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Motor cortex transcranial direct current stimulation effects on knee osteoarthritis pain in elderly subjects with dysfunctional descending pain inhibitory system: A randomized controlled trial

Open AccessPublished:March 04, 2021DOI:https://doi.org/10.1016/j.brs.2021.02.018

      Highlights

      • Fifteen daily sessions of tDCS decreases knee osteoarthritis pain in the elderly.
      • Motor cortex tDCS modulates the descending inhibitory pain system in the elderly.
      • 2 mA for 20 min of anodal tDCS is safe and well tolerated in the elderly.
      • tDCS alone did not induce long-term effects in the elderly with knee chronic pain.

      Abstract

      Background

      Although evidence has indicated a positive effect of transcranial direct current stimulation (tDCS) on reducing pain, few studies have focused on the elderly population with knee osteoarthritis (KOA).

      Objective

      To evaluate whether tDCS reduces KOA pain in elderly individuals with a dysfunctional descending pain inhibitory system (DPIS).

      Methods

      In a double-blind trial, individuals ≥ 60 years with KOA pain and a dysfunctional DPIS, we randomly assigned patients to receive 15 daily sessions of 2 mA tDCS over the primary motor cortex (anode) and contralateral supraorbital area (cathode) (M1-SO) for 20 min or sham tDCS. Change in pain perception indexed by the Brief Pain Inventory (BPI) at the end of intervention was the primary outcome. Secondary outcomes included: disability, quantitative sensory testing, pain pressure threshold and conditioned pain modulation (CPM). Subjects were followed-up for 2 months.

      Results

      Of the 104 enrolled subjects, with mean (SD) age of 73.9 (8.01) years and 88 (84.6%) female, 102 finished the trial. In the intention-to-treat analysis, the active tDCS group had a significantly greater reduction in BPI compared to the sham group (difference, 1.59; 95% CI, 0.95 to 2.23; P < 0.001; Cohen’s d, 0.58); and, also a significantly greater improvement in CPM-pressure in the knee (P = 0.01) and CPM-pain in the hand (P = 0.01). These effects were not sustained at follow-up. The intervention was well tolerated, with no severe adverse effects.

      Conclusion

      M1-SO tDCS is associated with a moderate effect size in reducing pain in elderly patients with KOA after 15 daily sessions of stimulation. This intervention has also shown to modulate the DPIS.

      Keywords

      Abbreviations:

      tDCS (transcranial direct current stimulation), KOA (knee osteoarthritis), DPIS (descending pain inhibitory system), DNIC (diffuse noxious inhibitory control), M1 (primary motor cortex), BPI (Brief Pain Inventory), PPT (pain pressure threshold), CPM (conditioned pain modulation), HRQol (health-related quality of life), NRS (numeric rating scale), SO (supraorbital), VAS (visual analogue scale), WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index), TUGT (timed up and go test)

      Introduction

      Knee osteoarthritis (KOA) is a leading source of chronic pain and disability in the elderly population [
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      ]. Previously, endogenous pain modulation has been shown to be reduced in the elderly, potentially increasing the risk of chronic pain development in this population [
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      ]. Current evidence suggests that healthy adults experience a reduction of approximately 23% in pain intensity during the CPM test. However, only approximately 17% is observed in the elderly population [
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      Descending control of nociceptive processing in knee osteoarthritis is associated with intracortical disinhibition: an exploratory study.
      ].
      Because of the central sensitization mechanism, and also considering the high risk for serious side effects with current pharmacological treatments in the elderly, there is a growing interest in non-pharmacological interventions that modulate the central nervous pain processing system [
      • O’Neil C.K.
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      Adverse effects of analgesics commonly used by older adults with osteoarthritis: focus on non-opioid and opioid analgesics.
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      ]. Transcranial direct current stimulation (tDCS) is a promising neuromodulation technique that modifies cortical excitability applying weak electrical current over the scalp in a safe and painless manner [
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      ]. Additionally, cumulative tDCS use can induce long-term effects at the synaptic level, reverting maladaptive neuroplasticity [
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      ]. Safety and efficacy of tDCS depend on specific parameters, such as polarity, current intensity, duration, and electrodes arrangement [
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      ]. For pain, stimulation is mostly applied with the anode electrode over the primary motor cortex (M1) and the cathode electrode over the contralateral supraorbital area (SO) (M1-SO), promoting pain relief by the modulation of the pain neuromatrix. Computational modelling studies have been showed that the combination of both electrodes can induce electric current flow in cortical regions (e.g. M1, pre-frontal cortex and orbitofrontal cortices) and also in deeper structures (e.g. insula, cingulate cortex and thalamus). Thus, modulating thalamocortical synapses in a top-down manner, and also promoting modulation of the emotional dimension of pain, since M1-SO montage can also modify the cortical excitability in the anterior areas of the cerebral cortex [
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      ].
      tDCS has shown promise in treating several chronic pain conditions, such as fibromyalgia and neuropathic pain; however, less is known about its effectiveness on KOA pain, especially in the elderly population [
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      ]. To date, few studies with small sample sizes (30–60 participants) have investigated such analgesic effect, and with a not entirely elderly population (aged 50 years and over) [
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      Intramuscular electrical stimulus potentiates motor cortex modulation effects on pain and descending inhibitory systems in knee osteoarthritis: a randomized, factorial, sham-controlled study.
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      Efficacy of transcranial direct current stimulation over primary motor cortex (anode) and contralateral supraorbital area (cathode) on clinical pain severity and mobility performance in persons with knee osteoarthritis: an experimenter- and participant-blinded, randomized, sham-controlled pilot clinical study.
      ,
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      Efficacy of combining home-based transcranial direct current stimulation with mindfulness-based meditation for pain in older adults with knee osteoarthritis: a randomized controlled pilot study.
      ,
      • Chang W.J.
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      ,
      • Ahn H.
      • Suchting R.
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      • Miao H.
      • Green C.
      • Cho R.Y.
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      Bayesian analysis of the effect of transcranial direct current stimulation on experimental pain sensitivity in older adults with knee osteoarthritis: randomized sham-controlled pilot clinical study.
      ]. Chang et al. demonstrated that the combination of tDCS with quadriceps strengthening exercises was effective in improving pain and function in patients with KOA (n = 30, over 50 years old) [
      • Chang W.J.
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      Addition of transcranial direct current stimulation to quadriceps strengthening exercise in knee osteoarthritis: a pilot randomised controlled trial.
      ]. On the other hand, Ahn et al. reported that the use of tDCS alone was effective in reducing pain intensity indexed by a numeric rating scale (NRS) and for mobility performance only marginally improvements were present with no statistical significance (n = 40, 50–70 years old) [
      • Ahn H.
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      • Kunik M.E.
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      • Chen Z.
      • Choi E.
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      ]. Besides that, Ahn et al. showed that the analgesic effect of tDCS in KOA were associated with reductions in experimental pain (n = 40, 50–70 years old) [
      • Ahn H.
      • Suchting R.
      • Woods A.J.
      • Miao H.
      • Green C.
      • Cho R.Y.
      • et al.
      Bayesian analysis of the effect of transcranial direct current stimulation on experimental pain sensitivity in older adults with knee osteoarthritis: randomized sham-controlled pilot clinical study.
      ].
      Other two studies provided additional evidence on the additive effects on pain control and DPIS modulation, combining tDCS with intramuscular electrical stimulation (60 women, 50–75 years old) and with mindfulness-based meditation (n = 30, 50–85 years old) [
      • da Graca-Tarrago M.
      • Lech M.
      • Angoleri L.D.M.
      • Santos D.S.
      • Deitos A.
      • Brietzke A.P.
      • et al.
      Intramuscular electrical stimulus potentiates motor cortex modulation effects on pain and descending inhibitory systems in knee osteoarthritis: a randomized, factorial, sham-controlled study.
      ,
      • Ahn H.
      • Zhong C.
      • Miao H.
      • Chaoul A.
      • Park L.
      • Yen I.H.
      • et al.
      Efficacy of combining home-based transcranial direct current stimulation with mindfulness-based meditation for pain in older adults with knee osteoarthritis: a randomized controlled pilot study.
      ]. Moreover, Suchting et al. showed a potential effect of tDCS in reducing inflammatory levels in KOA patients (n = 40, 50–70 years old) [
      • Suchting R.
      • Colpo G.D.
      • Rocha N.P.
      • Ahn H.
      The effect of transcranial direct current stimulation on inflammation in older adults with knee osteoarthritis: a Bayesian residual change analysis.
      ]. Given the structural and functional differences of the aged brain, such as white and gray matter atrophy, enlarged cerebrospinal fluid space, and altered functional connectivity of brain networks, studies investigating the efficacy of tDCS specifically in the elderly population are required [
      • Dotson V.M.
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      ,
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      ].
      Thus, this study aimed to investigate whether tDCS would be effective in reducing self-reported pain intensity in elderly individuals with KOA. This effect was assessed in aged subjects with dysfunctional DPIS since previous evidence demonstrated an enhanced therapeutic response in this population [
      • Castillo-Saavedra L.
      • Gebodh N.
      • Bikson M.
      • Diaz-Cruz C.
      • Brandao R.
      • Coutinho L.
      • et al.
      Clinically effective treatment of fibromyalgia pain with high-definition transcranial direct current stimulation: phase II open-label dose optimization.
      ,
      • Reidler J.S.
      • Mendonca M.E.
      • Santana M.B.
      • Wang X.
      • Lenkinski R.
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      Effects of motor cortex modulation and descending inhibitory systems on pain thresholds in healthy subjects.
      ]. Also, as secondary outcomes, we examined its safety and its effect on health-related quality of life (HRQol), disease-specific symptoms, physical function, CPM, pressure pain threshold (PPT), and quantitative sensory testing.

      Material and methods

      Study design

      This randomized, assessor- and participant-blinded, controlled and parallel clinical trial (NCT03117231) was approved by the Human Research Ethics Committee of São Paulo Hospital (1685/2016) and conducted according to the Declaration of Helsinki. All participants provided written informed consent.

      Participants

      The volunteers were recruited between March 2018 and May 2019, from the São Paulo Hospital outpatient clinics and from general population by advertisements posted in the city of São Paulo, Brazil. Subjects aged 60 years and over, which is the definition for the elderly population in Brazil, with diagnosis of KOA, according to the American College of Rheumatology criteria [
      • Altman R.
      • Asch E.
      • Bloch D.
      • Bole G.
      • Borenstein D.
      • Brandt K.
      • et al.
      Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association.
      ], were considered eligible if they (1) had KOA pain in the past 6 months, rating in average 4 or more on a 0–10 NRS, (2) had a dysfunctional DPIS, defined by a reduction < 10% in the pain intensity during the CPM test, based on Tarragó et al. findings [
      • Tarrago Mda G.
      • Deitos A.
      • Brietzke A.P.
      • Vercelino R.
      • Torres I.L.
      • Fregni F.
      • et al.
      Descending control of nociceptive processing in knee osteoarthritis is associated with intracortical disinhibition: an exploratory study.
      ].
      A detailed description of the exclusion criteria was reported previously [
      • Tavares D.R.B.
      • Okazaki J.E.F.
      • Rocha A.P.
      • Santana M.V.A.
      • Pinto A.
      • Civile V.T.
      • et al.
      Effects of transcranial direct current stimulation on knee osteoarthritis pain in elderly subjects with defective endogenous pain-inhibitory systems: protocol for a randomized controlled trial.
      ]. Briefly, the following were the exclusion criteria: contraindications to tDCS [
      • Antal A.
      • Alekseichuk I.
      • Bikson M.
      • Brockmoller J.
      • Brunoni A.R.
      • Chen R.
      • et al.
      Low intensity transcranial electric stimulation: safety, ethical, legal regulatory and application guidelines.
      ], acute or chronic uncompensated disease, cognitive impairment, severe depression, history of epilepsy or syncope, traumatic brain injury with residual neurological deficits, recent use of carbamazepine [
      • Nitsche M.A.
      • Fricke K.
      • Henschke U.
      • Schlitterlau A.
      • Liebetanz D.
      • Lang N.
      • et al.
      Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans.
      ], and alcohol abuse. Subjects were allowed to maintain their usual medications; however, they were guided to do not change the current prescription.

      Randomization

      An investigator who was not involved in the study procedures generated a computer-based blocked (blocks of 4 and 6) and stratified randomization list. The stratification was based on the pain intensity, thus generating stratum A (<7 on NRS pain score) and B (≥7 on NRS pain score). Participants were randomized with a ratio of 1:1 to one of the two study arms: active transcranial direct current stimulation or sham transcranial direct current stimulation. The allocation sequence was concealed in consecutively numbered, sealed opaque envelopes.

      Blinding

      Participants and outcome raters were blinded to group allocation. The researcher involved in tDCS delivering was not blinded. Additionally, to assess the success of participant blinding, at the end of the protocol, participants were asked, "Did you find out which group you were allocated to?", and if not, they were asked “Do you believe you received the real or sham stimulation?”.

      Intervention

      Participants received 15 daily sessions (Monday to Friday) of sham or active stimulation [
      • Castillo-Saavedra L.
      • Gebodh N.
      • Bikson M.
      • Diaz-Cruz C.
      • Brandao R.
      • Coutinho L.
      • et al.
      Clinically effective treatment of fibromyalgia pain with high-definition transcranial direct current stimulation: phase II open-label dose optimization.
      ]. tDCS (Soterix 1 x 1 Low-Intensity Stimulator) was delivered for 20 min per session using two 35 cm2 surface sponge electrodes (EASYpad™ Soterix Medical Inc.) soaked with physiologic saline. We used the sufficient amount of saline solution (about 10 ml) to provide a good contact under the electrode area, avoiding over-saturated sponges to do not alter the distribution of current delivery. The current intensity was set at 2 mA, and it was gradually ramped up (to 2 mA) and down (to 0 mA) during 30 s at the beginning and end of the stimulation, respectively. The anode was placed over M1 (C3/C4 according to the 10–20 electroencephalogram system) contralateral to the most affected knee and the cathode over the SO contralateral to the anode (M1-SO).
      For sham tDCS, electrodes location was identical as for active tDCS, however only included the 30s of each ramp-up/down periods, mimicking stimulation sensations of active tDCS [
      • Gandiga P.C.
      • Hummel F.C.
      • Cohen L.G.
      Transcranial DC stimulation (tDCS): a tool for double-blind sham-controlled clinical studies in brain stimulation.
      ]. Throughout the study, tDCS was administered by the same physician who was appropriately trained in this modality of intervention. Participants were scheduled to receive stimulation in the same period of the day (morning).

      Outcome measurements

      Screening and baseline assessments (visit 1) were collected one week prior to the beginning of treatment, and X-rays were made and classified according to Kellgren-Lawrence 0–4 grading scale [
      • Kellgren J.H.
      • Lawrence J.S.
      Radiological assessment of osteo-arthrosis.
      ]. Right before starting the treatment (visit 2), pain intensity, physical tests, quantitative sensory testing, PPT, and CPM were reassessed and considered as its baseline data in order to use a more accurate pre-treatment data. Secondary outcomes that involve questionnaires were not reassessed, as they are not expected to change in one week. All outcomes were assessed on visit 6 (after 5 sessions), visit 11 (after 10 sessions), visit 16 (at treatment end), visit 17 (15 days after end of treatment), visit 18 (1 month after end of treatment) and visit 19 (2 months after end of treatment). The primary outcome was the change on pain intensity from visit 2 to visit 16, assessed by the Brief Pain Inventory (BPI) pain items.
      A detailed description of the outcome assessments was reported in the protocol paper [
      • Tavares D.R.B.
      • Okazaki J.E.F.
      • Rocha A.P.
      • Santana M.V.A.
      • Pinto A.
      • Civile V.T.
      • et al.
      Effects of transcranial direct current stimulation on knee osteoarthritis pain in elderly subjects with defective endogenous pain-inhibitory systems: protocol for a randomized controlled trial.
      ]. Briefly, the following were included:
      Pain intensity (most painful knee) – indexed by the mean of the 4 items of BPI that measure pain intensity in the last 24 h using an NRS from 0 (“no pain”) to 10 (“the worst pain you can imagine”) [
      • Kapstad H.
      • Hanestad B.R.
      • Langeland N.
      • Rustoen T.
      • Stavem K.
      Cutpoints for mild, moderate and severe pain in patients with osteoarthritis of the hip or knee ready for joint replacement surgery.
      ]. Additionally, a 0–10 cm visual analogue scale (VAS) for pain over the past week was used as a secondary outcome.
      Health-related quality of life – assessed using the 12-Item Short Form Health Survey questionnaire. The physical component score and mental component score were calculated, with smaller scores indicating poorer quality of life [
      • Hungerer S.
      • Kiechle M.
      • von Ruden C.
      • Militz M.
      • Beitzel K.
      • Morgenstern M.
      Knee arthrodesis versus above-the-knee amputation after septic failure of revision total knee arthroplasty: comparison of functional outcome and complication rates.
      ].
      Disease-specific symptoms – OA-specific clinical symptoms were evaluated using two widely used questionnaires: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Lequesne Algofunctional Index [
      • Bellamy N.
      • Buchanan W.W.
      • Goldsmith C.H.
      • Campbell J.
      • Stitt L.W.
      Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee.
      ,
      • Faucher M.
      • Poiraudeau S.
      • Lefevre-Colau M.M.
      • Rannou F.
      • Fermanian J.
      • Revel M.
      Assessment of the test-retest reliability and construct validity of a modified Lequesne index in knee osteoarthritis.
      ].
      Physical functioning – two reliable physical tests were used: timed up and go test (TUGT) and one leg stance test [
      • Shumway-Cook A.
      • Brauer S.
      • Woollacott M.
      Predicting the probability for falls in community-dwelling older adults using the Timed up & Go Test.
      ,
      • Jonsson E.
      • Seiger A.
      • Hirschfeld H.
      One-leg stance in healthy young and elderly adults: a measure of postural steadiness?.
      ]. Both tests were performed twice, and the best time (in seconds) to complete the task was recorded. In the case of inability to complete the TUGT, the value of 71s was imputed, as suggested by Podsiadlo et al. [
      • Podsiadlo D.
      • Richardson S.
      The timed "Up & Go": a test of basic functional mobility for frail elderly persons.
      ]. In the one leg stance test, we determined a time limit of 30s to stop the test.
      In addition, the pain impact on functioning was assessed using the mean of the 7 BPI interference items, using a NRS from 0 (“no interference”) to 10 (“complete interference”) [
      • Kapstad H.
      • Hanestad B.R.
      • Langeland N.
      • Rustoen T.
      • Stavem K.
      Cutpoints for mild, moderate and severe pain in patients with osteoarthritis of the hip or knee ready for joint replacement surgery.
      ].
      Quantitative sensory testing – a kit with 20 Von Frey monofilaments (0.008 g–300 g) was used to detect mechanical detection threshold and mechanical pain threshold, and conducted as in Ref. [
      • Tavares D.R.B.
      • Okazaki J.E.F.
      • Rocha A.P.
      • Santana M.V.A.
      • Pinto A.
      • Civile V.T.
      • et al.
      Effects of transcranial direct current stimulation on knee osteoarthritis pain in elderly subjects with defective endogenous pain-inhibitory systems: protocol for a randomized controlled trial.
      ]. If the subject did not have a positive response in any step, the highest weighted fiber (300 g) was considered [
      • Komiyama O.
      • De Laat A.
      Tactile and pain thresholds in the intra- and extra-oral regions of symptom-free subjects.
      ,
      • Keizer D.
      • van Wijhe M.
      • Post W.J.
      • Wierda J.M.
      Quantifying allodynia in patients suffering from unilateral neuropathic pain using von frey monofilaments.
      ,
      • Walk D.
      • Sehgal N.
      • Moeller-Bertram T.
      • Edwards R.R.
      • Wasan A.
      • Wallace M.
      • et al.
      Quantitative sensory testing and mapping: a review of nonautomated quantitative methods for examination of the patient with neuropathic pain.
      ].
      Pain pressure threshold – a 1-cm2 rubber (Commander Echo Algometer, JTECH) probe was applied and the pressure (in Kg) at the first pain sensation was recorded. A mean score of 3 trials was calculated.
      Conditioned pain modulation – CPM procedure was conducted as described previously [
      • Tavares D.R.B.
      • Okazaki J.E.F.
      • Rocha A.P.
      • Santana M.V.A.
      • Pinto A.
      • Civile V.T.
      • et al.
      Effects of transcranial direct current stimulation on knee osteoarthritis pain in elderly subjects with defective endogenous pain-inhibitory systems: protocol for a randomized controlled trial.
      ]. CPM was measured as a percentage change in pain scores and PPT after CPM procedure, called CPM-pain and CPM-pressure, respectively. Both of them were calculated using the following equation: (post-CPM trial score − pre-CPM trial score/pre-CPM trial score) ∗ 100. It is expected, to indicate a functional pain inhibition after the conditioning stimulus, negative values for CPM-pain and positive values for CPM-pressure.
      Self-rated health – subjects were asked to rate their global health using VAS.
      Adverse effects – safety was assessed using a tDCS side effects questionnaire and also evaluating mood and cognition, as in Ref. [
      • Tavares D.R.B.
      • Okazaki J.E.F.
      • Rocha A.P.
      • Santana M.V.A.
      • Pinto A.
      • Civile V.T.
      • et al.
      Effects of transcranial direct current stimulation on knee osteoarthritis pain in elderly subjects with defective endogenous pain-inhibitory systems: protocol for a randomized controlled trial.
      ]. Mood and cognition were assessed on the same visits as the other outcomes. The side effects questionnaire was assessed after each visit, asking the participants to describe the presence of an adverse event (headache, neck pain, scalp pain, tingling, skin redness, skin burn, sleepiness, trouble concentrating, acute mood changes) and to rate its severity (mild, moderate and severe).

      Statistical analysis

      The sample size was estimated based on a minimal clinically important difference (20% reduction from the baseline) in the outcome of pain intensity [
      • Dworkin R.H.
      • Turk D.C.
      • Wyrwich K.W.
      • Beaton D.
      • Cleeland C.S.
      • Farrar J.T.
      • et al.
      Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations.
      ]. Considering an effect size of 0.59, a probability of error type I (alpha) of 0.05, and a probability of error type II (beta) of 0.2, a total sample size of 94 were required. To compensate for possible dropouts, 10% was added, totaling 104 subjects.
      All the outcomes were carried out using an intention-to-treat analysis, handling missing data with a regression-based single imputation method. The primary outcome was pain intensity changes, indexed by BPI pain items, between visit 2 and visit 16. A secondary analysis evaluated the changes on BPI pain intensity scores over stimulation sessions and follow-up visits, thus including visits 6, 11, 17, 18 and 19 in the analysis. The same analysis procedure was used for the secondary outcomes.
      Data distribution was assessed using histogram, Shapiro-Wilk test, and skewness/kurtosis evaluations. After that, except for the TUGT variable, the others were considered normally distributed. Baseline characteristics were reported by descriptive statistics and compared among groups using the unpaired t-test, Wilcoxon Rank Sum test, or Fisher’s exact test for continuous, ordinal and categorical variables, respectively.
      A mixed-model analysis of variance was conducted to assess the interaction between group of intervention and time. Therefore, the independent fixed variables were group (active tDCS or sham tDCS), time and group-time interactions. Similar models were conducted for each outcome as the dependent variable. Cohen’s d effect size was calculated for the primary outcome. For ordinal and non-normally distributed variables, differences between groups were investigated using Wilcoxon Rank Sum test. The frequency and severity of adverse effects between the groups was compared by chi-square test or Fisher’s exact test. The significance level was determined at 0.05.

      Results

      Of 298 subjects screened, 104 were enrolled and randomly allocated to one of the groups. A total of 51 participants were assigned to receive active tDCS (34 from stratum A and 17 from stratum B) and 53 to receive sham tDCS (35 from stratum A and 18 from stratum B). A total of 102 patients completed the study (two dropouts from the sham tDCS group for personal reasons). The study flow diagram is described in Fig. 1. Demographic and baseline characteristics were not significantly different between the groups (Table 1).
      Table 1Demographic and baseline characteristics.
      Active tDCSSham tDCS
      n = 51n = 53
      Age, years, mean (SD)74.78 (7.44)73.13 (8.51)
      Education, years, mean (SD)6.88 (5.48)7.15 (5.61)
      Female, n (%)42 (82.35)46 (86.79)
      Retired, n (%)44 (86.27)40 (75.47)
      Married, n (%)16 (31.37)19 (35.85)
      Self-declared white race, n (%)20 (39.22)23 (43.40)
      Right most affected knee, n (%)29 (56.86)28 (52.83)
      Radiological grade, n (%)
       KL I15 (30)11 (21.15)
       KL II15 (30)17 (32.69)
       KL III12 (24)18 (34.62)
       KL IV8 (16)6 (11.54)
       Unknown∗∗1 (0.02)1 (0.02)
      BPI pain, mean (SD)5.08 (1.49)4.60 (1.39)
      VAS pain, mean (SD)6.03 (1.52)6.11 (1.47)
      SF -12, mean (SD)
       Physical Component Summary (PCS)32.73 (8.53)32.92 (9.48)
       Mental Component Summary (MCS)48.89 (12.06)48.17 (10.10)
      WOMAC total score, mean (SD)48.20 (14.91)47.98 (16.29)
      Lequesne Index total score, mean (SD)13.76 (3.92)13.51 (3.34)
      BPI function interference, mean (SD)4.24 (2.03)4.02 (2.16)
      OLS, seconds, mean (SD)7.33 (8.81)8.77 (9.26)
      TUGT, seconds, median (IQR)15.65 (7.7)15 (7.66)
      VAS self-rated health, mean (SD)4.87 (2.50)4.46 (2.82)
      MMSE, mean (SD)24.88 (4.21)25.08 (3.77)
      BDI, mean (SD)12.25 (6.79)13.72 (6.37)
      Von-frey MDT, light touch, median (IQR)
       Knee0.6 (0.84)0.6 (1.24)
       Hand0.16 (0.33)0.16 (0.53)
      Von-frey MDT, pinprick, median (IQR)
       Knee4 (8)4 (8.6)
       Hand10 (58.6)4 (14)
      Von-frey MPT, hand, median (IQR)
       Knee26 (92)15 (92)
       Hand100 (274)60 (285)
      Von-frey NRS, mean (SD)
       Knee2.88 (2.04)2.90 (2.04)
       Hand1.83 (1.69)2.25 (1.77)
      PPT, mean (SD)
       Knee1.84 (1.12)2.13 (1.40)
       Hand2.45 (1.26)2.74 (1.47)
      CPM PPT, mean (SD)
       Knee32.68 (37.58)24.67 (28.59)
       Hand13.27 (29.27)14.91 (16.03)
      CPM P, mean (SD)
       Knee2.70 (11.69)4.12 (13.35)
       Hand3.12 (20.11)−4.73 (23.00)
      Abbreviations: KL: Kellgren-Lawrence; BPI: Brief Pain Inventory; VAS: Visual Analogue Scale; SF -12: 12-Item Short-Form Health Survey scale; WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index; OLS: One Leg Stance Test; TUGT: Timed Up and Go Test; MMSE: Mini-Mental State Examination; BDI: Beck Depression Inventory; MDT: Mechanical Detection Threshold; MPT: Mechanical Pain Threshold; NRS: Numeric Rating Scale; PPT: Pain Pressure Threshold; CPM: Conditioned Pain Modulation; IQR: Interquartile Range; SD: Standard Deviation.
      ∗∗Not classified due to the presence of bilateral knee prosthesis.

      Primary outcome

      Mixed-model analysis of variance revealed a significant time X group interaction (F = 24.33, P < 0.0001) between visits 2 (baseline) and 16 (end of stimulation) for pain intensity indexed by BPI pain scores, showing that there is a difference over time depending on the treatment group. Active tDCS was superior to sham tDCS (BPI pain score change difference, 1.59; 95% CI, 0.95 to 2.23; P < 0.001) (Table 2). The Cohen’s d effect size of this difference was 0.58 (95% CI, 0.18 to 0.97). We also did a sensitive analysis using a regression model that evaluated the group differences at the end of treatment (delta BPI between visits 2 and 16) adjusting for the baseline measurements and found a reduction 1.5 times greater in the BPI scores of the active group compared to the sham group (Table 3).
      Table 2Changes in primary and secondary efficacy outcomes.
      OutcometDCS group, Mean (SD)Sham tDCS group - Active tDCS group
      Active (n = 51)Sham (n = 53)Difference in score (95% CI)P Value
      Primary Outcome
      Change in BPI pain score at visit 16−2.88 (0.21)−1.29 (0.24)1.59 (0.95–2.23)<0.001∗
      Secondary Outcomes
      Change in scores at visit 16 (end of intervention)
      VAS pain−3.27 (1.70)−2.18 (2.14)1.09 (0.34–1.85)<0.005∗
      PCS3.68 (9.52)2.63 (7.10)−1.05 (−4.31 to 2.21)0.52
      MCS4.48 (10.62)3.91 (8.63)−0.56 (−4.32 to 3.19)0.77
      WOMAC total score−11.43 (15.86)−10.70 (15.54)0.73 (−5.38 to 6.84)0.81
      Lequesne Index total score−1.90 (4.24)−1.85 (3.35)0.05 (−1.43 to 1.53)0.95
      BPI function interference−2.27 (2.01)−2.19 (2.43)0.08 (−0.79 to 0.95)0.86
      OLS, seconds0.82 (6.73)2.04 (6.34)1.22 (−1.33 to 3.76)0.34
      VAS self-rated health−1.81 (2.65)−1.29 (2.82)0.52 (−0.54 to 1.58)0.33
      Von-frey NRS (Knee)−0.71 (2.10)−0.62 (2.34)0.09 (−0.77 to 0.96)0.83
      Von-frey NRS (Hand)0.15 (1.90)−0.38 (2.19)−0.53 (−1.33 to 0.27)0.19
      PPT Knee0.49 (1.04)0.11 (1.50)−0.37 (−0.88 to 0.13)0.14
      PPT Hand0.05 (1.19)−0.08 (1.71)−0.13 (−0.70 to 0.45)0.66
      CPM PPT (Knee)10.18 (31.21)−7.43 (37.59)−17.61 (−31.08 to −4.15)0.01∗
      CPM PPT (Hand)−0.1 (33.95)−3.49 (26.73)−3.39 (−15.25 to 8.47)0.57
      CPM P (Knee)−7.08 (23.74)−6.17 (27.72)0.91 (−9.15 to 10.96)0.86
      CPM P (Hand)−5.7 (29.19)9.12 (27.53)14.82 (3.78–25.85)0.01∗
      Change in scores at visit 19 (end of follow-up)
      BPI pain−2.05 (1.84)−1.38 (2.04)0.67 (−0.08 to 1.43)0.08
      VAS pain−2.81 (2.50)−2.63 (2.30)0.18 (−0.76 to 1.11)0.70
      PCS3.37 (9.06)2.17 (8.51)−1.20 (−4.62 to 2.22)0.49
      MCS2.07 (10.18)4.79 (9.57)2.72 (−1.12 to 6.56)0.16
      WOMAC total score−12.65 (15.08)−10.87 (16.08)1.77 (−4.30 to 7.84)0.56
      Lequesne Index total score−2.45 (3.73)−1.44 (2.99)1.02 (−0.30 to 2.33)0.13
      BPI function interference−2.12 (2.34)−1.71 (2.40)0.41 (−0.51 to 1.34)0.38
      OLS, seconds2.13 (6.24)0.98 (5.24)−1.15 (−3.39 to 1.08)0.31
      VAS self-rated health−2.07 (2.45)−1.40 (3.02)0.67 (−0.40 to 1.74)0.22
      Von-frey NRS (Knee)−0.15 (2.17)−0.63 (2.40)−0.48 (−1.38 to 0.41)0.28
      Von-frey NRS (Hand)0.17 (2.08)−0.33 (2.05)−0.50 (−1.31 to 0.30)0.22
      PPT Knee−0.03 (1.13)−0.12 (1.36)−0.10 (−0.58 to 0.39)0.70
      PPT Hand−0.47 (1.19)−0.57 (1.55)−0.10 (−0.63 to 0.44)0.72
      CPM PPT (Knee)−6.07 (43.34)2.74 (39.45)8.81 (−7.30 to 24.92)0.28
      CPM PPT (Hand)10.30 (38.12)2.21 (36.67)−8.09 (−22.64 to 6.45)0.27
      CPM P (Knee)2.11 (33.07)−4.82 (23.64)−6.93 (−18.08 to 4.22)0.22
      CPM P (Hand)−1.87 (25.59)4.16 (30.11)6.03 (−4.86 to 16.92)0.27
      Abbreviations: tDCS: transcranial direct current stimulation; BPI: Brief Pain Inventory; VAS: Visual Analogue Scale; PCS: Physical Component Summary; MCS: Mental Component Summary; WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index; OLS: One Leg Stance Test; NRS: Numeric Rating Scale; PPT: Pain Pressure Threshold; CPM: Conditioned Pain Modulation; P: pain.
      Table 3Multiple regression analysis.
      Dependent VariableAdjusted R2F-valueP Value∗PredictorsBSE BP Value
      Delta BPI0.2215.51<0.0001Intercept−0.080.560.88
      BPI baseline−0.260.110.02
      Group−1.470.32<0.0001
      Abbreviations: BPI: Brief Pain Inventory.

      Secondary outcomes

      Effects on pain intensity were not sustained during the follow-up: active tDCS was not superior to placebo after 15 days, 1 month and 2 months after the end of intervention (difference in mean scores between visits 2 and 19, 0.67 points; 95% CI, −0.08 to 1.43; P = 0.08) (Table 2). An analysis of pain score changes over time, including the time points at 5 and 10 days of stimulation, showed a positive and significant effect of active tDCS compared to sham tDCS on pain intensity only after 15 sessions of stimulation (Table A.1) (Fig. 2).
      Fig. 2
      Fig. 2Change in BPI Pain Score across the visits.
      The mean reduction in the BPI pain scores in the active transcranial direct current stimulation (tDCS) and sham tDCS groups from baseline to visit 19. Active tDCS was superior to sham tDCS at visit 16 (end of stimulation sessions) (BPI pain score point difference, 1.11; 95% CI, 0.36 to 1.86; adjusted P = 0.03). Error bars represent standard error (SE).
      A similar effect was found for pain intensity indexed by VAS. There was a significant time x group interaction (F = 8.29, P = 0.005), between visits 2 and 16. Active tDCS was superior to sham tDCS (VAS pain score change difference, 1.09; 95% CI, 0.34 to 1.85; P = 0.005). This effect was also not maintained over the follow-up assessments (Table 2).
      We also found a significant time X group interaction for CPM-pressure measured in the knee (F = 6.73, P = 0.01) and for CPM-pain measured in the hand (F = 7.09, P = 0.01), between visits 2 and 16. Active tDCS was superior to sham tDCS on increasing CPM-pressure in the knee, thus leading to a higher pain threshold (difference in mean scores, −17.61 points; 95% CI, −31.08 to −4.15; P = 0.01). Additionally, active tDCS was superior to sham tDCS on decreasing CPM-pain in the hand (indicating CPM improved in the active tDCS group compared to sham tDCS), therefore leading to a smaller value of pain scores during CPM (difference in mean scores, 14.82 points; 95% CI, 3.78 to 25.85; P = 0.01) (Table 2). Effects on CPM-pressure in the knee and CPM-pain in the hand were not sustained over the follow-up (Table 2).
      No significant time x group interactions were observed for the others secondary outcomes, between visits 2 and 16 (end of stimulation), and also between visits 2 and 19 (end of follow-up). The data on the mean and standard deviations are listed in Table 2. For the ordinal and non-normal distributed variables, as the groups were similar in the baseline, we compared the scores between the groups at the end of treatment and at the end of follow up, using the Wilcoxon Rank Sum test, and no statistically significant differences between the groups in the TUGT and in the quantitative sensory testing were found. (Table 4).
      Table 4Ordinal and non-Normally distributed secondary outcomes at visits 16 and 19.
      OutcometDCS group, Median (IQR)
      Active (n = 51)Sham (n = 53)zP Value
      At visit 16 (end of intervention)
      TUGT, seconds14.44 (8.33)13.40 (6.48)−0.760.44
      Von-frey MDT, light touch (Knee)0.40 (0.53)0.58 (0.84)1.180.24
      Von-frey MDT, light touch (Hand)0.16 (0.33)0.16 (0.33)−0.030.98
      Von-frey MDT, pinprick (Knee)4 (7)4 (6)0.550.58
      Von-frey MDT, pinprick (Hand)4 (14)4 (6.6)−0.320.75
      Von-frey MPT (Knee)60 (170)15 (172)−0.560.58
      Von-frey MPT (Hand)26 (172)60 (285)1.050.30
      At visit 19 (end of follow-up)
      TUGT, seconds13.64 (6.19)14.40 (6.32)0.090.92
      Von-frey MDT, light touch (Knee)0.4 (0.93)0.6 (0.84)0.700.48
      Von-frey MDT, light touch (Hand)0.40 (0.33)0.16 (0.33)−0.530.60
      Von-frey MDT, pinprick (Knee)4 (6.6)4 (4.6)−0.470.64
      Von-frey MDT, pinprick (Hand)4 (7)4 (6.6)0.120.91
      Von-frey MPT (Knee)15 (94)15 (79.57)−0.310.75
      Von-frey MPT (Hand)60 (290)60 (165)−0.440.66
      Abbreviations: TUGT: Timed Up and Go Test; MDT: Mechanical Detection Threshold; MPT: Mechanical Pain Threshold.

      Adverse effects and safety

      We observed no significant time x group interactions for cognition and mood assessments across the intervention and follow-up period. The data on the mean and standard deviations are listed in Table 5. The reporting of scalp pain and skin redness were significantly higher in the active tDCS group (P = 0.03 and P < 0.001, respectively). On the other hand, the reporting of headache and tingling were significantly higher in the sham tDCS group (P < 0.01 and P < 0.001, respectively). There were no significant differences in the others tDCS-related adverse effects between groups (Table 6). The majority of adverse events were classified as mild (Table A.2). No serious adverse effects that required specific treatment or hospitalization were reported.
      Table 5Changes in safety outcomes.
      OutcometDCS group, Mean (SD)Sham tDCS group - Active tDCS group
      Active (n = 51)Sham (n = 53)Difference in score (95% CI)P Value
      Change in score at visit 16 (end of intervention)
      MMSE2.73 (2.13)2.58 (2.54)−0.15 (−1.06 to 0.76)0.75
      VAMS Anxiety−2.47 (2.68)−2.15 (2.60)0.32 (−0.70 to 1.35)0.53
      VAMS Depression−1.71 (2.32)−0.94 (2.48)0.77 (−0.16 to 1.70)0.11
      VAMS Stress−1.59 (2.31)−0.90 (2.64)0.70 (−0.27 to 1.66)0.15
      VAMS Sleepiness−1.53 (3.00)−0.64 (2.83)0.90 (−0.23 to 2.03)0.12
      Change in score at visit 19 (end of follow-up)
      MMSE2.63 (2.16)1.79 (2.55)−0.84 (−1.76 to 0.09)0.08
      VAS Anxiety−1.87 (2.70)−1.75 (2.81)0.12 (−0.96 to 1.19)0.83
      VAS Depression−1.27 (2.43)−0.83 (2.56)0.45 (−0.53 to 1.42)0.36
      VAS Stress−1.46 (2.44)−0.98 (2.80)0.48 (−0.54 to 1.50)0.35
      VAS Sleepiness−1.69 (3.06)−0.95 (2.90)0.73 (−0.43 to 1.89)0.21
      Abbreviations: MMSE: Mini-Mental State Examination; VAS: Visual Analogue Scale.
      Table 6tDCS-related adverse effects until the end of follow-up.
      Active tDCSSham tDCSP value
      n = 916n = 921
      Headache, N (%)93 (10.2)134 (14.5)<0.01
      Scalp pain, N (%)77 (8.4)53 (5.8)0.03
      Neck pain, N (%)79 (8.6)104 (11.3)0.06
      Tingling, N (%)246 (26.9)334 (36.3)<0.001
      Skin redness, N (%)267 (29.1)193 (21.0)<0.001
      Skin burn, N (%)00NA
      Sleepiness, N (%)280 (30.6)260 (28.2)0.27
      Acute mood changes, N (%)20 (2.2)15 (1.6)0.39
      Trouble concentrating, N (%)64 (7.0)56 (6.1)0.432
      N = number of tDCS-related adverse events; (%) = incidence of event (N/total visits).
      χ2 test.

      Blinding integrity

      Blinding was successful, participants were unable to guess the type of stimulation they have received during the protocol, since no participant reported knowing the allocated group. Besides that, when asked to guess the intervention group they believed they were allocated, 62 participants chose the active and 42 the sham group; only 25 in the active group (49%) and 16 (30%) in the sham group correctly guessed their group (χ2 = 1.41; P = 0.23). Moreover, there were significantly higher reporting of tingling sensations in the sham group when compared with the active tDCS group (Table 6 and Table A.2). This result increases the evidence of our sham method efficacy in simulate the sensations generated by the active stimulation; together with the fact that all participants remained blind until the end of the study.

      Discussion

      Our findings provide evidence that 15 sessions of M1-SO tDCS reduce pain scores in elderly subjects (mean age 73.9 ± 8.01 years) with KOA. Also, we observed greater improvements in the DPIS during the CPM task in the active tDCS group compared to sham group. These beneficial effects on clinical and experimental pain were not sustained during the follow-up. Additionally, the treatment was safe and tolerable, with no serious adverse effects being reported during the study.
      Our results suggested that the tDCS effectiveness on pain relief in the elderly is related to the number of sessions, as we only saw significant effects after 15 daily tDCS sessions, even thought there was a pain reduction after 5 and 10 sessions, there was not a statistically significant difference when compared with the sham stimulation. Our decision to perform 15 sessions of the intervention was based on a previous study from our group, which showed that 15 sessions of tDCS is the median number of sessions required to generate a clinically significant benefit of at least 50% pain reduction in fibromyalgia patients [
      • Castillo-Saavedra L.
      • Gebodh N.
      • Bikson M.
      • Diaz-Cruz C.
      • Brandao R.
      • Coutinho L.
      • et al.
      Clinically effective treatment of fibromyalgia pain with high-definition transcranial direct current stimulation: phase II open-label dose optimization.
      ]. To date, the majority of tDCS protocols on chronic pain used 5 to 10 daily stimulation sessions, some of them associated with pain relief as shown by Ahn et al. [
      • Ahn H.
      • Woods A.J.
      • Kunik M.E.
      • Bhattacharjee A.
      • Chen Z.
      • Choi E.
      • et al.
      Efficacy of transcranial direct current stimulation over primary motor cortex (anode) and contralateral supraorbital area (cathode) on clinical pain severity and mobility performance in persons with knee osteoarthritis: an experimenter- and participant-blinded, randomized, sham-controlled pilot clinical study.
      ], however negative results were also found. For instance, Wrigley et al. showed no positive effects on chronic neuropathic pain due to spinal cord injury after 5 sessions of M1-SO tDCS [
      • Wrigley P.J.
      • Gustin S.M.
      • McIndoe L.N.
      • Chakiath R.J.
      • Henderson L.A.
      • Siddall P.J.
      Long standing neuropathic pain following spinal cord injury is refractory to transcranial direct current stimulation: a randomized controlled trial.
      ]. Recent findings suggest that increasing the number of sessions would improve the tDCS magnitude of effect [
      • Pinto C.B.
      • Teixeira C.B.
      • Duarte D.
      • Fregni F.
      Transcranial direct current stimulation as a therapeutic tool for chronic pain.
      ].
      We found a reduction of 56.7% on pain perception, indexed by BPI, after 15 sessions of active tDCS against a reduction of 28% after sham tDCS, resulting in moderate effect size. A similar effect size (pooled standardized mean difference = 0.59) was found in a meta-analysis that included 6 clinical trials evaluating the effect of M1-SO tDCS on fibromyalgia pain [
      • Zhu C.
      • Yu B.
      • Zhang W.
      • Chen W.
      • Qi Q.
      • Miao Y.
      Effectiveness and safety of transcranial direct current stimulation in fibromyalgia: a systematic review and meta-analysis.
      ]. Ahn et al. found an effect size even greater (d = 0.89) for the reduction of NRS KOA pain in the active M1-SO tDCS group compared to the sham tDCS group [
      • Ahn H.
      • Woods A.J.
      • Kunik M.E.
      • Bhattacharjee A.
      • Chen Z.
      • Choi E.
      • et al.
      Efficacy of transcranial direct current stimulation over primary motor cortex (anode) and contralateral supraorbital area (cathode) on clinical pain severity and mobility performance in persons with knee osteoarthritis: an experimenter- and participant-blinded, randomized, sham-controlled pilot clinical study.
      ]. On the other hand, the effect size of non-steroidal anti-inflammatory drugs on KOA pain was estimated in 0.32 (95% CI, 0.24–0.39) [
      • Bjordal J.M.
      • Ljunggren A.E.
      • Klovning A.
      • Slørdal L.
      Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials.
      ]. We also evaluated pain intensity using VAS, and a similar positive effect was found in favor of the active tDCS stimulation.
      Nevertheless, the treatment did not produce lasting effects on pain reduction, which may be partially explained by the use of tDCS alone instead of combined with another therapy and also by the age of individuals. Therefore, 15 sessions of tDCS were capable of modulating the pain processing, however, for a short-term period, which raises the question of whether using a larger number of daily sessions or using intermittent sessions of stimulation after the 15 daily sessions would lead to long-term effects. There is a growing interesting in understand the optimal number of sessions to enhance duration of the after-effects and also to promote a clinically meaningful effect on pain [
      • Pinto C.B.
      • Teixeira C.B.
      • Duarte D.
      • Fregni F.
      Transcranial direct current stimulation as a therapeutic tool for chronic pain.
      ].
      It has been well established that the effectiveness of tDCS and its long-term effects in several chronic pain conditions is potentiated when combined with other therapies, such as aerobic exercises [
      • Choi Y.H.
      • Jung S.J.
      • Lee C.H.
      • Lee S.U.
      Additional effects of transcranial direct-current stimulation and trigger-point injection for treatment of myofascial pain syndrome: a pilot study with randomized, single-blinded trial.
      ,
      • Boggio P.S.
      • Amancio E.J.
      • Correa C.F.
      • Cecilio S.
      • Valasek C.
      • Bajwa Z.
      • et al.
      Transcranial DC stimulation coupled with TENS for the treatment of chronic pain: a preliminary study.
      ,
      • Hazime F.A.
      • Baptista A.F.
      • de Freitas D.G.
      • Monteiro R.L.
      • Maretto R.L.
      • Hasue R.H.
      • et al.
      Treating low back pain with combined cerebral and peripheral electrical stimulation: a randomized, double-blind, factorial clinical trial.
      ]. It has been hypothesized that tDCS modulates the DPIS in a top-down manner, thus combining another therapy that may act in a bottom-up manner may produce an additive effect, enhancing tDCS efficacy [
      • Schabrun S.M.
      • Jones E.
      • Elgueta Cancino E.L.
      • Hodges P.W.
      Targeting chronic recurrent low back pain from the top-down and the bottom-up: a combined transcranial direct current stimulation and peripheral electrical stimulation intervention.
      ]. Mendonça et al. assessed the analgesic effect of combining aerobic exercise with tDCS in fibromyalgia and showed that the combination of interventions was superior to each individual treatment [
      • Mendonca M.E.
      • Simis M.
      • Grecco L.C.
      • Battistella L.R.
      • Baptista A.F.
      • Fregni F.
      Transcranial direct current stimulation combined with aerobic exercise to optimize analgesic responses in fibromyalgia: a randomized placebo-controlled clinical trial.
      ]. Despite that, Ahn et al. were able to show significant sustained reductions in NRS-rated knee pain over a 3-weeks follow-up period, using 5 daily sessions of tDCS alone [
      • Ahn H.
      • Woods A.J.
      • Kunik M.E.
      • Bhattacharjee A.
      • Chen Z.
      • Choi E.
      • et al.
      Efficacy of transcranial direct current stimulation over primary motor cortex (anode) and contralateral supraorbital area (cathode) on clinical pain severity and mobility performance in persons with knee osteoarthritis: an experimenter- and participant-blinded, randomized, sham-controlled pilot clinical study.
      ]. To date, no other study assessing the effects of tDCS on KOA pain included a long-term follow up period.
      Few studies with small sample sizes have investigated the analgesic effect of tDCS in KOA patients [
      • Suchting R.
      • Colpo G.D.
      • Rocha N.P.
      • Ahn H.
      The effect of transcranial direct current stimulation on inflammation in older adults with knee osteoarthritis: a Bayesian residual change analysis.
      ,
      • da Graca-Tarrago M.
      • Lech M.
      • Angoleri L.D.M.
      • Santos D.S.
      • Deitos A.
      • Brietzke A.P.
      • et al.
      Intramuscular electrical stimulus potentiates motor cortex modulation effects on pain and descending inhibitory systems in knee osteoarthritis: a randomized, factorial, sham-controlled study.
      ,
      • Ahn H.
      • Woods A.J.
      • Kunik M.E.
      • Bhattacharjee A.
      • Chen Z.
      • Choi E.
      • et al.
      Efficacy of transcranial direct current stimulation over primary motor cortex (anode) and contralateral supraorbital area (cathode) on clinical pain severity and mobility performance in persons with knee osteoarthritis: an experimenter- and participant-blinded, randomized, sham-controlled pilot clinical study.
      ,
      • Ahn H.
      • Zhong C.
      • Miao H.
      • Chaoul A.
      • Park L.
      • Yen I.H.
      • et al.
      Efficacy of combining home-based transcranial direct current stimulation with mindfulness-based meditation for pain in older adults with knee osteoarthritis: a randomized controlled pilot study.
      ,
      • Chang W.J.
      • Bennell K.L.
      • Hodges P.W.
      • Hinman R.S.
      • Young C.L.
      • Buscemi V.
      • et al.
      Addition of transcranial direct current stimulation to quadriceps strengthening exercise in knee osteoarthritis: a pilot randomised controlled trial.
      ,
      • Ahn H.
      • Suchting R.
      • Woods A.J.
      • Miao H.
      • Green C.
      • Cho R.Y.
      • et al.
      Bayesian analysis of the effect of transcranial direct current stimulation on experimental pain sensitivity in older adults with knee osteoarthritis: randomized sham-controlled pilot clinical study.
      ]. The precise mechanisms underlying the effectiveness of M1-SO tDCS on reducing pain are not completely understood. Previous reports suggest that this montage may modify intracortical motor connectivity and thalamic activity, therefore modulating descending pain processing pathways [
      • Fregni F.
      • Pascual-Leone A.
      • Freedman S.D.
      Pain in chronic pancreatitis: a salutogenic mechanism or a maladaptive brain response?.
      ,
      • Peyron R.
      • Faillenot I.
      • Mertens P.
      • Laurent B.
      • Garcia-Larrea L.
      Motor cortex stimulation in neuropathic pain. Correlations between analgesic effect and hemodynamic changes in the brain. A PET study.
      ]. It is also possible that other cortico-cortical connections, including prefrontal circuits related to emotional modulation may play a role in the decrease of pain [
      • Costa B.
      • Ferreira I.
      • Trevizol A.
      • Thibaut A.
      • Fregni F.
      Emerging targets and uses of neuromodulation for pain.
      ].
      In the secondary-outcome analysis, we demonstrated the potential of tDCS on boosting DPIS function, improving CPM-pressure in the knee and CPM-pain in the hand. It suggests that tDCS is able to produce a systemic effect, since it altered CPM response in a remote area from the knee [
      • Ahn H.
      • Suchting R.
      • Woods A.J.
      • Miao H.
      • Green C.
      • Cho R.Y.
      • et al.
      Bayesian analysis of the effect of transcranial direct current stimulation on experimental pain sensitivity in older adults with knee osteoarthritis: randomized sham-controlled pilot clinical study.
      ]. However, the effect on CPM-pain in the hand should be interpreted with caution, since the active tDCS group had a more dysfunctional baseline CPM-pain in the hand, although without statistical difference as compared to the sham group. This CPM result is also aligned to results of previous studies, for instance, Reidler et al. showed that M1-SO tDCS enhances CPM efficiency as detected by pain threshold [
      • Reidler J.S.
      • Mendonca M.E.
      • Santana M.B.
      • Wang X.
      • Lenkinski R.
      • Motta A.F.
      • et al.
      Effects of motor cortex modulation and descending inhibitory systems on pain thresholds in healthy subjects.
      ].
      In the present study, active tDCS was not superior to sham tDCS on improving physical function, HRQol, self-rated health, PPT, CPM-pressure in the hand, CPM-pain in the knee, quantitative sensory testing, which can also be explained by the lack of a combined intervention and by the lack of enough power to the secondary outcomes. In fact, previously, M1-SO tDCS alone was effective in reducing pain, but not in improving physical function and WOMAC scores [
      • Ahn H.
      • Woods A.J.
      • Kunik M.E.
      • Bhattacharjee A.
      • Chen Z.
      • Choi E.
      • et al.
      Efficacy of transcranial direct current stimulation over primary motor cortex (anode) and contralateral supraorbital area (cathode) on clinical pain severity and mobility performance in persons with knee osteoarthritis: an experimenter- and participant-blinded, randomized, sham-controlled pilot clinical study.
      ]. In contrast, a recent trial reported that 10 sessions of tDCS combined with mindfulness-based meditation reduced disease-specific symptoms indexed by WOMAC and improved PPT and CPM in KOA subjects [
      • Ahn H.
      • Zhong C.
      • Miao H.
      • Chaoul A.
      • Park L.
      • Yen I.H.
      • et al.
      Efficacy of combining home-based transcranial direct current stimulation with mindfulness-based meditation for pain in older adults with knee osteoarthritis: a randomized controlled pilot study.
      ]. Also, in an elderly population, it is reasonable to suppose that their physical function and HRQol may be influenced by other aspects not related to pain, such as social aspects, multiple chronic diseases, and the aging-related loss of muscles.
      This study largely contributes to the feasibility of using tDCS to treat chronic pain conditions, such as KOA pain, in the elderly population. Indeed, given its safety profile, tDCS could be considered as an adjuvant treatment for elderly individuals with KOA pain, since traditional pharmacological therapies can lead to relevant adverse effects decreasing treatment compliance [
      • O’Neil C.K.
      • Hanlon J.T.
      • Marcum Z.A.
      Adverse effects of analgesics commonly used by older adults with osteoarthritis: focus on non-opioid and opioid analgesics.
      ]. To what extent age-related neuroanatomical and functional features (e.g. atrophy, skull thickness, declined brain plasticity) influence current flow remains poorly understood [
      • Raz N.
      • Lindenberger U.
      • Rodrigue K.M.
      • Kennedy K.M.
      • Head D.
      • Williamson A.
      • et al.
      Regional brain changes in aging healthy adults: general trends, individual differences and modifiers.
      ]. Thus, further studies with tDCS could investigate if increasing the current intensity, number of sessions and/or the addition of maintenance sessions following the daily 15 sessions (e.g. 2 days by week) would enhance tDCS effectiveness in the elderly.
      Another important aspect to take into account is that we only selected patients with dysfunctional DPIS, based on pain reduction in the CPM task. However, among the 139 excluded subjects, only 33 (23.7%) of them were excluded due to the CPM criteria. Therefore, it is reasonable that our cut-off for dysfunctional CPM was low, and in fact we can hypothesize that some individuals with functional DPIS were also included. This highlights the importance to further studies to determine the cut-off of CPM to be considered as dysfunctional, perhaps including not only the pain intensity but also the PPT in the criteria. Thus, a better cut-off may better select the individuals who would respond more to tDCS.
      This study has some limitations: (1) we only included elderly individuals, which is a limitation when generalizing our results; though it is also a strength as it shows the effects of tDCS in the elderly; (2) the investigator who performed the intervention was not blinded, however it does not seem to have influenced the results as patients and assessment evaluators were blinded; (3) we were not able to fully control possible changes in the participants’ medications; however, they were strongly instructed not to change them; (4) although we have measured different aspects of pain (pain perception, psychosocial factors, and aspects related to peripheral and central sensitization), we have not specifically assessed some pain features in a more detailed way (such as, the dimension of the local area involved by pain and, if it is permanent or only caused by the movement), as well we have not used screening instruments of central sensitization syndromes, such as the Central Sensitization Inventory. Therefore, future studies assessing these outcomes may obtain additional valuable insights on the relationship of these aspects with the physiology of pain control. Despite these limitations, this study has several strengths. First, the study was well powered to the primary outcome. In addition, the dropout rate was low, and the blinding effective. Finally, we stratified the randomization for pain intensity, ensuring similar groups in the main outcome.

      Conclusion

      M1-SO tDCS were effective and safe to reduce pain and to improve the DPIS function in elderly patients with KOA chronic pain, however, these effects were not sustained over the 2-months follow-up period. Further studies testing tDCS combined with other interventions in the KOA elderly population are needed to understand the full potential of tDCS. Also, different parameters of stimulation are needed to determine the optimal dose of tDCS for the elderly population.

      Funding

      This research was funded by the following Brazilian agency: “Fundação de Amparo à Pesquisa do Estado de São Paulo” (FAPESP ; process number 2017/09740-8) . However, this entity had no involvement in the design of the study; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

      CRediT authorship contribution statement

      Daniela Regina Brandão Tavares: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing – original draft. Jane Erika Frazao Okazaki: Data curation, Investigation, Conceptualization, Methodology, Writing – review & editing. Marcia Valéria de Andrade Santana: Data curation, Conceptualization, Investigation, Writing – review & editing. Ana Carolina Pereira Nunes Pinto: Data curation, Conceptualization, Investigation, Writing – review & editing. Karina Kuraoka Tutiya: Data curation, Investigation, Resources, Writing – review & editing. Fernanda Martins Gazoni: Data curation, Investigation, Resources, Writing – review & editing. Camila Bonin Pinto: Formal analysis, Writing – review & editing, Visualization. Fania Cristina Santos: Conceptualization, Resources, Supervision, Writing – review & editing. Felipe Fregni: Conceptualization, Methodology, Supervision, Project administration, Funding acquisition, Formal analysis, Writing – review & editing. Virginia Fernandes Moça Trevisani: Conceptualization, Methodology, Writing – review & editing, Project administration, Funding acquisition, Supervision.

      Declaration of competing interest

      None.

      Acknowledgments

      We would like to thank all the physicians and collaborators of the Geriatrics and Gerontology outpatient service in the Federal University of São Paulo.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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