Research Paper
Transcranial direct current stimulation as a treatment for patients with fibromyalgia: a randomized controlled trial Asbjørn J. Fagerlunda,b,*, Odd A. Hansenc, Per M. Aslaksenb,d
Abstract Previous studies suggest that transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) reduces chronic pain levels. In this randomized controlled trial, we investigated the effects of 5 consecutive 20-minute sessions of 2-mA anodal tDCS directed to the M1 in 48 patients (45 females) with fibromyalgia. Changes in pain, stress, daily functioning, psychiatric symptoms, and health-related quality of life were measured. Pain and stress were measured 30 days before treatment, at each treatment, and 30 days after treatment by using short message service on mobile phones. Patients were randomized to the active or sham tDCS group by receiving individual treatment codes associated either with the sham or active tDCS in the stimulator. Adverse effects were registered using a standardized form. A small but significant improvement in pain was observed under the active tDCS condition but not under the sham condition. Fibromyalgia-related daily functioning improved in the active tDCS group compared with the sham group. The stimulation was well tolerated by the patients, and no significant difference in the adverse effects between the groups was observed. The results suggest that tDCS has the potential to induce statistically significant pain relief in patients with fibromyalgia, with no serious adverse effects, but small effect sizes indicate that the results are unlikely to reflect clinically important changes. Keywords: Fibromyalgia, Pain, Randomized controlled trial (RCT), Transcranial direct current stimulation (tDCS)
1. Introduction Fibromyalgia (FIM) is a chronic pain condition with a prevalence of 2% to 5% that occurs more often in women.28,43 Fibromyalgia is associated with widespread pain, fatigue, sleep disturbance, depression, and reduced quality of life.16 The most common treatment guidelines recommend aerobic exercise, pharmacological treatment, cognitive behavioral therapy, and various multicomponent treatments. 16 Following the recommended methods, treatment effects on pain caused by FIM are usually modest.25 Imaging studies suggest that FIM is associated with functional changes in the brain through reduced connectivity in efferent pain inhibitory networks and central sensitization in afferent pain networks.8 Transcranial direct current stimulation (tDCS) is a noninvasive brain-stimulation technique that has the potential to become cost-effective,45 and has limited adverse effects.6 Thus, tDCS is suitable for chronic pain conditions such as FIM that have relatively high prevalence Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. a
Department of Surgery and Anesthesia, University Hospital of North Norway, Tromsø, Norway, b Department of Psychology, University of Tromsø, Tromsø, Norway, c Department of Physical Medicine and Rehabilitation, University Hospital of North Norway, Tromsø, Norway, d Division of Child and Adolescent Health Services, Department of Child and Adolescent Psychiatry, University Hospital of North Norway, Tromsø, Norway * Corresponding author. Address: Department of Psychology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, Norway. Tel.: 149 97604709; fax: 147 77645291. E-mail address: [email protected] (A. J. Fagerlund). PAIN 156 (2015) 62–71 © 2014 International Association for the Study of Pain http://dx.doi.org/10.1016/j.pain.0000000000000006
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and an absence of effective treatment options. Several studies suggest that tDCS may be effective in ameliorating chronic pain in general21,31,40 and specifically in FIM.14,26,38,41 However, a recent extensive review32 suggests that tDCS has limited efficacy in treatment of chronic pain and states the need for larger and more rigorously designed studies. Transcranial direct current stimulation can be used in randomized clinical trials because of efficient technical solutions to conduct blinded studies of both the patients and experimenters.15 However, even if sophisticated blinding procedures are available, the efficacy of patient blinding has been questioned because patients may be able to discriminate between the active and sham tDCS procedures.30 Insufficient blinding may especially be present at stimulation intensities of 2 mA compared with lower intensities. Recently, a study showed that by using a stimulator with a computerized study mode to administer sham and active tDCS, the patients were unable to reliably discriminate between the conditions; however, the experimenter performing the blinding may have been compromised by observing increased skin redness after the active tDCS stimulation.34 Based on the observation that experimenter blinding may be insufficient, electrode positions on patients should be covered during the assessment of clinical outcomes to reduce the risk of experimenter’s influence on the clinical outcome measures.34 Using these recommendations, this study used short message service (SMS) text messages to obtain pain ratings using the numerical rating scales (NRSs), separating assessment from the clinic. Additionally, SMS enables collection of more data points per individual compared with obtaining pain reports in the clinic, which may reduce measurement error. PAIN®
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The aim of this study was to test the effect of tDCS stimulation on pain in patients with FIM in a hospital setting using a procedure that facilitated participant blinding and reduced experimenter influence on endpoint ratings. We hypothesized that patients receiving active tDCS for 5 consecutive days should report significantly better improvement in FIM-related symptoms (pain, stress, daily functioning, depression, psychiatric symptoms, and general mental and physical health) compared with the group that received the sham tDCS.
2. Methods 2.1. Subjects Patients were recruited in Tromsø, which is located in Northern Norway, and treated at the Pain Clinic, University Hospital of Northern Norway, Tromsø (Fig. 1). Information regarding the study and informed consent were sent by mail to patients with FIM who had been treated in Pain and Rheumatic Clinics at the University Hospital of Northern Norway during the previous 2 years and to members in the local chapter of the National Fibromyalgia Patient Association. Furthermore, the study was advertised in a local newspaper in which patients were invited to declare interest in participation by mail or telephone and then received an informed consent through mail. All patient correspondence was conducted by traditional mail; therefore,
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recruitment uniformity was ensured. The patients had to be #18 years of age, diagnosed with FIM (ICD-10 M79.7) according to the ACR-90 criteria,44 and a manual examination of the patients’ tender points was performed before inclusion. All patients who otherwise adhered to the criteria for participation had a positive FIM diagnostic status. If patients were using prescribed medication, the use had to be stable for 3 months before inclusion. The exclusion criteria included severe psychiatric conditions defined as bipolar disorder, severe depression, and schizophrenia. Additional exclusion criteria consisted of neurological conditions, developmental disorders, pregnancy, and drug abuse. Furthermore, before starting treatment, the participant’s medical records were screened by a neurologist for conditions that counterindicate the use of electrical stimulation. The study was ethically approved by the Regional Committee for Medical and Health Research Ethics (2010/2256) and registered in clinicaltrials.gov (NCT01598181). All patients provided written informed consent by mail. Patients were considered dropouts if they missed 2 or more days (of 5) of treatment or failed to provide at least 1 pain report (of 3) on 2 or more days of treatment. 2.1.1. Design The study aimed to test the effect of tDCS on pain in a hospital setting; therefore, we analyzed data from patients who were
n = 4)
Figure 1. Participant flow and randomization.
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randomized and received the treatment and did not conduct further analysis on participant’s attrition and compliance. Because of the low number of published studies, exact parameters for mean and SD of expected pain levels were not used to calculate the desired sample size because the method of obtaining pain reports and the number of reported pain ratings per patient was different from previous studies.14,38 Instead, sample size was based on previous studies that investigated the effect of tDCS on FIM that found significant interactions between stimulation and time (P , 0.01),14,38 with sample sizes of 32 and 41. To achieve sufficient power to observe effects of the interventions, the sample size of this study was set to be at least as large as these studies. The study was designed as a randomized controlled trial to investigate the pain-ameliorating effect of anodal and sham tDCS administered over 5 consecutive days on pain in patients with FIM. Outcomes were evaluated as the following 7 repeated measures (RMs): pretreatment period of 30 days, 5 days of tDCS stimulation, and posttreatment period of 30 days (pretreatment: Time1, 5 days of tDCS stimulation: Time2-Time6, posttreatment: Time7). In addition, general FIM-related function (Fibromyalgia Impact Questionnaire [FIQ]), depression and anxiety (Hospital Anxiety and Depression Scale [HADS]), physical and psychiatric symptoms (Symptom Checklist 90 [SCL-90R]), and general health-related quality of life (SF36v2) were measured before the active and sham tDCS treatments and 30 days after the last treatment. 2.1.2. Adverse effects Adverse effects were registered using a standard form6 after each session. The patients were asked to report whether they had any headache, neck pain, scalp pain, tingling, itching, burning sensation, sleepiness, trouble concentrating, acute mood change, and other adverse effects after the stimulation, and skin redness was evaluated by the experimenter. The intensity of the adverse effects was rated as “mild,” “moderate,” or “intense,” and the degree to which they were related to the stimulation was rated as “none,” “remote,” “possible,” “probable,” or “definite.” 2.1.3. Transcranial direct current stimulation Direct current stimulation was administered using a neuroConn DC-Stimulator (neuroConn, Ilmenau, Germany), a battery-driven device that constantly monitors electrical impedance and terminates the stimulation if the voltage exceeds safety limits. The stimulation duration was 20 minutes with an intensity of 2 mA. Direct current was transferred by a pair of 35-cm2 rubber electrodes inserted into sponge pads soaked with 10 mL of sterile water. To further reduce electrical impedance, Ten20 neurodiagnostic electrode paste (Weaver and Company, Aurora, CO) was applied to the scalp at the stimulation site. Pilot testing indicated that the use of sterile water and electrode paste provided similar impedance and less skin sensation at the 2-mA stimulation amplitude compared with saline solution, providing improved patient blinding. Furthermore, the use of paste provided better contact between the electrode and scalp on patients with thick hair. The large majority of our patients were females who typically had more scalp hair than men; therefore, we opted to use the combination of sterile water and paste. New electrode sponges were used for every patient, and they were cleaned between sessions. Overall, the montage was similar to Fregni et al.14 To stimulate M1, the anode was placed at the C3 position in the 10/20 system for the EEG electrode
positions. The cathode was placed on the contralateral supraorbital area. We did not change the side of the anode according to the patient reports of pain lateralization because the distribution of electric current in the brain when using 2 large electrodes is not focal, 27 and the FIM according to the ACR-90 criteria is not typically a lateralized pain condition. Sham tDCS consisted of an 8-second fade-in period followed by 30 seconds of direct current stimulation that was terminated by a 5-second fade-out. The sham condition mimics the skin sensation of active tDCS with insufficient duration to induce changes in cortical excitability.29 2.1.4. Double blinding The patients were assigned to a list containing unique 5-digit codes by order of inclusion. The codes were associated with the active or sham tDCS condition and randomized using the online Web service www.randomize.org. The ratio of active and sham codes was 1:1. The key to decipher the codes was kept separately from the experimenters until they had no further contact with the patients. The stimulator was started by entering a 5-digit code in the display of the stimulator, and the displayed impedance information looked similar in both the active and sham conditions. Each patient received stimulation associated with their unique code from a randomized list containing codes for active and sham stimulation. The nature of stimulation for each subject was decoded after the study was completed, allowing data analysis to separate the active and sham stimulation conditions. After this procedure, the active and sham groups received similar treatment with the exception of the stimulation. 2.1.5. Measuring pain-related outcomes by mobile phone Pain intensity, pain unpleasantness, stress, and anxiety were measured daily using SMS from the mobile phones of the subjects. In the morning (9 AM), afternoon (3 PM), and evening (9 PM), the subjects received an SMS consisting of the following 4 questions: “what is your pain level now?,” “how unpleasant is the pain now?,” “how tense are you now?,” and “how anxious are you now?.” The response to the questions was delivered through a reply SMS containing the NRS values (0-10). If no response was obtained after 15 minutes of receiving the SMS, a reminder was sent. Responses obtained within 2 hours were considered valid. Responses with invalid formatting were answered with an SMS containing instructions for correct formatting. To make the scoring more intuitive, the subjects were supplied with a visual analogous scale with a sliding indicator in the initial consultancy with a clinical psychologist. By flipping the scale, a numeric value that corresponded to their analogous rating was read and used to translate the visual analog scale into the NRS. All of the patients who showed interest in participating had access to an SMScompatible mobile device, which was expected because prevalence of mobile phones in the general adult Norwegian population is close to 100%. 2.1.6. Psychological and functional measures At the start and end of participation, the subjects completed 4 surveys electronically. The FIQ, a validated tool used to measure the impact of FIM symptoms, was used to study the effects of FIM on daily functioning.3 The Norwegian translation used in this study was based on the validated Swedish translation.17 Norwegian and Swedish are semantically and phonetically similar languages; therefore, we assumed the Norwegian translation to have similar
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testing characteristics as the validated Swedish version. A higher score indicates a more severe impact of FIM symptoms on functioning. The maximum score is 100, and the average FIM patient scores are approximately 50.3 The HADS is a widely used and validated screening tool to measure anxiety and depression in both psychiatric and nonpsychiatric patients.4 This survey has a Norwegian translation that has excellent psychometrical characteristics that are similar to other translations.33 Regarding the anxiety and depression scale, a score of 8 to 10 indicates a mild case, 11 to 15 denotes a moderate case, and above 16 is a severe case. The mean score in a nonclinical population is approximately 6 for the anxiety scale and 3 for the depression scale.9 The SCL-90R, a survey that has been extensively used worldwide, 11 was used to measure psychiatric symptoms and distress, and this study used the official Norwegian translation of this survey (NCS Pearson, Inc). The SCL-90R contains 3 global score indexes. The global severity index measures the patient’s psychological distress status. The positive symptom distress index is considered an intensity distress style measure, and the positive symptom total reveals the total number of symptoms reported by the patient. The Short Form 36 (SF36v2) was used to measure general physical and mental health. The Norwegian translation possesses similar psychometric properties as other translated versions of the survey.24 For scoring, we used the Physical Component Summary and Mental Component Summary because they are considered to sufficiently summarize the SF36v2 8-score profile.42 The scores range from 100 (no impairment) to 0 (maximum impairment). 2.2. Procedure After inclusion, the patients attended an individual consultancy with a clinical psychologist (Fig. 2). The content of the meeting was scripted to keep the information uniform across the patients. During the meeting, the patients completed surveys and received instructions on how to submit pain and stress reports by mobile phone. The time between interview and the first session of tDCS was defined as the pretest period. The length of this period was planned to be 30 days; however, 11 subjects had a 14-day pretest period for practical reasons such as patient plans, scheduling, and holidays. Stimulation was administered in 5 sessions from Monday through Friday. After 5 days of treatment, the patients reported on their pain and stress for 30 days, and this period was defined as the posttest period. On concluding the posttest period, the subjects completed the surveys from the inclusion interview a second time. 2.3. Statistical analysis SPSS version 19 (IBM, Armonk, NY) was used for all statistical analyses. Before analyzing the effects of active and sham tDCS on our endpoints, we compared baseline results between the
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2 groups to eliminate the possibility that the differences observed after intervention were due to the groups being different at baseline. For this analysis, the independent t test for equality of means was used. To test the effect of the tDCS intervention on pain, pain unpleasantness, and the stress and anxiety levels, we conducted RMs analysis of variance (ANOVA) with 7 RMs (Time 5 pretest Time1, treatment 3 5 Time2-Time6, posttest Time7) and 2 measures between group conditions (Condition 5 active or sham tDCS). Simple contrasts were used to compare the different time points with the pretest as the reference. One-way ANOVA was used to analyze the mean changes from pretest to posttest and to analyze between-group differences at the individual time points. The Kolmogorov–Smirnov test for independent samples was used to test the equal distribution between conditions, and 1-sample Kolmogorov–Smirnov test was used to test normal distribution within conditions. Levene test was used to assess the homogeneity of variance between the conditions. Partial h2 p was used to calculate the effect sizes. Alpha levels were set to #0.05.
3. Results 3.1. Effect of stimulation on pain intensity Recruitment commenced in September 2011, and trial was completed in July 2013 because of reaching the target sample size. Global compliance for SMS pain reports was 94%. An RM ANOVA revealed no primary significant effect on the group regarding pain intensity (F[1,46] 5 1.67, P 5 0.204, h2p 5 0.04). However, a significant effect of Time (F[6,276] 5 3.65, P 5 0.002, h2p 5 0.07) and a significant interaction effect of Time by Condition (F[6,276] 5 2.33, P 5 0.032, h2p 5 0.05) were observed. To investigate at what points this interaction was significant compared with the pretest, contrast analyses with Time1 as the reference revealed that the interaction term Time by Condition was significant at Time5 (day 4 of tDCS treatment) (F[1,46] 5 7.91, P 5 0.007, h2p 5 0.15) and at Time7 (posttest) (F[1,46] 5 6.82, P 5 0.012, h2p 5 0.13). 3.2. Change in pain intensity from pretest to posttest The mean NRS pain intensity reduction in the active tDCS group from pretest to posttest was 0.66 NRS points (95% confidence interval, 0.36-0.96) and 0.09 NRS points in the sham tDCS group (95% confidence interval, 20.26 to 0.43) (Fig. 3). Thus, a 13.6% mean pain reduction in the active group and 1.70% pain reduction in the sham group were observed. One-way ANOVA showed that the difference in pain reduction between conditions was significant (F[1,47] 5 6.82, P 5 0.012, h2p 5 0.13). Responders were identified using a minimum clinically significant change of 1.2 NRS points.19 There were 4 responders in the active group, and 1 responder in the sham group.
Figure 2. Overview of the procedure.
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At the posttest, the response rates ranged from 71% to 79% in the Active condition and from 71% to 75% in the Sham condition. Fibromyalgia Impact Questionnaire had the highest compliance in both conditions at the posttest, whereas HADS, SCL-90, and SF36v2 had similar response rates. 3.6.1. Fibromyalgia Impact Questionnaire
Figure 3. Mean NRS pain intensity (0–10) by time (1 5 mean of 30-day pretest, 2–6 5 mean on treatment days 1–5, 7 5 mean of 30-day posttest). Error bars denote SEM. Independent samples Kolmogorov–Smirnov test was nonsignificant for all variables indicating equal distribution between groups. Levene test was nonsignificant for all time points, indicating equal variance between groups.
We used RM ANOVA to investigate the effect of stimulation on daily functioning and health using psychometrical surveys. On FIQ, no primary significant effect of the Condition was observed (F[1,34] 5 0.16, P 5 0.695, h2p , 0.01). A general reduction as a function of Time (F[1,34] 5 12.10, P 5 0.001, h2p 5 0.26) and a significant Time by Condition interaction term were observed (F[1,34] 5 5.15, P 5 0.030, h2p 5 0.13), indicating that the active tDCS had a larger reduction in function loss compared with the sham tDCS group. 3.6.2. Hospital Anxiety and Depression Scale
3.3. Pain unpleasantness No significant differences between the group effects on pain unpleasantness were found (F[1,46] 5 0.05, P 5 0.834, h2p , 0.01); however, a significant effect of Time (F[6,276] 5 3.04, P 5 0.007, h2 p 5 0.06) was observed. Furthermore, no interaction effect between Time and Condition was found (F[6,276] 5 0.94, P 5 0.464, h2p 5 0.02), indicating that the tDCS stimulation had no significant effect on pain unpleasantness.
On the HADS, no primary significant effect of condition was observed (F[1,32] 5 0.14, P 5 0.713, h2p , 0.01). A general reduction in the total HADS score from pretest to posttest occurred (F[1,32] 5 4.42, P 5 0.044, h2p 5 0.12); however, the interaction between Time by Condition did not reach significance (F[1,32] 5 3.11, P 5 0.087, h2p 5 0.09), indicating that the effect of tDCS on anxiety and depression was minor. Analysis of the HADS subscales anxiety (F[1,32] 5 2.89, P 5 0.099, h2p 5 0.08) and depression (F[1,32] 5 3.31, P 5 0.261, h2p 5 0.04) did not reveal specific interaction effects of tDCS on these measures.
3.4. Tension and stress No significant difference between the group effects on tension (F[1,46] 5 0.34, P 5 0.561, h2p , 0.01) and stress (F[1,46] 5 0.36, P 5 0.543, h2p , 0.01) was found; however, tension changed during the observed participation period as an effect of Time (F[6,276] 5 2.17, P 5 0.046, h2p 5 0.05), but this effect was not evident for stress (F[2,276] 5 1.06, P 5 0.388, h2p 5 0.02). Furthermore, there was no interaction between the 2 treatment conditions and tension (F[6,276] 5 0.74, P 5 0.619, h2p 5 0.02) or stress (F[6,276] 5 0.52, P 5 0.796, h2p 5 0.01). 3.5. Day-to-day difference in pain intensity between active and sham transcranial direct current stimulation The changes in pain intensity over time were affected by the type of stimulation; therefore, RM ANOVA was conducted to compare the mean pain levels for the groups at each time point. Significant findings indicate a difference between the Active and Sham conditions (Time1: F[1,46] 5 0.75, P 5 0.392; Time2: F[1,46] 5 0.82, P 5 0.369; Time3: F[1,46] 5 0.13, P 5 0.720; Time4: F[1,46] 5 0.57, P 5 0.453; Time 5 : F[1,46] 5 4.32, P 5 0.043, h2p 5 0.09; Time 6 : F[1,46] 5 1.74, P 5 0.194; Time7: F[1,46] 5 3.76, P 5 0.058). Pain levels in the Active and Sham conditions were different at Time5, the day of the fourth stimulation session. A similar tendency was found during the posttest, but the difference did not reach significance. 3.6. Effects of stimulation on psychological and functional outcomes Compliance rates at the pretest ranged from 83% to 92% in the Active condition and were 96% in the Sham condition.
3.6.3. Symptom Checklist 90 Regarding the SCL-90 global severity index, no primary significant effect of condition (F[1,32] 5 0.46, P 5 0.502, h2p 5 0.01) and no significant reduction for the entire sample of patients from pretest to the posttest were observed (F[1,32] 5 4.05, P 5 0.053, h2p 5 0.11). A significant interaction between Time by Condition (F[1,32] 5 6.19, P 5 0.018, h2p 5 0.16) occurred, indicating that tDCS stimulation had an effect on general symptom severity in the patients. On the SCL-90 positive symptom total index, no primary significant effect of condition (F[1,32] 5 0.59, P 5 0.447, h2p 5 0.02) was found, but an overall reduction between pretest and posttest (F[1,32] 5 6.85, P 5 0.013, h2p 5 0.18) was observed. The Time by Condition interaction term was significant (F[1,32] 5 6.44, P 5 0.016, h2p 5 0.17), indicating that the active tDCS had an effect on the number of symptoms in the patients. On the SCL-90 positive symptom distress index, no primary significant effect of condition (F[1,32] 5 0.22, P 5 0.640, h2p # 0.01) and no overall reduction occurred (F[1,32] 5 2.91, P 5 0.098, h2p 5 0.08), but the Time by Condition interaction term was significant (F[1,32] 5 4.36, P 5 0.045, h2p 5 0.12). 3.6.4. SF36v2 On the SF36v2 general mental health, no primary significant effect of condition (F[1,32] 5 0.54, P 5 0.468, h2p 5 0.02) and no improvement (F[1,32] 5 0.01, P 5 0.89, h2p , 0.01) from pretest to posttest occurred. Regarding general physical heath, no primary significant effect of condition (F[1,32] 5 1.61, P 5 0.213, h2p 5 0.05) was observed, but an improvement for all patients from pretest to posttest (F[1,32] 5 6.70, P 5 0.014, h2p 5 0.17) occurred; however, this improvement had no significant
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Table 1
Mean demographic characteristics at pretest, and mean values for all variables at pretest and posttest, and the change score. Pretest Number, n Males Age (SD), y Years with FIM symptoms Mean pain intensity (SD) Mean pain unpleasantness (SD) Mean stress (SD) Mean tension (SD) FIQ (SD) HADS anxiety (SD) HADS depression (SD) SCL-90 GSI (SD) SCL-90 PSDI (SD) SCL-90 PST (SD) SF36v2 PCS SF36v2 MCS
Posttest
Pretest–posttest
Active
Sham
P
Active
Sham
P
Active
Sham
P
24 0 49.04 (8.63) 17.73 (7.54) 4.93 (1.58) 4.79 (1.83) 1.91 (1.76) 0.96 (1.61) 55.54 (14.17) 6.90 (3.99) 5.33 (3.04) 0.81 (0.43) 1.79 (0.32) 39.14 (16.12) 31.39 (7.70) 45.50 (12.55)
24 3 48.17 (10.56) 18.50 (11.48) 5.31 (1.49) 4.78 (1.50) 1.75 (1.80) 0.71 (1.06) 49.21 (14.86) 6.48 (3.48) 6.13 (3.53) 0.82 (0.41) 1.72 (0.41) 41.30 (14.80) 34.43 (6.43) 45.11 (12.52)
0.76 0.8 0.39 0.98 0.76 0.53 0.15 0.71 0.43 0.93 0.55 0.65 0.17 0.92
4.26 (1.90) 4.23 (2.03) 1.76 (1.84) 0.89 (1.53) 41.51 (23.99) 5.47 (4.16) 3.76 (2.77) 0.57 (0.43) 1.57 (0.40) 30.35 (16.65) 34.78 (9.42) 48.20 (12.35)
5.22 (1.50) 4.64 (1.70) 1.59 (1.89) 0.71 (1.16) 47.27 (18.16) 5.82 (3.36) 5.41 (3.37) 0.79 (0.53) 1.75 (0.44) 38.29 (17.01) 35.92 (7.34) 45.40 (10.85)
0.06 0.45 0.76 0.66 0.42 0.79 0.13 0.21 0.24 0.18 0.70 0.49
0.66 (0.71) 0.57 (0.85) 0.15 (0.99) 0.07 (0.55) 14.97 (18.85) 1.53 (2.96) 1.18 (1.81) 0.21 (0.24) 0.21 (0.30) 7.65 (9.43) 24.95 (7.75) 20.04 (11.26)
0.09 (0.82) 0.14 (1.02) 0.16 (0.76) 0.00 (0.26) 3.15 (10.86) 20.06 (2.46) 0.29 (2.62) 20.02 (0.29) 20.02 (0.35) 0.12 (7.79) 21.36 (6.42) 0.48 (10.36)
0.01* 0.12 0.98 0.55 0.03* 0.10 0.26† 0.02* 0.04 0.02* 0.15 0.89
Independent samples Kolmogorov–Smirnov test nonsignificant for all variables indicating equal distribution between groups. * t test, P , 0.05, indicating difference in means between groups. † Levene test, P , 0.05, indicating unequal variance between groups. FIM, fibromyalgia; FIQ, Fibromyalgia Impact Questionnaire; GSI, global severity index; HADS, Hospital Anxiety and Depression Scale; MCS, Mental Component Summary; PCS, Physical Component Summary; SCL-90, Symptom Checklist 90; PSDI, positive symptom distress index; PST, positive symptom total.
interaction with the treatment condition (F[1,32] 5 2.16, P 5 0.151, h2p 5 0.06) (Table 1). 3.7. Adverse effects Table 2 displays an overview of the adverse effects analyzed in this study. Acute mood change occurred more frequently after sham sessions (6.78%) than after active sessions (0.84%). Other adverse effects had statistically equal frequency after active and sham sessions. The most frequent adverse effects were skin redness active/sham (56.30%/68.64%), sleepiness (55.46%/50.58%), and tingling (53.78%/65.25%). 3.8. Medication Ongoing medical treatment was not manipulated in this study. All patients reported constant medication intake throughout their participation. Of all patients, 81.25% used medication for
Table 2
Number of sessions the adverse effects were reported (% of total sessions). Total sessions Headache Neck pain Scalp pain Tingling* Itching Burning sensation* Skin redness Sleepiness Trouble concentrating* Acute mood change* Others
Active
Sham
P
119 18 (15.13) 13 (10.92) 18 (15.13) 64 (53.78) 15 (12.61) 38 (31.93) 67 (56.30) 66 (55.46) 18 (15.13) 1 (0.84) 16 (13.45)
118 12 (10.17) 10 (8.47) 9 (7.63) 77 (65.25) 21 (17.80) 53 (44.92) 81 (68.64) 60 (50.85) 5 (4.24) 8 (6.78) 12 (10.17)
0.42 0.65 0.26 0.32 0.46 0.28 0.27 0.64 0.11 0.04† 0.55
Independent samples Kolmogorov–Smirnov test nonsignificant for all variables indicating equal distribution between groups. * Levene test, P , 0.05, indicating unequal variance between groups. † t test, P , 0.05, indicating difference in means between groups.
treatment of pain (paracetamol 39.58%, nonsteroidal antiinflammatory drugs 56.25%, tricyclic antidepressants 14.58%, neuroleptics 2.08%, antiepileptics 6.25%, opioids 31.25%, migraine medication 2.08%), 6.25% used antidepressants other than tricyclic antidepressants, 14.58% used benzodiazepines, and 29.17% used other medications. Regarding medication, there were no statistical differences between treatment groups (Tables 3 and 4).
4. Discussion 4.1. Pain reduction This study investigated the effect of 5 consecutive sessions of anodal tDCS over the M1 on pain, daily functioning, psychiatric symptoms, and health-related quality of life in patients with FIM. Using SMS to obtain pain data, we aimed to increase the number of data points and reduce missing data, and to the best of our knowledge, this method has not been previously used in similar studies. Demographical and clinical characteristics at baseline are summarized in Table 1. No significant differences between the groups on the measured demographical and clinical characteristics at the pretest were observed. Active tDCS had a significant effect on pain intensity ratings compared with the sham, with a significant difference between the groups at treatment day 4. Patients who received active tDCS had better pain reduction when comparing the 30-day pretest period with the 30-day posttest period. In addition to painameliorating effects, we also observed a small improvement in FIM related to daily functioning measured with the FIQ and psychiatric symptoms as measured with the SCL-90 in patients who received active tDCS. The results from several other studies indicate that tDCS provides significant pain relief to patients with chronic pain conditions. For example, Fregni et al. 14 used a stimulation protocol similar to this study and found a 59% pain reduction in 32 patients with FIM and 58% reduction in a sample of 17 patients with chronic pain after traumatic injury of the
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Table 3
Mean values for outcome measures at all time points (1 5 pretest; 2-6 5 treatment days, Monday to Friday; 7 5 posttest) with 95% CIs. Pain intensity Time 1 2 3 4 5 6 7
Pain unpleasantness
Tension
Active
Sham
Active
Sham
Active
Sham
4.93 (4.26-5.60) 4.84 (3.99-5.69) 4.92 (4.16-5.68) 4.59 (3.86-5.33) 4.15 (3.40-4.48) 4.26 (3.50-5.01) 4.26 (3.46-5.07)
5.31 (4.68-5.94) 5.32 (4.51-6.93) 5.10 (4.39-5.81) 4.98 (4.23-5.72) 5.25 (4.45-6.05) 4.91 (4.21-5.62) 5.22 (4.59-5.86)
4.79 (4.02-5.57) 4.72 (3.78-5.66) 4.78 (3.93-5.63) 4.47 (3.64-5.30) 4.13 (3.29-4.98) 4.21 (3.41-5.02) 4.23 (3.37-5.08)
4.78 (4.14-5.41) 4.75 (3.97-5.53) 4.61 (3.86-5.36) 4.45 (3.72-5.18) 4.57 (3.70-5.45) 4.28 (3.50-5.06) 4.64 (3.92-5.36)
1.91 (1.16-2.65) 2.16 (1.18-3.15)* 2.10 (1.21-2.99)* 2.01 (1.11-2.90)* 1.85 (1.08-2.61)* 1.74 (1.02-2.47)* 1.76 (0.98-2.53)*
1.75 (.99-2.51) 1.72 (0.92-2.52)* 1.58 (0.77-2.40)* 1.62 (0.82-2.43)* 1.58 (0.75-2.42)* 1.46 (0.62-2.29)* 1.59 (0.79-2.39)*
FIQ 1 7
HADS anxiety
Stress Active
Sham
0.96 (0.28-1.64)* 1.03 (0.21-1.85)* 0.97 (0.30-1.65)* 0.97 (0.24-1.71)* 0.86 (0.29-1.43)* 0.90 (0.24-1.57)* 0.89 (0.24-1.53)*
HADS depression
0.71 (0.26-1.16)* 0.79 (0.31-1.27)* 0.62 (0.17-1.08)* 0.69 (0.18-1.20)* 0.71 (0.18-1.24)* 0.62 (0.12-1.13)* 0.71 (0.22-1.21)*
HADS total
Active
Sham
Active
Sham
Active
Sham
Active
Sham
57.00 (49.29-64.72) 41.93 (29.86-54.00)
48.41 (40.50-56.31) 45.26 (36.76-53.76)
7.00 (4.75-9.25) 5.47 (3.33-7.61)
5.76 (3.93-7.60) 5.82 (4.10-7.55)
4.94 (3.48-6.40) 3.76 (2.34-5.19)
5.71 (4.00-7.41) 5.41 (3.68-7.15)
11.94 (8.70-15.19) 9.24 (5.85-12.62)
11.47 (8.31-14.64) 11.24 (7.99-14.48)
SCL-90 GSI
SCL-90 PSDI
Active 1 7
Sham
0.78 (0.56-1.00)* 0.57 (0.35-0.80)*
0.76 (0.56-0.97) 0.79 (0.51-1.06)*
SCL-90 PST
Active
Sham
Active
Sham
1.78 (1.63-1.94) 1.57 (1.37-1.78)
1.73 (1.52-1.93) 1.75 (1.52-1.97)
38.00 (29.20-46.80)* 30.35 (21.79-38.91)*
38.41 (30.89-45.94) 38.29 (29.55-47.04)
SC36 PCS 1 7
SF36 MCS
Active
Sham
Active
Sham
29.83 (26.17-33.49) 34.78 (29.94-39.63)
34.55 (31.37-37.74) 35.92 (32.14-39.69)
48.16 (42.54-53.78) 48.20 (41.85-54.55)*
45.88 (39.92-51.83) 45.40 (29.82-50.98)
Independent samples Kolmogorov–Smirnov test nonsignificant for all variables indicating equal distribution between groups. Levene test nonsignificant for all variables indicating equal variance between groups. * One-sample Kolmogorov–Smirnov test, P , 0.05, indicating that data were not normally distributed within group. CI, confidence interval; FIQ, Fibromyalgia Impact Questionnaire; GSI, global severity index; HADS, Hospital Anxiety and Depression Scale; MCS, Mental Component Summary; PCS, Physical Component Summary; SCL-90, Symptom Checklist 90; PSDI, positive symptom distress index; PST, positive symptom total.
spinal cord.13 Both studies observed the largest pain reduction compared with baseline after 5 sessions of tDCS. In a sample including 23 patients with various chronic pain conditions, Antal et al.2 found that anodal tDCS over the M1 with an intensity of 1 mA resulted in a 37% reduction in pain ratings after 3 stimulation sessions. A study of patients with neurogenic arm pain 5 showed a 15.5% pain reduction after a single 30-minute session of anodal M1 tDCS. In this study, containing a sample of 48 patients, the results revealed that patients receiving active tDCS reported a 13.6% reduction in pain when comparing the pain level in the pretest with the posttest pain levels. Although using similar stimulation
protocols but with altered methods of blinding and pain assessment, this study was unable to replicate the results from the study by Fregni et al. 14 regarding pain reduction in patients with FIM. In contrast, the results of this study only revealed an effect on pain intensity, compared with sham, on the fourth day of stimulation, the results being more in line with the latest Cochrane review32 regarding the efficacy of tDCS over the motor cortex. Only 4 patients in the active group and 1 patient in the sham group reached the preset threshold for clinically significant pain reduction of 1.2 NRS points, making the results from this study unlikely to reflect clinically important change.
Table 4
Between-group differences, sham tDCS–active tDCS, at all time points (1 5 pretest; 2-6 5 treatment days, Monday to Friday; 7 5 posttest) with 95% CIs. Time 1 Pain intensity Pain unpleasantness Stress Tension
0.38 (20.51 to 1.28) 20.01 (20.99 to 0.96)
2
3
4
0.49 (20.59 to 1.28) 0.18 (20.83 to 1.19) 0.38 (20.63 to 1.40) 0.03 (21.16 to 1.22) 20.17 (21.28 to 0.93) 20.02 (21.10 to 1.05)
5
6 1.10 (0.03 to 2.17) 0.44 (20.74 to 1.63)
7 0.66 (20.35 to 1.66) 0.07 (21.02 to 1.16)
0.96 (20.03 to 1.95) 0.41 (20.67 to 1.50)
20.16 (21.19 to 0.88) 20.44 (21.68 to 0.79) 20.51 (21.69 to 0.66) 20.38 (21.55 to 0.79) 20.26 (21.36 to 0.84) 20.28 (21.36 to 0.79) 20.17 (21.25 to 0.92) 20.25 (21.04 to 0.54) 20.24 (21.16 to 0.68) 20.35 (21.14 to 0.44) 20.28 (21.15 to 0.59) 20.15 (20.91 to 0.61) 20.28 (21.09 to 0.53) 20.17 (20.96 to 0.62) Time
FIQ HADS anxiety HADS depression SCL-90 GSI SCL-90 PSDI SCL-90 PST SF36v2 PCS SF36v2 MCS
1
7
26.33 (215.07 to 2.41) 20.43 (22.70 to 1.84) 0.80 (21.22 to 2.81) 0.01 (20.25 to 0.27) 0.07 (20.29 to 0.16) 2.16 (27.24 to 11.57) 3.04 (21.31 to 7.39) 20.39 (28.13 to 7.35)
5.76 (28.50 to 20.02) 0.35 (22.29 to 2.99) 1.65 (20.51 to 3.80) 0.21 (20.13 to 0.55) 0.17 (20.12 to 0.46) 7.94 (23.82 to 19.70) 1.14 (24.77 to 7.04) 22.80 (210.92 to 5.32)
CI, confidence interval; FIQ, Fibromyalgia Impact Questionnaire; GSI, global severity index; HADS, Hospital Anxiety and Depression Scale; SCL-90, Symptom Checklist 90; MCS, Mental Component Summary; PCS, Physical Component Summary; SCL-90, Symptom Checklist 90; PSDI, positive symptom distress index; PST, positive symptom total; tDCS, transcranial direct current stimulation.
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4.2. Transcranial direct current stimulation pain reduction mechanisms The mechanisms through which tDCS ameliorates pain are yet to be fully examined. Anodal tDCS increases cortical excitability29 caused by a stimulation-induced polarity shift of the resting membrane potential.7 At the synaptic level, anodal tDCS may decrease the concentration of g-aminobutyric acid in the cortex,36 which contributes to the after effects of tDCS. In addition to the proximal changes in excitability in the cortex, excitability changes in structures that are remote to the electrode may also contribute to the pain-reducing effects. For example, anodal tDCS over the M1 was found to increase the functional coupling between the M1 and the ipsilateral thalamus.35 In addition to the corticothalamic effects, another study found that anodal tDCS increased neuronal activity in the anterior cingulate cortex, parieto-occipital junction, superior temporal sulcus, and cerebellum, potentially by acting through cortico-cortical and cortico-subcortical connections.23 Therefore, the upregulation of the M1 may modulate pain through the indirect effects on the brain areas involved in pain perception. In this study, all of the patients received the same amplitude and duration of stimulation. Recent evidence based on computational models suggest that interindividual differences in head anatomy may affect the distribution of the electric field in the brain and that a uniform dose of stimulation for all patients may not be the most efficient procedure.10 However, the costs associated with individual modeling required to tailor the stimulation on an individual basis should be balanced against potential benefits.37 Furthermore, the electric field distribution in the brain when using 2 35-cm2 electrodes is not crucial.27 The widespread effect of brain stimulation makes interpretations about the relationships between affected brain tissue and subjective pain relief complicated. This problem may be remedied by using high-definition tDCS techniques that make the stimulation more specific.22 Although the superiority of this method in terms of clinical and behavioral outcomes compared with a conventional electrode montage has not yet been demonstrated, it is likely that individually tailored stimulation based on new knowledge of cerebral pain processing, and more precise means of delivering electric current can increase the clinical efficacy of tDCS. 4.3. Adverse effects Adverse effects that were reported as having a greater relatedness to tDCS than “none” are summarized in Table 2. In general, the treatment was well tolerated by the patients, and only 1 patient withdrew from the study because of adverse effects. However, this patient had received the sham tDCS. Thus, the perceived symptoms were most likely due to reasons other than the treatment. The frequency of adverse effects was similar under both the active and the sham conditions, with the exception of mood changes, which occurred more often in the sham condition. For side effects rated as “severe,” sleepiness was the most common with 16 instances in the active group and 15 in the sham group, otherwise no pattern was observed. Regarding the adverse effects, the conclusion from this study correlates with the conclusions in previous studies,2,5,13,14 suggesting that tDCS is a generally well-tolerated treatment with no serious adverse effects. Interestingly, skin redness, an observable effect of tDCS that may impede double blinding,34 was observed equally in the active and sham conditions, which indicates that skin redness may be more of a result of skin
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reactions to electrode pressure and conductive paste, rather than a result of electric stimulation. Future studies may achieve a more uniform distribution of skin redness across conditions by applying improved techniques for electrode preparation. 4.4. Response rates Regarding the surveys administered at the start and end of participation, we observed a higher compliance at the pretest than at the posttest. For example, the global response rate in both conditions for the FIQ was 94% at the pretest and 77% at posttest. Of the 9 patients who completed the FIQ at the pretest but not at posttest, 6 had received sham tDCS and 3 had received active tDCS, which implies that the effect of previously undergoing the treatment influenced participant compliance. We did not observe this discrepancy in the pretest and posttest compliance in the SMS pain reports. Of 8247 SMS queries, 7742 (93.88%) valid reports were obtained. As responses were done using a single SMS containing 4 NRS values, there was no discrepancy between the sampled variables regarding response rates. Other studies suggest that SMS yielded high response rates from adult20 and children patients,1 while being a cheaper method than retrospective telephone interviews.18 Confidentiality was ensured by secure storage of data and encrypted data transfer from the service provider. In this study, we conclude that the compliance was high and that SMS text messaging was a convenient way of obtaining longitudinal NRS pain reports. 4.5. Limitations We did not investigate the efficacy of the blinding conditions in this study because the patient beliefs regarding the nature of stimulation may have affected their expectations for pain relief 39 and their response patterns. Explicitly asking about the beliefs of the patients regarding the nature of stimulation before the posttest ended may have increased the impact of the beliefs on the responses and may have compromised the identical treatment of the groups. If patients were asked after the posttest, with the obligation to inform about the active or sham conditions, the potential pain relief from the placebo response may have been undermined, and this procedure was not performed for ethical reasons. The patients were given the opportunity to contact us after their participation had ended for information regarding whether they had received active or sham stimulation, and 2 patients did contact us. However, a recent article 12 suggested that active tDCS potentiated the mechanisms involved in placebo analgesia. Therefore, it is likely that patient expectations might have influenced the results.
5. Conclusions In conclusion, the results of this study suggest that tDCS reduces the pain levels in patients with FIM, but the effect sizes are small and unlikely to reflect clinically important change. The patients experienced no serious adverse effects, indicating that tDCS with an intensity of 2 mA over 5 consecutive days was well tolerated.
Conflicts of interest statement This study was funded by a grant from the Norwegian Extra Foundation for Health and Rehabilitation through the Norwegian Fibromyalgia Association to Dr Per M. Aslaksen. The authors declare no conflicts of interest.
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Acknowledgements The authors thank the Pain Clinic at the University Hospital of Northern Norway for the use of their infrastructure during data collection, the physiotherapist Tove Hansen, MA, for examining the diagnostic status of the patients, and the anesthesiologists Lena Danielsson, MD, and Just Thoner, MD, for medical consultancy.
[18]
Article history: Received 11 July 2014 Received in revised form 16 October 2014 Accepted 21 October 2014
[21]
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[40] Vaseghi B, Zoghi M, Jaberzadeh S. Does anodal transcranial direct current stimulation modulate sensory perception and pain? A meta-analysis study. Clin Neurophysiol 2014;125:1847–58. [41] Villamar MF, Wivatvongvana P, Patumanond J, Bikson M, Truong DQ, Datta A, Fregni F. Focal modulation of the primary motor cortex in fibromyalgia using 4 3 1-ring high-definition transcranial direct current stimulation (HD-tDCS): immediate and delayed analgesic effects of cathodal and anodal stimulation. J Pain 2013;14:371–83. [42] Ware JE Jr, Kosinski M, Bayliss MS, McHorney CA, Rogers WH, Raczek A. Comparison of methods for the scoring and statistical analysis of SF-36 health profile and summary measures: summary of results from the medical outcomes study. Med Care 1995;33: AS264–79.
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Transcranial direct current stimulation as a treatment for patients with fibromyalgia: a randomized controlled trial Asbjørn J. Fagerlunda,b,*, Odd A. Hansenc, Per M. Aslaksenb,d
Abstract Previous studies suggest that transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) reduces chronic pain levels. In this randomized controlled trial, we investigated the effects of 5 consecutive 20-minute sessions of 2-mA anodal tDCS directed to the M1 in 48 patients (45 females) with fibromyalgia. Changes in pain, stress, daily functioning, psychiatric symptoms, and health-related quality of life were measured. Pain and stress were measured 30 days before treatment, at each treatment, and 30 days after treatment by using short message service on mobile phones. Patients were randomized to the active or sham tDCS group by receiving individual treatment codes associated either with the sham or active tDCS in the stimulator. Adverse effects were registered using a standardized form. A small but significant improvement in pain was observed under the active tDCS condition but not under the sham condition. Fibromyalgia-related daily functioning improved in the active tDCS group compared with the sham group. The stimulation was well tolerated by the patients, and no significant difference in the adverse effects between the groups was observed. The results suggest that tDCS has the potential to induce statistically significant pain relief in patients with fibromyalgia, with no serious adverse effects, but small effect sizes indicate that the results are unlikely to reflect clinically important changes. Keywords: Fibromyalgia, Pain, Randomized controlled trial (RCT), Transcranial direct current stimulation (tDCS)
1. Introduction Fibromyalgia (FIM) is a chronic pain condition with a prevalence of 2% to 5% that occurs more often in women.28,43 Fibromyalgia is associated with widespread pain, fatigue, sleep disturbance, depression, and reduced quality of life.16 The most common treatment guidelines recommend aerobic exercise, pharmacological treatment, cognitive behavioral therapy, and various multicomponent treatments. 16 Following the recommended methods, treatment effects on pain caused by FIM are usually modest.25 Imaging studies suggest that FIM is associated with functional changes in the brain through reduced connectivity in efferent pain inhibitory networks and central sensitization in afferent pain networks.8 Transcranial direct current stimulation (tDCS) is a noninvasive brain-stimulation technique that has the potential to become cost-effective,45 and has limited adverse effects.6 Thus, tDCS is suitable for chronic pain conditions such as FIM that have relatively high prevalence Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. a
Department of Surgery and Anesthesia, University Hospital of North Norway, Tromsø, Norway, b Department of Psychology, University of Tromsø, Tromsø, Norway, c Department of Physical Medicine and Rehabilitation, University Hospital of North Norway, Tromsø, Norway, d Division of Child and Adolescent Health Services, Department of Child and Adolescent Psychiatry, University Hospital of North Norway, Tromsø, Norway * Corresponding author. Address: Department of Psychology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, Norway. Tel.: 149 97604709; fax: 147 77645291. E-mail address: [email protected] (A. J. Fagerlund). PAIN 156 (2015) 62–71 © 2014 International Association for the Study of Pain http://dx.doi.org/10.1016/j.pain.0000000000000006
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and an absence of effective treatment options. Several studies suggest that tDCS may be effective in ameliorating chronic pain in general21,31,40 and specifically in FIM.14,26,38,41 However, a recent extensive review32 suggests that tDCS has limited efficacy in treatment of chronic pain and states the need for larger and more rigorously designed studies. Transcranial direct current stimulation can be used in randomized clinical trials because of efficient technical solutions to conduct blinded studies of both the patients and experimenters.15 However, even if sophisticated blinding procedures are available, the efficacy of patient blinding has been questioned because patients may be able to discriminate between the active and sham tDCS procedures.30 Insufficient blinding may especially be present at stimulation intensities of 2 mA compared with lower intensities. Recently, a study showed that by using a stimulator with a computerized study mode to administer sham and active tDCS, the patients were unable to reliably discriminate between the conditions; however, the experimenter performing the blinding may have been compromised by observing increased skin redness after the active tDCS stimulation.34 Based on the observation that experimenter blinding may be insufficient, electrode positions on patients should be covered during the assessment of clinical outcomes to reduce the risk of experimenter’s influence on the clinical outcome measures.34 Using these recommendations, this study used short message service (SMS) text messages to obtain pain ratings using the numerical rating scales (NRSs), separating assessment from the clinic. Additionally, SMS enables collection of more data points per individual compared with obtaining pain reports in the clinic, which may reduce measurement error. PAIN®
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The aim of this study was to test the effect of tDCS stimulation on pain in patients with FIM in a hospital setting using a procedure that facilitated participant blinding and reduced experimenter influence on endpoint ratings. We hypothesized that patients receiving active tDCS for 5 consecutive days should report significantly better improvement in FIM-related symptoms (pain, stress, daily functioning, depression, psychiatric symptoms, and general mental and physical health) compared with the group that received the sham tDCS.
2. Methods 2.1. Subjects Patients were recruited in Tromsø, which is located in Northern Norway, and treated at the Pain Clinic, University Hospital of Northern Norway, Tromsø (Fig. 1). Information regarding the study and informed consent were sent by mail to patients with FIM who had been treated in Pain and Rheumatic Clinics at the University Hospital of Northern Norway during the previous 2 years and to members in the local chapter of the National Fibromyalgia Patient Association. Furthermore, the study was advertised in a local newspaper in which patients were invited to declare interest in participation by mail or telephone and then received an informed consent through mail. All patient correspondence was conducted by traditional mail; therefore,
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recruitment uniformity was ensured. The patients had to be #18 years of age, diagnosed with FIM (ICD-10 M79.7) according to the ACR-90 criteria,44 and a manual examination of the patients’ tender points was performed before inclusion. All patients who otherwise adhered to the criteria for participation had a positive FIM diagnostic status. If patients were using prescribed medication, the use had to be stable for 3 months before inclusion. The exclusion criteria included severe psychiatric conditions defined as bipolar disorder, severe depression, and schizophrenia. Additional exclusion criteria consisted of neurological conditions, developmental disorders, pregnancy, and drug abuse. Furthermore, before starting treatment, the participant’s medical records were screened by a neurologist for conditions that counterindicate the use of electrical stimulation. The study was ethically approved by the Regional Committee for Medical and Health Research Ethics (2010/2256) and registered in clinicaltrials.gov (NCT01598181). All patients provided written informed consent by mail. Patients were considered dropouts if they missed 2 or more days (of 5) of treatment or failed to provide at least 1 pain report (of 3) on 2 or more days of treatment. 2.1.1. Design The study aimed to test the effect of tDCS on pain in a hospital setting; therefore, we analyzed data from patients who were
n = 4)
Figure 1. Participant flow and randomization.
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randomized and received the treatment and did not conduct further analysis on participant’s attrition and compliance. Because of the low number of published studies, exact parameters for mean and SD of expected pain levels were not used to calculate the desired sample size because the method of obtaining pain reports and the number of reported pain ratings per patient was different from previous studies.14,38 Instead, sample size was based on previous studies that investigated the effect of tDCS on FIM that found significant interactions between stimulation and time (P , 0.01),14,38 with sample sizes of 32 and 41. To achieve sufficient power to observe effects of the interventions, the sample size of this study was set to be at least as large as these studies. The study was designed as a randomized controlled trial to investigate the pain-ameliorating effect of anodal and sham tDCS administered over 5 consecutive days on pain in patients with FIM. Outcomes were evaluated as the following 7 repeated measures (RMs): pretreatment period of 30 days, 5 days of tDCS stimulation, and posttreatment period of 30 days (pretreatment: Time1, 5 days of tDCS stimulation: Time2-Time6, posttreatment: Time7). In addition, general FIM-related function (Fibromyalgia Impact Questionnaire [FIQ]), depression and anxiety (Hospital Anxiety and Depression Scale [HADS]), physical and psychiatric symptoms (Symptom Checklist 90 [SCL-90R]), and general health-related quality of life (SF36v2) were measured before the active and sham tDCS treatments and 30 days after the last treatment. 2.1.2. Adverse effects Adverse effects were registered using a standard form6 after each session. The patients were asked to report whether they had any headache, neck pain, scalp pain, tingling, itching, burning sensation, sleepiness, trouble concentrating, acute mood change, and other adverse effects after the stimulation, and skin redness was evaluated by the experimenter. The intensity of the adverse effects was rated as “mild,” “moderate,” or “intense,” and the degree to which they were related to the stimulation was rated as “none,” “remote,” “possible,” “probable,” or “definite.” 2.1.3. Transcranial direct current stimulation Direct current stimulation was administered using a neuroConn DC-Stimulator (neuroConn, Ilmenau, Germany), a battery-driven device that constantly monitors electrical impedance and terminates the stimulation if the voltage exceeds safety limits. The stimulation duration was 20 minutes with an intensity of 2 mA. Direct current was transferred by a pair of 35-cm2 rubber electrodes inserted into sponge pads soaked with 10 mL of sterile water. To further reduce electrical impedance, Ten20 neurodiagnostic electrode paste (Weaver and Company, Aurora, CO) was applied to the scalp at the stimulation site. Pilot testing indicated that the use of sterile water and electrode paste provided similar impedance and less skin sensation at the 2-mA stimulation amplitude compared with saline solution, providing improved patient blinding. Furthermore, the use of paste provided better contact between the electrode and scalp on patients with thick hair. The large majority of our patients were females who typically had more scalp hair than men; therefore, we opted to use the combination of sterile water and paste. New electrode sponges were used for every patient, and they were cleaned between sessions. Overall, the montage was similar to Fregni et al.14 To stimulate M1, the anode was placed at the C3 position in the 10/20 system for the EEG electrode
positions. The cathode was placed on the contralateral supraorbital area. We did not change the side of the anode according to the patient reports of pain lateralization because the distribution of electric current in the brain when using 2 large electrodes is not focal, 27 and the FIM according to the ACR-90 criteria is not typically a lateralized pain condition. Sham tDCS consisted of an 8-second fade-in period followed by 30 seconds of direct current stimulation that was terminated by a 5-second fade-out. The sham condition mimics the skin sensation of active tDCS with insufficient duration to induce changes in cortical excitability.29 2.1.4. Double blinding The patients were assigned to a list containing unique 5-digit codes by order of inclusion. The codes were associated with the active or sham tDCS condition and randomized using the online Web service www.randomize.org. The ratio of active and sham codes was 1:1. The key to decipher the codes was kept separately from the experimenters until they had no further contact with the patients. The stimulator was started by entering a 5-digit code in the display of the stimulator, and the displayed impedance information looked similar in both the active and sham conditions. Each patient received stimulation associated with their unique code from a randomized list containing codes for active and sham stimulation. The nature of stimulation for each subject was decoded after the study was completed, allowing data analysis to separate the active and sham stimulation conditions. After this procedure, the active and sham groups received similar treatment with the exception of the stimulation. 2.1.5. Measuring pain-related outcomes by mobile phone Pain intensity, pain unpleasantness, stress, and anxiety were measured daily using SMS from the mobile phones of the subjects. In the morning (9 AM), afternoon (3 PM), and evening (9 PM), the subjects received an SMS consisting of the following 4 questions: “what is your pain level now?,” “how unpleasant is the pain now?,” “how tense are you now?,” and “how anxious are you now?.” The response to the questions was delivered through a reply SMS containing the NRS values (0-10). If no response was obtained after 15 minutes of receiving the SMS, a reminder was sent. Responses obtained within 2 hours were considered valid. Responses with invalid formatting were answered with an SMS containing instructions for correct formatting. To make the scoring more intuitive, the subjects were supplied with a visual analogous scale with a sliding indicator in the initial consultancy with a clinical psychologist. By flipping the scale, a numeric value that corresponded to their analogous rating was read and used to translate the visual analog scale into the NRS. All of the patients who showed interest in participating had access to an SMScompatible mobile device, which was expected because prevalence of mobile phones in the general adult Norwegian population is close to 100%. 2.1.6. Psychological and functional measures At the start and end of participation, the subjects completed 4 surveys electronically. The FIQ, a validated tool used to measure the impact of FIM symptoms, was used to study the effects of FIM on daily functioning.3 The Norwegian translation used in this study was based on the validated Swedish translation.17 Norwegian and Swedish are semantically and phonetically similar languages; therefore, we assumed the Norwegian translation to have similar
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testing characteristics as the validated Swedish version. A higher score indicates a more severe impact of FIM symptoms on functioning. The maximum score is 100, and the average FIM patient scores are approximately 50.3 The HADS is a widely used and validated screening tool to measure anxiety and depression in both psychiatric and nonpsychiatric patients.4 This survey has a Norwegian translation that has excellent psychometrical characteristics that are similar to other translations.33 Regarding the anxiety and depression scale, a score of 8 to 10 indicates a mild case, 11 to 15 denotes a moderate case, and above 16 is a severe case. The mean score in a nonclinical population is approximately 6 for the anxiety scale and 3 for the depression scale.9 The SCL-90R, a survey that has been extensively used worldwide, 11 was used to measure psychiatric symptoms and distress, and this study used the official Norwegian translation of this survey (NCS Pearson, Inc). The SCL-90R contains 3 global score indexes. The global severity index measures the patient’s psychological distress status. The positive symptom distress index is considered an intensity distress style measure, and the positive symptom total reveals the total number of symptoms reported by the patient. The Short Form 36 (SF36v2) was used to measure general physical and mental health. The Norwegian translation possesses similar psychometric properties as other translated versions of the survey.24 For scoring, we used the Physical Component Summary and Mental Component Summary because they are considered to sufficiently summarize the SF36v2 8-score profile.42 The scores range from 100 (no impairment) to 0 (maximum impairment). 2.2. Procedure After inclusion, the patients attended an individual consultancy with a clinical psychologist (Fig. 2). The content of the meeting was scripted to keep the information uniform across the patients. During the meeting, the patients completed surveys and received instructions on how to submit pain and stress reports by mobile phone. The time between interview and the first session of tDCS was defined as the pretest period. The length of this period was planned to be 30 days; however, 11 subjects had a 14-day pretest period for practical reasons such as patient plans, scheduling, and holidays. Stimulation was administered in 5 sessions from Monday through Friday. After 5 days of treatment, the patients reported on their pain and stress for 30 days, and this period was defined as the posttest period. On concluding the posttest period, the subjects completed the surveys from the inclusion interview a second time. 2.3. Statistical analysis SPSS version 19 (IBM, Armonk, NY) was used for all statistical analyses. Before analyzing the effects of active and sham tDCS on our endpoints, we compared baseline results between the
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2 groups to eliminate the possibility that the differences observed after intervention were due to the groups being different at baseline. For this analysis, the independent t test for equality of means was used. To test the effect of the tDCS intervention on pain, pain unpleasantness, and the stress and anxiety levels, we conducted RMs analysis of variance (ANOVA) with 7 RMs (Time 5 pretest Time1, treatment 3 5 Time2-Time6, posttest Time7) and 2 measures between group conditions (Condition 5 active or sham tDCS). Simple contrasts were used to compare the different time points with the pretest as the reference. One-way ANOVA was used to analyze the mean changes from pretest to posttest and to analyze between-group differences at the individual time points. The Kolmogorov–Smirnov test for independent samples was used to test the equal distribution between conditions, and 1-sample Kolmogorov–Smirnov test was used to test normal distribution within conditions. Levene test was used to assess the homogeneity of variance between the conditions. Partial h2 p was used to calculate the effect sizes. Alpha levels were set to #0.05.
3. Results 3.1. Effect of stimulation on pain intensity Recruitment commenced in September 2011, and trial was completed in July 2013 because of reaching the target sample size. Global compliance for SMS pain reports was 94%. An RM ANOVA revealed no primary significant effect on the group regarding pain intensity (F[1,46] 5 1.67, P 5 0.204, h2p 5 0.04). However, a significant effect of Time (F[6,276] 5 3.65, P 5 0.002, h2p 5 0.07) and a significant interaction effect of Time by Condition (F[6,276] 5 2.33, P 5 0.032, h2p 5 0.05) were observed. To investigate at what points this interaction was significant compared with the pretest, contrast analyses with Time1 as the reference revealed that the interaction term Time by Condition was significant at Time5 (day 4 of tDCS treatment) (F[1,46] 5 7.91, P 5 0.007, h2p 5 0.15) and at Time7 (posttest) (F[1,46] 5 6.82, P 5 0.012, h2p 5 0.13). 3.2. Change in pain intensity from pretest to posttest The mean NRS pain intensity reduction in the active tDCS group from pretest to posttest was 0.66 NRS points (95% confidence interval, 0.36-0.96) and 0.09 NRS points in the sham tDCS group (95% confidence interval, 20.26 to 0.43) (Fig. 3). Thus, a 13.6% mean pain reduction in the active group and 1.70% pain reduction in the sham group were observed. One-way ANOVA showed that the difference in pain reduction between conditions was significant (F[1,47] 5 6.82, P 5 0.012, h2p 5 0.13). Responders were identified using a minimum clinically significant change of 1.2 NRS points.19 There were 4 responders in the active group, and 1 responder in the sham group.
Figure 2. Overview of the procedure.
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At the posttest, the response rates ranged from 71% to 79% in the Active condition and from 71% to 75% in the Sham condition. Fibromyalgia Impact Questionnaire had the highest compliance in both conditions at the posttest, whereas HADS, SCL-90, and SF36v2 had similar response rates. 3.6.1. Fibromyalgia Impact Questionnaire
Figure 3. Mean NRS pain intensity (0–10) by time (1 5 mean of 30-day pretest, 2–6 5 mean on treatment days 1–5, 7 5 mean of 30-day posttest). Error bars denote SEM. Independent samples Kolmogorov–Smirnov test was nonsignificant for all variables indicating equal distribution between groups. Levene test was nonsignificant for all time points, indicating equal variance between groups.
We used RM ANOVA to investigate the effect of stimulation on daily functioning and health using psychometrical surveys. On FIQ, no primary significant effect of the Condition was observed (F[1,34] 5 0.16, P 5 0.695, h2p , 0.01). A general reduction as a function of Time (F[1,34] 5 12.10, P 5 0.001, h2p 5 0.26) and a significant Time by Condition interaction term were observed (F[1,34] 5 5.15, P 5 0.030, h2p 5 0.13), indicating that the active tDCS had a larger reduction in function loss compared with the sham tDCS group. 3.6.2. Hospital Anxiety and Depression Scale
3.3. Pain unpleasantness No significant differences between the group effects on pain unpleasantness were found (F[1,46] 5 0.05, P 5 0.834, h2p , 0.01); however, a significant effect of Time (F[6,276] 5 3.04, P 5 0.007, h2 p 5 0.06) was observed. Furthermore, no interaction effect between Time and Condition was found (F[6,276] 5 0.94, P 5 0.464, h2p 5 0.02), indicating that the tDCS stimulation had no significant effect on pain unpleasantness.
On the HADS, no primary significant effect of condition was observed (F[1,32] 5 0.14, P 5 0.713, h2p , 0.01). A general reduction in the total HADS score from pretest to posttest occurred (F[1,32] 5 4.42, P 5 0.044, h2p 5 0.12); however, the interaction between Time by Condition did not reach significance (F[1,32] 5 3.11, P 5 0.087, h2p 5 0.09), indicating that the effect of tDCS on anxiety and depression was minor. Analysis of the HADS subscales anxiety (F[1,32] 5 2.89, P 5 0.099, h2p 5 0.08) and depression (F[1,32] 5 3.31, P 5 0.261, h2p 5 0.04) did not reveal specific interaction effects of tDCS on these measures.
3.4. Tension and stress No significant difference between the group effects on tension (F[1,46] 5 0.34, P 5 0.561, h2p , 0.01) and stress (F[1,46] 5 0.36, P 5 0.543, h2p , 0.01) was found; however, tension changed during the observed participation period as an effect of Time (F[6,276] 5 2.17, P 5 0.046, h2p 5 0.05), but this effect was not evident for stress (F[2,276] 5 1.06, P 5 0.388, h2p 5 0.02). Furthermore, there was no interaction between the 2 treatment conditions and tension (F[6,276] 5 0.74, P 5 0.619, h2p 5 0.02) or stress (F[6,276] 5 0.52, P 5 0.796, h2p 5 0.01). 3.5. Day-to-day difference in pain intensity between active and sham transcranial direct current stimulation The changes in pain intensity over time were affected by the type of stimulation; therefore, RM ANOVA was conducted to compare the mean pain levels for the groups at each time point. Significant findings indicate a difference between the Active and Sham conditions (Time1: F[1,46] 5 0.75, P 5 0.392; Time2: F[1,46] 5 0.82, P 5 0.369; Time3: F[1,46] 5 0.13, P 5 0.720; Time4: F[1,46] 5 0.57, P 5 0.453; Time 5 : F[1,46] 5 4.32, P 5 0.043, h2p 5 0.09; Time 6 : F[1,46] 5 1.74, P 5 0.194; Time7: F[1,46] 5 3.76, P 5 0.058). Pain levels in the Active and Sham conditions were different at Time5, the day of the fourth stimulation session. A similar tendency was found during the posttest, but the difference did not reach significance. 3.6. Effects of stimulation on psychological and functional outcomes Compliance rates at the pretest ranged from 83% to 92% in the Active condition and were 96% in the Sham condition.
3.6.3. Symptom Checklist 90 Regarding the SCL-90 global severity index, no primary significant effect of condition (F[1,32] 5 0.46, P 5 0.502, h2p 5 0.01) and no significant reduction for the entire sample of patients from pretest to the posttest were observed (F[1,32] 5 4.05, P 5 0.053, h2p 5 0.11). A significant interaction between Time by Condition (F[1,32] 5 6.19, P 5 0.018, h2p 5 0.16) occurred, indicating that tDCS stimulation had an effect on general symptom severity in the patients. On the SCL-90 positive symptom total index, no primary significant effect of condition (F[1,32] 5 0.59, P 5 0.447, h2p 5 0.02) was found, but an overall reduction between pretest and posttest (F[1,32] 5 6.85, P 5 0.013, h2p 5 0.18) was observed. The Time by Condition interaction term was significant (F[1,32] 5 6.44, P 5 0.016, h2p 5 0.17), indicating that the active tDCS had an effect on the number of symptoms in the patients. On the SCL-90 positive symptom distress index, no primary significant effect of condition (F[1,32] 5 0.22, P 5 0.640, h2p # 0.01) and no overall reduction occurred (F[1,32] 5 2.91, P 5 0.098, h2p 5 0.08), but the Time by Condition interaction term was significant (F[1,32] 5 4.36, P 5 0.045, h2p 5 0.12). 3.6.4. SF36v2 On the SF36v2 general mental health, no primary significant effect of condition (F[1,32] 5 0.54, P 5 0.468, h2p 5 0.02) and no improvement (F[1,32] 5 0.01, P 5 0.89, h2p , 0.01) from pretest to posttest occurred. Regarding general physical heath, no primary significant effect of condition (F[1,32] 5 1.61, P 5 0.213, h2p 5 0.05) was observed, but an improvement for all patients from pretest to posttest (F[1,32] 5 6.70, P 5 0.014, h2p 5 0.17) occurred; however, this improvement had no significant
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Table 1
Mean demographic characteristics at pretest, and mean values for all variables at pretest and posttest, and the change score. Pretest Number, n Males Age (SD), y Years with FIM symptoms Mean pain intensity (SD) Mean pain unpleasantness (SD) Mean stress (SD) Mean tension (SD) FIQ (SD) HADS anxiety (SD) HADS depression (SD) SCL-90 GSI (SD) SCL-90 PSDI (SD) SCL-90 PST (SD) SF36v2 PCS SF36v2 MCS
Posttest
Pretest–posttest
Active
Sham
P
Active
Sham
P
Active
Sham
P
24 0 49.04 (8.63) 17.73 (7.54) 4.93 (1.58) 4.79 (1.83) 1.91 (1.76) 0.96 (1.61) 55.54 (14.17) 6.90 (3.99) 5.33 (3.04) 0.81 (0.43) 1.79 (0.32) 39.14 (16.12) 31.39 (7.70) 45.50 (12.55)
24 3 48.17 (10.56) 18.50 (11.48) 5.31 (1.49) 4.78 (1.50) 1.75 (1.80) 0.71 (1.06) 49.21 (14.86) 6.48 (3.48) 6.13 (3.53) 0.82 (0.41) 1.72 (0.41) 41.30 (14.80) 34.43 (6.43) 45.11 (12.52)
0.76 0.8 0.39 0.98 0.76 0.53 0.15 0.71 0.43 0.93 0.55 0.65 0.17 0.92
4.26 (1.90) 4.23 (2.03) 1.76 (1.84) 0.89 (1.53) 41.51 (23.99) 5.47 (4.16) 3.76 (2.77) 0.57 (0.43) 1.57 (0.40) 30.35 (16.65) 34.78 (9.42) 48.20 (12.35)
5.22 (1.50) 4.64 (1.70) 1.59 (1.89) 0.71 (1.16) 47.27 (18.16) 5.82 (3.36) 5.41 (3.37) 0.79 (0.53) 1.75 (0.44) 38.29 (17.01) 35.92 (7.34) 45.40 (10.85)
0.06 0.45 0.76 0.66 0.42 0.79 0.13 0.21 0.24 0.18 0.70 0.49
0.66 (0.71) 0.57 (0.85) 0.15 (0.99) 0.07 (0.55) 14.97 (18.85) 1.53 (2.96) 1.18 (1.81) 0.21 (0.24) 0.21 (0.30) 7.65 (9.43) 24.95 (7.75) 20.04 (11.26)
0.09 (0.82) 0.14 (1.02) 0.16 (0.76) 0.00 (0.26) 3.15 (10.86) 20.06 (2.46) 0.29 (2.62) 20.02 (0.29) 20.02 (0.35) 0.12 (7.79) 21.36 (6.42) 0.48 (10.36)
0.01* 0.12 0.98 0.55 0.03* 0.10 0.26† 0.02* 0.04 0.02* 0.15 0.89
Independent samples Kolmogorov–Smirnov test nonsignificant for all variables indicating equal distribution between groups. * t test, P , 0.05, indicating difference in means between groups. † Levene test, P , 0.05, indicating unequal variance between groups. FIM, fibromyalgia; FIQ, Fibromyalgia Impact Questionnaire; GSI, global severity index; HADS, Hospital Anxiety and Depression Scale; MCS, Mental Component Summary; PCS, Physical Component Summary; SCL-90, Symptom Checklist 90; PSDI, positive symptom distress index; PST, positive symptom total.
interaction with the treatment condition (F[1,32] 5 2.16, P 5 0.151, h2p 5 0.06) (Table 1). 3.7. Adverse effects Table 2 displays an overview of the adverse effects analyzed in this study. Acute mood change occurred more frequently after sham sessions (6.78%) than after active sessions (0.84%). Other adverse effects had statistically equal frequency after active and sham sessions. The most frequent adverse effects were skin redness active/sham (56.30%/68.64%), sleepiness (55.46%/50.58%), and tingling (53.78%/65.25%). 3.8. Medication Ongoing medical treatment was not manipulated in this study. All patients reported constant medication intake throughout their participation. Of all patients, 81.25% used medication for
Table 2
Number of sessions the adverse effects were reported (% of total sessions). Total sessions Headache Neck pain Scalp pain Tingling* Itching Burning sensation* Skin redness Sleepiness Trouble concentrating* Acute mood change* Others
Active
Sham
P
119 18 (15.13) 13 (10.92) 18 (15.13) 64 (53.78) 15 (12.61) 38 (31.93) 67 (56.30) 66 (55.46) 18 (15.13) 1 (0.84) 16 (13.45)
118 12 (10.17) 10 (8.47) 9 (7.63) 77 (65.25) 21 (17.80) 53 (44.92) 81 (68.64) 60 (50.85) 5 (4.24) 8 (6.78) 12 (10.17)
0.42 0.65 0.26 0.32 0.46 0.28 0.27 0.64 0.11 0.04† 0.55
Independent samples Kolmogorov–Smirnov test nonsignificant for all variables indicating equal distribution between groups. * Levene test, P , 0.05, indicating unequal variance between groups. † t test, P , 0.05, indicating difference in means between groups.
treatment of pain (paracetamol 39.58%, nonsteroidal antiinflammatory drugs 56.25%, tricyclic antidepressants 14.58%, neuroleptics 2.08%, antiepileptics 6.25%, opioids 31.25%, migraine medication 2.08%), 6.25% used antidepressants other than tricyclic antidepressants, 14.58% used benzodiazepines, and 29.17% used other medications. Regarding medication, there were no statistical differences between treatment groups (Tables 3 and 4).
4. Discussion 4.1. Pain reduction This study investigated the effect of 5 consecutive sessions of anodal tDCS over the M1 on pain, daily functioning, psychiatric symptoms, and health-related quality of life in patients with FIM. Using SMS to obtain pain data, we aimed to increase the number of data points and reduce missing data, and to the best of our knowledge, this method has not been previously used in similar studies. Demographical and clinical characteristics at baseline are summarized in Table 1. No significant differences between the groups on the measured demographical and clinical characteristics at the pretest were observed. Active tDCS had a significant effect on pain intensity ratings compared with the sham, with a significant difference between the groups at treatment day 4. Patients who received active tDCS had better pain reduction when comparing the 30-day pretest period with the 30-day posttest period. In addition to painameliorating effects, we also observed a small improvement in FIM related to daily functioning measured with the FIQ and psychiatric symptoms as measured with the SCL-90 in patients who received active tDCS. The results from several other studies indicate that tDCS provides significant pain relief to patients with chronic pain conditions. For example, Fregni et al. 14 used a stimulation protocol similar to this study and found a 59% pain reduction in 32 patients with FIM and 58% reduction in a sample of 17 patients with chronic pain after traumatic injury of the
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Table 3
Mean values for outcome measures at all time points (1 5 pretest; 2-6 5 treatment days, Monday to Friday; 7 5 posttest) with 95% CIs. Pain intensity Time 1 2 3 4 5 6 7
Pain unpleasantness
Tension
Active
Sham
Active
Sham
Active
Sham
4.93 (4.26-5.60) 4.84 (3.99-5.69) 4.92 (4.16-5.68) 4.59 (3.86-5.33) 4.15 (3.40-4.48) 4.26 (3.50-5.01) 4.26 (3.46-5.07)
5.31 (4.68-5.94) 5.32 (4.51-6.93) 5.10 (4.39-5.81) 4.98 (4.23-5.72) 5.25 (4.45-6.05) 4.91 (4.21-5.62) 5.22 (4.59-5.86)
4.79 (4.02-5.57) 4.72 (3.78-5.66) 4.78 (3.93-5.63) 4.47 (3.64-5.30) 4.13 (3.29-4.98) 4.21 (3.41-5.02) 4.23 (3.37-5.08)
4.78 (4.14-5.41) 4.75 (3.97-5.53) 4.61 (3.86-5.36) 4.45 (3.72-5.18) 4.57 (3.70-5.45) 4.28 (3.50-5.06) 4.64 (3.92-5.36)
1.91 (1.16-2.65) 2.16 (1.18-3.15)* 2.10 (1.21-2.99)* 2.01 (1.11-2.90)* 1.85 (1.08-2.61)* 1.74 (1.02-2.47)* 1.76 (0.98-2.53)*
1.75 (.99-2.51) 1.72 (0.92-2.52)* 1.58 (0.77-2.40)* 1.62 (0.82-2.43)* 1.58 (0.75-2.42)* 1.46 (0.62-2.29)* 1.59 (0.79-2.39)*
FIQ 1 7
HADS anxiety
Stress Active
Sham
0.96 (0.28-1.64)* 1.03 (0.21-1.85)* 0.97 (0.30-1.65)* 0.97 (0.24-1.71)* 0.86 (0.29-1.43)* 0.90 (0.24-1.57)* 0.89 (0.24-1.53)*
HADS depression
0.71 (0.26-1.16)* 0.79 (0.31-1.27)* 0.62 (0.17-1.08)* 0.69 (0.18-1.20)* 0.71 (0.18-1.24)* 0.62 (0.12-1.13)* 0.71 (0.22-1.21)*
HADS total
Active
Sham
Active
Sham
Active
Sham
Active
Sham
57.00 (49.29-64.72) 41.93 (29.86-54.00)
48.41 (40.50-56.31) 45.26 (36.76-53.76)
7.00 (4.75-9.25) 5.47 (3.33-7.61)
5.76 (3.93-7.60) 5.82 (4.10-7.55)
4.94 (3.48-6.40) 3.76 (2.34-5.19)
5.71 (4.00-7.41) 5.41 (3.68-7.15)
11.94 (8.70-15.19) 9.24 (5.85-12.62)
11.47 (8.31-14.64) 11.24 (7.99-14.48)
SCL-90 GSI
SCL-90 PSDI
Active 1 7
Sham
0.78 (0.56-1.00)* 0.57 (0.35-0.80)*
0.76 (0.56-0.97) 0.79 (0.51-1.06)*
SCL-90 PST
Active
Sham
Active
Sham
1.78 (1.63-1.94) 1.57 (1.37-1.78)
1.73 (1.52-1.93) 1.75 (1.52-1.97)
38.00 (29.20-46.80)* 30.35 (21.79-38.91)*
38.41 (30.89-45.94) 38.29 (29.55-47.04)
SC36 PCS 1 7
SF36 MCS
Active
Sham
Active
Sham
29.83 (26.17-33.49) 34.78 (29.94-39.63)
34.55 (31.37-37.74) 35.92 (32.14-39.69)
48.16 (42.54-53.78) 48.20 (41.85-54.55)*
45.88 (39.92-51.83) 45.40 (29.82-50.98)
Independent samples Kolmogorov–Smirnov test nonsignificant for all variables indicating equal distribution between groups. Levene test nonsignificant for all variables indicating equal variance between groups. * One-sample Kolmogorov–Smirnov test, P , 0.05, indicating that data were not normally distributed within group. CI, confidence interval; FIQ, Fibromyalgia Impact Questionnaire; GSI, global severity index; HADS, Hospital Anxiety and Depression Scale; MCS, Mental Component Summary; PCS, Physical Component Summary; SCL-90, Symptom Checklist 90; PSDI, positive symptom distress index; PST, positive symptom total.
spinal cord.13 Both studies observed the largest pain reduction compared with baseline after 5 sessions of tDCS. In a sample including 23 patients with various chronic pain conditions, Antal et al.2 found that anodal tDCS over the M1 with an intensity of 1 mA resulted in a 37% reduction in pain ratings after 3 stimulation sessions. A study of patients with neurogenic arm pain 5 showed a 15.5% pain reduction after a single 30-minute session of anodal M1 tDCS. In this study, containing a sample of 48 patients, the results revealed that patients receiving active tDCS reported a 13.6% reduction in pain when comparing the pain level in the pretest with the posttest pain levels. Although using similar stimulation
protocols but with altered methods of blinding and pain assessment, this study was unable to replicate the results from the study by Fregni et al. 14 regarding pain reduction in patients with FIM. In contrast, the results of this study only revealed an effect on pain intensity, compared with sham, on the fourth day of stimulation, the results being more in line with the latest Cochrane review32 regarding the efficacy of tDCS over the motor cortex. Only 4 patients in the active group and 1 patient in the sham group reached the preset threshold for clinically significant pain reduction of 1.2 NRS points, making the results from this study unlikely to reflect clinically important change.
Table 4
Between-group differences, sham tDCS–active tDCS, at all time points (1 5 pretest; 2-6 5 treatment days, Monday to Friday; 7 5 posttest) with 95% CIs. Time 1 Pain intensity Pain unpleasantness Stress Tension
0.38 (20.51 to 1.28) 20.01 (20.99 to 0.96)
2
3
4
0.49 (20.59 to 1.28) 0.18 (20.83 to 1.19) 0.38 (20.63 to 1.40) 0.03 (21.16 to 1.22) 20.17 (21.28 to 0.93) 20.02 (21.10 to 1.05)
5
6 1.10 (0.03 to 2.17) 0.44 (20.74 to 1.63)
7 0.66 (20.35 to 1.66) 0.07 (21.02 to 1.16)
0.96 (20.03 to 1.95) 0.41 (20.67 to 1.50)
20.16 (21.19 to 0.88) 20.44 (21.68 to 0.79) 20.51 (21.69 to 0.66) 20.38 (21.55 to 0.79) 20.26 (21.36 to 0.84) 20.28 (21.36 to 0.79) 20.17 (21.25 to 0.92) 20.25 (21.04 to 0.54) 20.24 (21.16 to 0.68) 20.35 (21.14 to 0.44) 20.28 (21.15 to 0.59) 20.15 (20.91 to 0.61) 20.28 (21.09 to 0.53) 20.17 (20.96 to 0.62) Time
FIQ HADS anxiety HADS depression SCL-90 GSI SCL-90 PSDI SCL-90 PST SF36v2 PCS SF36v2 MCS
1
7
26.33 (215.07 to 2.41) 20.43 (22.70 to 1.84) 0.80 (21.22 to 2.81) 0.01 (20.25 to 0.27) 0.07 (20.29 to 0.16) 2.16 (27.24 to 11.57) 3.04 (21.31 to 7.39) 20.39 (28.13 to 7.35)
5.76 (28.50 to 20.02) 0.35 (22.29 to 2.99) 1.65 (20.51 to 3.80) 0.21 (20.13 to 0.55) 0.17 (20.12 to 0.46) 7.94 (23.82 to 19.70) 1.14 (24.77 to 7.04) 22.80 (210.92 to 5.32)
CI, confidence interval; FIQ, Fibromyalgia Impact Questionnaire; GSI, global severity index; HADS, Hospital Anxiety and Depression Scale; SCL-90, Symptom Checklist 90; MCS, Mental Component Summary; PCS, Physical Component Summary; SCL-90, Symptom Checklist 90; PSDI, positive symptom distress index; PST, positive symptom total; tDCS, transcranial direct current stimulation.
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4.2. Transcranial direct current stimulation pain reduction mechanisms The mechanisms through which tDCS ameliorates pain are yet to be fully examined. Anodal tDCS increases cortical excitability29 caused by a stimulation-induced polarity shift of the resting membrane potential.7 At the synaptic level, anodal tDCS may decrease the concentration of g-aminobutyric acid in the cortex,36 which contributes to the after effects of tDCS. In addition to the proximal changes in excitability in the cortex, excitability changes in structures that are remote to the electrode may also contribute to the pain-reducing effects. For example, anodal tDCS over the M1 was found to increase the functional coupling between the M1 and the ipsilateral thalamus.35 In addition to the corticothalamic effects, another study found that anodal tDCS increased neuronal activity in the anterior cingulate cortex, parieto-occipital junction, superior temporal sulcus, and cerebellum, potentially by acting through cortico-cortical and cortico-subcortical connections.23 Therefore, the upregulation of the M1 may modulate pain through the indirect effects on the brain areas involved in pain perception. In this study, all of the patients received the same amplitude and duration of stimulation. Recent evidence based on computational models suggest that interindividual differences in head anatomy may affect the distribution of the electric field in the brain and that a uniform dose of stimulation for all patients may not be the most efficient procedure.10 However, the costs associated with individual modeling required to tailor the stimulation on an individual basis should be balanced against potential benefits.37 Furthermore, the electric field distribution in the brain when using 2 35-cm2 electrodes is not crucial.27 The widespread effect of brain stimulation makes interpretations about the relationships between affected brain tissue and subjective pain relief complicated. This problem may be remedied by using high-definition tDCS techniques that make the stimulation more specific.22 Although the superiority of this method in terms of clinical and behavioral outcomes compared with a conventional electrode montage has not yet been demonstrated, it is likely that individually tailored stimulation based on new knowledge of cerebral pain processing, and more precise means of delivering electric current can increase the clinical efficacy of tDCS. 4.3. Adverse effects Adverse effects that were reported as having a greater relatedness to tDCS than “none” are summarized in Table 2. In general, the treatment was well tolerated by the patients, and only 1 patient withdrew from the study because of adverse effects. However, this patient had received the sham tDCS. Thus, the perceived symptoms were most likely due to reasons other than the treatment. The frequency of adverse effects was similar under both the active and the sham conditions, with the exception of mood changes, which occurred more often in the sham condition. For side effects rated as “severe,” sleepiness was the most common with 16 instances in the active group and 15 in the sham group, otherwise no pattern was observed. Regarding the adverse effects, the conclusion from this study correlates with the conclusions in previous studies,2,5,13,14 suggesting that tDCS is a generally well-tolerated treatment with no serious adverse effects. Interestingly, skin redness, an observable effect of tDCS that may impede double blinding,34 was observed equally in the active and sham conditions, which indicates that skin redness may be more of a result of skin
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reactions to electrode pressure and conductive paste, rather than a result of electric stimulation. Future studies may achieve a more uniform distribution of skin redness across conditions by applying improved techniques for electrode preparation. 4.4. Response rates Regarding the surveys administered at the start and end of participation, we observed a higher compliance at the pretest than at the posttest. For example, the global response rate in both conditions for the FIQ was 94% at the pretest and 77% at posttest. Of the 9 patients who completed the FIQ at the pretest but not at posttest, 6 had received sham tDCS and 3 had received active tDCS, which implies that the effect of previously undergoing the treatment influenced participant compliance. We did not observe this discrepancy in the pretest and posttest compliance in the SMS pain reports. Of 8247 SMS queries, 7742 (93.88%) valid reports were obtained. As responses were done using a single SMS containing 4 NRS values, there was no discrepancy between the sampled variables regarding response rates. Other studies suggest that SMS yielded high response rates from adult20 and children patients,1 while being a cheaper method than retrospective telephone interviews.18 Confidentiality was ensured by secure storage of data and encrypted data transfer from the service provider. In this study, we conclude that the compliance was high and that SMS text messaging was a convenient way of obtaining longitudinal NRS pain reports. 4.5. Limitations We did not investigate the efficacy of the blinding conditions in this study because the patient beliefs regarding the nature of stimulation may have affected their expectations for pain relief 39 and their response patterns. Explicitly asking about the beliefs of the patients regarding the nature of stimulation before the posttest ended may have increased the impact of the beliefs on the responses and may have compromised the identical treatment of the groups. If patients were asked after the posttest, with the obligation to inform about the active or sham conditions, the potential pain relief from the placebo response may have been undermined, and this procedure was not performed for ethical reasons. The patients were given the opportunity to contact us after their participation had ended for information regarding whether they had received active or sham stimulation, and 2 patients did contact us. However, a recent article 12 suggested that active tDCS potentiated the mechanisms involved in placebo analgesia. Therefore, it is likely that patient expectations might have influenced the results.
5. Conclusions In conclusion, the results of this study suggest that tDCS reduces the pain levels in patients with FIM, but the effect sizes are small and unlikely to reflect clinically important change. The patients experienced no serious adverse effects, indicating that tDCS with an intensity of 2 mA over 5 consecutive days was well tolerated.
Conflicts of interest statement This study was funded by a grant from the Norwegian Extra Foundation for Health and Rehabilitation through the Norwegian Fibromyalgia Association to Dr Per M. Aslaksen. The authors declare no conflicts of interest.
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Acknowledgements The authors thank the Pain Clinic at the University Hospital of Northern Norway for the use of their infrastructure during data collection, the physiotherapist Tove Hansen, MA, for examining the diagnostic status of the patients, and the anesthesiologists Lena Danielsson, MD, and Just Thoner, MD, for medical consultancy.
[18]
Article history: Received 11 July 2014 Received in revised form 16 October 2014 Accepted 21 October 2014
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