17 (0.4) 0.51 ( 1.7 to 0.7) 0.31 ( 0.4 to 1.1) CPM = conditioned pain modulation, FU = at 3-mo follow-up, PPT = pressure pain threshold, TS = temporal summation, VAS = Visual Analog Scale. ∗ Significant difference within group. # Significant difference between group, P < .05 (95% confidence interval). 6 Udina-Cortés et al. Medicine (2020) 99:51 www.md-journal.com Table 3 Disability and quality of life. Mean (SD) for outcomes at all study visits for each group, mean (SD) difference within groups, and mean (95% CI) difference between groups. Groups Difference within groups Difference between groups Baseline 4-wk Follow-up Post minus Pre FU minus Pre Post FU Active Active Active Sham Active Sham Active Sham Active Sham Active Sham minus sham minus sham Outcomes (n = 20) (n = 17) (n = 20) (n = 17) (n = 20) (n = 17) (n = 20) (n = 17) (n = 20) (n = 17) (n = 37) (n = 37) ∗ ∗ FIQ 57.3 (14.6) 55.5 (13.2) 34.9 (11.0) 44.2 (15.9) 46.3 (19.1) 44.3 (18.5) 22.4 (3.0) 11.3 (3.2) 11.0 (4.8) 11.1 (5.2) 9.3#( 18.3 to 0.3) 1.9 ( 10.6 to 14.6) SF-36 (physical) 50.6 (3.6) 50.5 (2.5) 51.1 (5.4) 51.2 (4.3) 51.0 (5.8) 51.1 (5.0) 0.5 (1.1) 0.7 (1.2) 0.4 (1.3) 0.6 (1.2) 0.2 ( 3.5 to 3.1) 0.2 ( 2.8 to 4.5) SF-36 (mental) 44.6 (3.2) 45.9 (3.2) 46.1 (6.2) 46.9 (2.5) 43.0 (6.3) 45.6 (26.5) 1.6 (1.2) 1.0 (1.3) 1.6 (1.7) 0.3 (1.7) 0.7 ( 4.1 to 2.5) 2.6 ( 6.9 to 1.6) Global SF-36 66.0 (4.0) 66.9 (2.6) 67.4 (7.6) 68.1 (4.1) 65.2 (7.8) 66.5 (7.1) 1.4 (1.4) ∗ 1.2 (1.6) 0.8 (1.7) 0.4 (1.8) 0.7 ( 4.8 to 3.9) 1.3 ( 6.3 to 3.7) JSS 14.6 (3.8) 15.9 (4.1) 10.4 (4.5) 14.4 (4.3) 12.3 (4.4) 14.1 (4.3) 4.2 (1.0) 1.5 (1.0) 2.3 (1.0) 1.8 (1.3) 4.0#( 7.0 to 1.0) 1.8 ( 4.9 to 1.2) FIQ = Fibromyalgia Impact Questionnaire, FU = at 3-mo follow-up, JSS = Jenkins Sleep Scale, SF-36 = the 36-item Short Form Health Survey questionnaire. ∗ Significant difference within group. # Significant difference between groups, P < .05 (95% confidence interval). Table 4 Psychological outcomes. Mean (SD) for outcomes at all study visits for each group, mean (SD) difference within groups, and mean (95% CI) difference between groups. Groups Difference within groups Difference between groups Baseline 4-wk Follow-up Post minus Pre FU minus Pre Post FU Active Active Active Sham Active Sham Active Sham Active Sham Active Sham minus sham minus sham Outcomes (n = 20) (n = 17) (n = 20) (n = 17) (n = 20) (n = 17) (n = 20) (n = 17) (n = 20) (n = 17) (n = 37) (n = 37) ∗ ∗ ∗ PCS 22.2 (12.8) 18.7 (8.1) 14.2 (7.4) 13.2 (5.1) 17.8 (10.7) 12.6 (7.5) 8.0 (1.9) 5.5 (2.0) 4.5 (2.0) 6.1 (2.2) 1.0 ( 3.3 to 5.3) 5.1 ( 1.1 to 11.4) TSK 29.3 (5.7) 32.9 (4.6) 30.1 (5.6) 31.4 (5.8) 29.8 (5.3) 31.2 (5.6) 0.8 (1.0) 1.5 (1.0) 0.5 (1.2) 1.7 (1.3) 1.3 ( 5.2 to 2.5) 1.4 ( 5.0 to 2.3) STAI-S 26.2 (9.8) 27.7 (10.8) 19.3 (8.1) 24.5 (11.5) 21.8 (13.0) 24.2 (13.2) 6.8 (7.0) 3.2 (7.3) 4.4 (13.2) 3.4 (9.3) 6.6 ( 0.4 to 14) 3.8 ( 5.0 to 13) STAI-T 30.7 (12.1) 28.5 (11.7) 25.2 (9.8) 26.7 (11.6) 27.6 (11.7) 27.6 (11.9) 5.7 (9.5) 1.7 (4.8) 3.1 (9.9) 0 (0) 2.7 ( 4.4 to 9.8) 1.5 ( 6.6 to 9.6) BDI 17.4 (8.2) 15.9 (9.4) 11.9 (6.5) 13.5 (6.6) 13.1 (8.6) 12.6 (6.5) 5.5 (9.0) 2.3 (5.9) 4.3 (7.8) 0 (0) 2.2 ( 1.3 to 5.7) 0.1 ( 4 to 4.2) BDI = Beck Depression Inventory, FU = at 3-mo follow-up, PCS = pain catastrophizing scale, STAI-S = state anxiety, STAI-T = trait anxiety, TSK = Tampa Scale of Kinesiophobia. ∗ Significant difference within group. In a previous study in which SCENAR was used, disability neuroscience education, showed a 22% reduction of catastroph- improved by 14.3 points (60%) compared with TENS treatment in izing (4.2 points) and a 15.8% reduction in anxiety (6.1 points) in patients with whiplash-associated disorders.[26] This finding is at FM patients at 3 months’ follow-up.[31] odds with ours, since in our NAE group disability fell by 23.9%. Our study has some limitations. The first one is the short The difference may be due to the fact that those authors applied 20 follow-up; we have not been able to identify changes that sessions and their sample comprised patients with whiplash- occurred over a longer time period after applying NAE. Another associated disorders. However, our data for the FIQ score (14%) is limitation is the small sample size, which means that we are not considered a clinically important difference.[27] unable to extrapolate the data to the entire FM population, and In our study, patients undergoing NAE therapy improved the may have induce type II errors. Finally, patients were not asked if quality of sleep. These results corroborate those found by they knew that they had been assigned to the placebo group, so Lauretti et al[28] who found an improvement in sleep quality we do not know the reliability of the placebo method. Additional when applying a TENS either at 2 sites or at a single site. They studies are now needed to address these issues. applied seven 20-minute sessions, a dosage similar to ours, but In summary, this study found that NAE therapy significantly the results were evaluated only immediately after the end of relieved pain and improved health-related quality of life treatment, not after follow-up. In our study there were (disability) at 4 weeks compared with the sham-controlled improvements compared with placebo (a change of – 3.61 group, but not after 3 months of follow-up. points) at the end of treatment, but not at 3-month follow-up. Studies which have applied pharmacological treatment achieved 5. Conclusions a higher improvement, reaching – 6.2 points.[29] In our study the change was only observed immediately after the end of the NAE therapy demonstrated an improvement in pain intensity, treatment, with a reduction of 36% (8 points) in catastrophizing disability, and sleep impairment immediately after treatment but in the NAE group, but not at the 3-month follow-up. Although not at 3 months; it also showed a benefit for conditioned pain the placebo group improved as well, with a change of 32.7% (6.1 modulation at 3 months’ follow-up though the effect size was points) at 3 months’ follow-up, the results reflect a reduction in small. Further more rigorous studies with larger sample sizes and catastrophizing in the NAE group. Electrotherapy interventions longer follow-up periods are urgently required to increase our like tDCS have also demonstrated positive effects for anxiety/ knowledge about the effectiveness of NAE in pain relief and depression in FM patients.[30] Another intervention, pain disability in fibromyalgia. 7 Udina-Cortés et al. Medicine (2020) 99:51 Medicine Author contributions mechanical neck pain: a preliminary randomized, sham-controlled trial. J Altern Complement Med 2012;18:946–52. CU-C, JF-C, AAR, and IMA-D conceived and planned the [11] Selfe TK, Bourguignon C, Taylor AG. Effects of noninvasive interactive experiments. CU-C carried out the trial. CU-C, JF-C, and IMA-D neurostimulation on symptoms of osteoarthritis of the knee: a planned and carried out the simulations. CU-C, JF-C, and JNC-Z randomized, sham-controlled pilot study. J Altern Complement Med 2008;14:1075–81. contributed to the interpretation of the results. CU-C, JF-C, JHV, [12] Villafane JH, Valdes K, Imperio G, et al. Neural manual vs. robotic and JC-M took the lead in writing the manuscript. All authors assisted mobilization to improve motion and reduce pain hypersensitivity have contributed significantly to the work with critical feedback in hand osteoarthritis: study protocol for a randomized controlled trial. J and have reviewed and approved the final version of the Phys Ther Sci 2017;29:801–6. [13] Pedersini P, Valdes K, Cantero-Tellez R, et al. The effects of manuscript. neurodynamic mobilizations on pain hypersensitivity in patients with Conceptualization: Carlos Udina-Cortés, Josue Fernández-Car- hand osteoarthritis compared to robotic assisted mobilization: a nero, Isabel Maria Alguacil-Diego. randomized clinical trial. Arthritis Care Res (Hoboken) 2019;doi: Data curation: Alberto Arribas Romano, Juan Nicolás Cuenca- 10.1002/acr.24103. Online ahead of print. Zaldívar, Isabel Maria Alguacil-Diego. [14] Kamper SJ, Maher CG, Hush JM, et al. Relationship between pressure pain thresholds and pain ratings in patients with whiplash-associated Formal analysis: Josue Fernández-Carnero, Juan Nicolás disorders. Clin J Pain 2011;27:495–501. Cuenca-Zaldívar. [15] Villafane JH, Cleland JA, Fernandez-de-Las-Penas C. Bilateral sensory Investigation: Carlos Udina-Cortés, Josue Fernández-Carnero, effects of unilateral passive accessory mobilization in patients with Alberto Arribas Romano, Isabel Maria Alguacil-Diego. thumb carpometacarpal osteoarthritis. J Manipulative Physiol Ther 2013;36:232–7. Methodology: Carlos Udina-Cortés, Josue Fernández-Carnero, [16] Cathcart S, Winefield AH, Rolan P, et al. Reliability of temporal Isabel Maria Alguacil-Diego. summation and diffuse noxious inhibitory control. Pain Res Manag Project administration: Carlos Udina-Cortés, Josue Fernández- 2009;14:433–8. Carnero, Isabel Maria Alguacil-Diego. 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