Combining Transcranial Direct Current Stimulation With Non-Invasive Interventions for Chronic Primary Pain: A Systematic Review and Meta-Analysis

Abstract

Background

A growing number of studies has combined transcranial direct current stimulation (tDCS) with other non-invasive non-pharmacological therapies (NINPT) to enhance effects in pain reduction. However, the efficacy of these combined approaches in treating chronic primary pain (CPP) warrants thorough investigation.

Objective

This study aims to evaluate the efficacy of tDCS in conjunction with other NINPT in alleviating pain severity among CPP patients.

Methods

We conducted a systematic search for randomized controlled trials (RCTs) comparing the efficacy of tDCS combined with NINPT against control treatments in adult CPP patients. The search spanned multiple databases, including PubMed, EMBASE, LILACS, Scopus, Web of Science, and CENTRAL.

Results

Our systematic review included 11 RCTs with a total of 449 participants. In our meta-analysis, which comprised 228 participants receiving active-tDCS and 221 receiving sham-tDCS, we found a significant reduction in pain intensity (Standard Mean Difference = −0.73; 95% Confidence Interval (CI) = −1.18 to −0.27; P = .002) with the use of active-tDCS combined with NINPT.

Conclusion

These findings substantiate the therapeutic potential of combining tDCS with other NINPT, highlighting it as an effective treatment modality for reducing pain intensity in CPP patients.

Keywords

chronic pain tDCS pain management systematic review

Introduction

Chronic primary pain (CPP) is characterized by pain in 1 or more anatomical regions that persists or recurs for more than 3 months, as classified by the International Association for the Study of Pain and detailed in the eleventh edition of the International Classification of Diseases (ICD-11). This pain is notably accompanied by significant emotional distress or functional impairment and cannot be better attributed to another chronic pain condition.^1,2

Nociplastic pain, frequently observed in various forms of CPP, plays a significant role in numerous chronic pain syndromes.^3,4 This pain category arises from alterations in pain processing, predominantly due to central sensitization. Central sensitization amplifies neural signaling and modulates pain processing, leading to an altered perception of pain.⁵ This shift in pain modulation can be attributed to either an increase in excitability or a decrease in inhibition within specific neural pathways.⁶ Moreover, these changes involve epigenetic processes across various tissues, which adapt to these alterations in the nervous system.⁷

In CPP management, neuromodulation strategies has garnered attention,⁸ especially given the limited efficacy of pharmacological treatments in addressing nociplastic pain.³ Among these strategies, transcranial direct current stimulation (tDCS) stands out as a non-invasive neuromodulatory technique that delivers direct currents through electrodes placed on the scalp. tDCS is a viable option due to its portability, accessibility, and promising results in pain relief.^9-12 As a novel application, tDCS is used as a priming tool before the administration of another non-invasive non-pharmacological therapies (NINPT). This priming effect seems to enhance the therapeutic outcomes of subsequent NINPT.¹³ Along those lines, recent studies that have used tDCS in addition to other NINPT have shown improved individual benefits of NINPT, with encouraging results in pain reduction.^13,14-16 NINPT encompasses various interventions such as physical modalities, psychological interventions, complementary and alternative therapies, and other innovative techniques. In chronic pain conditions, NINPT modulates pain through peripheral, spinal, and supraspinal mechanisms. These mechanisms include the modulation of nociceptive signaling, facilitation of neuroplastic changes in pain pathways through processes like long-term potentiation or long-term depression, and the limitation of central sensitization underlying chronic pain.¹⁷

The current literature reveals a gap in systematic reviews with meta-analyses evaluating the clinical effects of combining tDCS with other types of NINPT in chronic pain conditions (CPP). To address this, we conducted a systematic review of randomized controlled trials investigating the combined use of tDCS and various NINPT modalities for alleviating pain in patients with CPP. We hypothesize that the synergistic effects of active tDCS and NINPT will enhance pain management effectiveness compared to sham tDCS.

Methods

This study was carried out in accordance with the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.^18,19 Furthermore, the study protocol was registered in the PROSPERO database under the protocol number CRD42023416391.

Eligibility Criteria

Types of Study

For this review, we included randomized clinical trials, published in English, that compared the efficacy of the tDCS combined with another NINPT. The control group consists of either the tDCS sham or the NINPT placebo. To ensure the rigor of our analysis, we excluded case studies and uncontrolled trials from our review.

Participants

This review focused on adult individuals diagnosed with any form of CPP (MG30.0) as defined in the ICD-11. Inclusion was specifically limited to the following subcategories:

Chronic widespread pain (MG30.01), including fibromyalgia syndrome;

Chronic primary musculoskeletal pain (MG30.02), encompassing conditions such as primary chronic low back pain, chronic primary neck pain, chronic primary chest pain, and primary chronic pain in the limbs;

Chronic primary headache or orofacial pain (MG30.03), which covers chronic primary orofacial pain and chronic pain from primary temporomandibular disorder;

Chronic migraine (8A80.2).

Exclusion criteria were set to omit trials involving participants with neuropathic pain, as well as studies focusing on children, adolescents, and animals.

Types of Interventions

Clinical trials offering any type of NINPT within the scope of behavioral and psychological therapy, as well as physical activity, physiotherapy, and acupuncture combined with tDCS, were eligible for inclusion. Only trials with interventions administered by qualified professionals at least once a week were included. Trials involving invasive interventions were excluded.

Types of Comparisons

Clinical trials comprising an active control group (either an active single intervention or standard treatment) and/or an inactive control group (no intervention, waitlist, or placebo-type intervention) were accepted.

Types of Outcome Measures

The primary outcome of our study was pain intensity. This was quantitatively assessed using continuous scales, including the Visual Analog Scale (VAS), which consists of a 100-mm line ranging from “no pain” to “the worst possible pain,” and the Numeric Rating Scale (NRS), an 11-point numeric scale where 0 represents “no pain” and 10 represents “the worst pain imaginable.”²⁰ Additionally, percentage improvements (eg, 50% pain reduction) and qualitative changes in pain state (eg, “mild pain”) were also considered as measures of pain severity.²¹

As for the secondary outcome, it focused on the quality of life, based on 2 instruments: (1) Fibromyalgia Impact Questionnaire (FIQ), which includes scores ranging from 0 to 100, with higher scores indicating negative impact on life quality,²² (2) Short-Form Health Survey Questionnaire (SF-36), which comprises 36 items across 9 subcategories, including functional capacity, physical role limitations, bodily pain, general health perception, vitality, social functioning, emotional role limitations, and mental health. In the SF-36, higher scores are indicative of a better quality of life.^23,24

Search Methods for Identification of Studies

Information Sources

Two independent researchers (DDAS and RELBA) conducted a systematic search in relevant electronic databases for medical and related health literature: PubMed, EMBASE, LILACS, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL). The literature search cutoff date was June 1, 2023.

Search Strategy

Medical Subject Heading terms and natural language terms were combined in the search strategy. The search terms included population, type of intervention, type of study, and outcomes. The following search terms were combined using the Population, Intervention, Control, and Outcomes strategy:

Population

chronic pain OR pain

Intervention

acupuncture OR cognitive therapy OR biofeedback OR mindfulness OR physical therapy OR manual therapy OR exercise AND neuromodulation OR tDCS OR transcranial direct current stimulation

Comparison

Sham-tDCS

Outcome

pain intensity OR quality of life OR adverse effects of tDCS OR patient-reported symptoms

The search was limited using filters for “humans” and “clinical trials.” The search strategy used in PubMed is presented in Table 1.

Table 1.

PubMed Search Strategy.

Search	Add to builder in advanced search	Query	Items found
#5	Add	Search: ((chronic pain[Title/Abstract] OR pain[Title/Abstract]) AND (acupuncture[Title/Abstract] OR cognitive therapy[Title/Abstract] OR biofeedback[Title/Abstract] OR mindfulness[Title/Abstract] OR physical therapy[Title/Abstract] OR manual therapy[Title/Abstract] OR exercise[Title/Abstract])) AND (neuromodulation[Title/Abstract] OR tDCS[Title/Abstract] OR transcranial direct current stimulation[Title/Abstract]) Filters: Clinical Trial	20
#4	Add	Search: ((chronic pain[Title/Abstract] OR pain[Title/Abstract]) AND (acupuncture[Title/Abstract] OR cognitive therapy[Title/Abstract] OR biofeedback[Title/Abstract] OR mindfulness[Title/Abstract] OR physical therapy[Title/Abstract] OR manual therapy[Title/Abstract] OR exercise[Title/Abstract])) AND (neuromodulation[Title/Abstract] OR tDCS[Title/Abstract] OR transcranial direct current stimulation[Title/Abstract])	182
#3	Add	Search: neuromodulation[Title/Abstract] OR tDCS[Title/Abstract] OR transcranial direct current stimulation[Title/Abstract]	18 771
#2	Add	Search: acupuncture[Title/Abstract] OR cognitive therapy[Title/Abstract] OR biofeedback[Title/Abstract] OR mindfulness[Title/Abstract] OR physical therapy[Title/Abstract] OR manual therapy[Title/Abstract] OR exercise[Title/Abstract]	392 363
#1	Add	Search: chronic pain[Title/Abstract] OR pain[Title/Abstract]	766 102

Study Selection Process and Data Extraction

First, 2 independent researchers (DDAS and RELBA) conducted a comprehensive search in the databases. Titles and abstracts were selected based on the predefined eligibility criteria. In the subsequent phase, full texts were evaluated, reapplying the eligibility criteria.

The inter-reviewer agreement on study eligibility showed strong concordance (Cohen’s kappa coefficient, k = 0.83; P < .001).²⁵ In cases of disagreement between the 2 primary reviewers, a third reviewer (JDSN) was consulted to reach a consensus.

Following the study selection, we used a standardized data extraction form for the chosen articles. This form captured crucial details such as author(s), publication year, study location, overall sample size, study population characteristics (including age range, diagnosis, and sex), outcome measures, definitions of intervention groups, and descriptions of the non-invasive intervention protocols. Additionally, we detailed the tDCS protocol, including time of application, stimulation site, parameters, number of sessions, and results (primary outcomes for pain intensity and secondary outcomes for quality of life, expressed as a function of the mean and standard deviation). Studies with incomplete descriptive outcome data were excluded from the meta-analysis.

Risks of Bias

Risk of bias assessment was independently conducted by 2 authors (RELBA and JDSN). Any disagreements were resolved through discussions among the reviewers. The assessment of bias was conducted using the Physiotherapy Evidence Database (PEDro) scale, which assigns methodological quality scores as follows: less than 4 (poor), 4 to 5 (fair), 6 to 8 (good), and 9 to 10 (excellent).²⁶

Summary Measures and Evaluation of the Quality of Evidence

The quality of evidence from studies included in the meta-analysis was analyzed, considering the risk of bias, results inconsistency, imprecision, and publication bias, with the final classification presented in 4 levels (high, moderate, low, and very low).²⁷ We followed the recommendations described in the “Grading of Recommendations, Assessment, Development, and Evaluation” (GRADE) available in the GRADEpro GDT software (https://gdt.gradepro.org).

Data Analysis

The meta-analysis was conducted using Review Manager software (v.5.4). We used the mean values, standard deviations, and sample sizes obtained for each group in the included studies. Measurements in centimeters were converted to millimeters. For the studies that reported results graphically, we used http://plotdigitizer.com to extract mean and standard deviation (SD) values. The SD for each intervention group was calculated from their confidence intervals using the formula: SD = √N × (upper limit − lower limit)/3.92. When standard error (SE) was reported, it was converted to SD using: SD = SE × √N. For the studies that exclusively reported the SD of the mean difference, we used the substitution method recommended in Chapter 6 of the Cochrane Handbook.¹⁸

To assess homogeneity, we employed the heterogeneity test. A P-value greater than .05 and an I² index up to 25% were considered indicative of homogeneity. In cases where heterogeneity exceeded 25%, we applied a random-effects model. Conversely, if the I² index was 25% or less, a fixed-effects model was used. We also conducted pre-specified subgroup analyses based on the timing of tDCS application (priming or additive).

For the meta-analysis, we compared the means from the VAS, NRS, and Verbal Numeric Scale (VNS) of 2 groups: those receiving active-tDCS with another NINPT and those receiving sham-tDCS with another NINPT, immediately post-intervention. A random-effects model and the Standardized Mean Difference (SMD) were used to assess effects on pain severity, with a 95% confidence interval (CI), following the guidelines in Chapter 10 of the Cochrane Handbook.¹⁸ For interpreting SMD, we referred to Cohen’s d values, considering an SMD of 0.2 to 0.3 as a “small” effect, around 0.5 as a “medium” effect, and 0.8 as a “large” effect.²⁸

Results

Identification and Selection of Studies

Figure 1 illustrates the flowchart of the study selection process for our meta-analysis. Initially, our search strategy yielded 1,343 articles. Upon removing duplicates, the number decreased to 1,099 articles. A detailed review of titles and abstracts led to the selection of 23 manuscripts for full-text evaluation. Out of these, 11 studies met our criteria and were included in the quantitative analysis. These studies, published between 2011 and 2022, involved a total of 449 subjects, with 228 receiving active-tDCS combined with other non-invasive interventions and 221 receiving sham-tDCS with another non-invasive intervention. We observed that most of the included studies applied the anode to the primary motor cortex (M1), with only 1 study choosing the dorsolateral prefrontal cortex (DLPFC) region. No crossover between these studies was identified. Detailed sample characteristics and baseline measures are outlined in Table 2. The protocol characteristics of the included studies are presents in Table 3 and summarized in Figure 2.

Figure 1.

Flowchart of literature search and selection process.

Table 2.

Characteristics of the Patients at the Baseline.

Study ID	Intervention place	Total sample size	Age range mean (SD)	Sex	Diagnostic criterion	Outcome	Sample size analyzed by group		Basal pain intensity active-tDCS group mean (SD)	Basal pain intensity sham-tDCS group mean (SD)
Study ID	Intervention place	Total sample size	Age range mean (SD)	Sex	Diagnostic criterion	Outcome	Active-tDCS	Sham-tDCS	Basal pain intensity active-tDCS group mean (SD)	Basal pain intensity sham-tDCS group mean (SD)
Arroyo-Fernández et al. 2022	Spain	120	50.29 ± 7.28	W: 113 M: 07	Fibromyalgia	VAS	40	40	59.90 ± 14.36	60.42 ± 14.32
Jafarzadeh et al. 2019	Iran	36	31.59 ± 10.08	W: 30 M: 06	non-specific chronic low back pain	VAS	12	12	5.87 ± 0.90	5.42 ± 0.62
Kim et al. 2022	Korea	25	76.9 ± 5.05	W: 16 M: 09	chronic musculoskeletal pain	VAS	13	12	5.92 ± 0.52	5.04 ± 0.54
Luedtke et al. 2015	Germany	135	44.5 ± 9.5	W: 63 M: 72	non-specific chronic low back pain	VAS	60	58	48 ± 21	48 ± 18
Matias et al. 2022	Brazil	31	49.18 ± 14.48	W: 31 M: 00	Fibromyalgia	VAS	17	14	5.52 ± 4.53	7.30 ± 3.00
Mendonca et al. 2016	Brazil	44	47.4 ± 12.1	W: 44 M: 00	Fibromyalgia	VNS	15	15	7.3 ± 1.75	6.8 ± 2.0
Oliveira et al. 2015	Brazil	32	24.65 ± 6.80	W: 29 M: 3	temporomandibular disorders	VAS	16	16	5.50 ± 1.36	6.30 ± 1.23
Ramasawmy et al, 2022	Germany	30	53.60 ± 1.73	W: 28 M: 02	Fibromyalgia	NRS	10	10	5.71 ± 1.66	5.65 ± 1.60
Riberto et al., 2011	Brazil	23	55.35 ± 11.90	W: 23 M: 00	Fibromyalgia	VAS	11	12	5.1 ± 2.3	5.2 ± 2.9
Sakrajai et al. 2014	Thailand	31	47.93 ± 9.24	W: 22 M: 09	chronic myofascial pain in the shoulder	NRS	16	15	4.22 ± 0.52	4.37 ± 0.48
Straudi et al. 2018	Italy	35	55.1 ± 12.50	W: 26 M: 09	non-specific chronic low back pain	VAS	18	17	55.7 ± 18.3	50.3 ± 24.4

Abbreviations: W, women; M, man; VAS, Visual Analog Scale; NRS, Numerical Rating Scale; VNS, Visual Numeric Scale.

Table 3.

Characteristics of the Studies.

tDCS priming
Study ID	Treatment received (all groups)	Protocol of the non-invasive non-pharmacological therapies associated	tDCS application time	tDCS parameters					Total time each session	Non-invasive non-pharmacological therapies sessions frequency	Total number sessions	Total duration of interventions
Study ID	Treatment received (all groups)		tDCS application time	Allocation	Intensity	Time	Total area	No. of tDCS sessions	Total time each session		Total number sessions	Total duration of interventions
Kim et al¹³	Group 1: Active tDCS + physical therapy Group 2: Sham tDCS + physical therapy	Physical Therapy (manual therapy, exercises, and use of physical agents, such as hot-packs, ultrasound, and interferential current therapy) on the pain site	tDCS priming (Before physical therapy)	Anode: F3 Cathode: F4	2 mA	30 min	36 cm²	24 alternated sessions	Not clear	3×/wk	24 sessions	8 wk
Luedtke et al²⁹	Group 1: Active tDCS + CBM Group 2: Sham tDCS + CBM	Cardiovascular exercises, machine assisted muscle strength training, specific muscle stabilization exercises for the trunk muscles, and work hardening sessions, as well as educational sessions on the neurophysiology of pain, pain coping strategies, and relaxation classes (CBM)	tDCS priming (Only tDCS for 5 sessions)	Anode: C3 Cathode: Fp2	2 mA	20 min	35 cm²	5 consecutive sessions (in the first week)	5 h	Consecutive days (4 wk)	33 sessions	5 wk
Matias et al³⁰	Group 1: Active tDCS + functional exercise Group 2: Sham tDCS + functional exercise	(1) warm-up on a bicycle or walking; (2) physical conditioning using neuromuscular (strength and localized muscular resistance and power) and neuromotor exercises (agility, coordination, and balance); (3) cool-down self-stretching. Participants performed 8-10 exercises per session (circuit model) in the physical conditioning phase.	tDCS priming (In the first week: 5 consecutive sessions of tDCS and 3 alternating days of exercise)	Anode: C3 Cathode: Fp2	2 mA	20 min	35 cm²	5 consecutive sessions (in the first week)	40 min	3×/wk (7 wk)	26 sessions	8 wk
Mendonca et al³¹	Group 1: Active tDCS + aerobic exercise Group 2: Sham tDCS + aerobic exercise Group 3: Active tDCS + placebo aerobic exercise	Aerobic exercise was performed on a treadmill. Placebo aerobic exercise consisted of subjects undergoing the training on the treadmill, but heart rate (HR) was maintained within 5% of the resting HR at the minimum speed on the treadmill.	tDCS priming (In the first week: 5 consecutive sessions of tDCS and 3 alternating days of exercise)	Anode: C3 Cathode: Fp2	2 mA	20 min	35 cm²	5 consecutive sessions (in the first week)	30 min	3×/wk (3 wk)	14 sessions	4 wk
Oliveira et al³²	Group 1: Active tDCS + exercises Group 2: Sham tDCS + exercises	myofascial technique in cervical region + active protocol (6 repetitions of each exercise): (i) cervical traction and self-stretching of the posterior muscles of the head and neck (ii) active mouth opening until the amplitude limit imposed by keeping the tip of the tongue in contact with the hard palate; (iii) lateral movement of the mandible with hyperboloid; (iv) protrusion of the mandible with bite action starting at the end of protraction returning to the overbite position with hyperboloid; (v) contraction of the masseter muscle; (vi) joint mobilization.	tDCS priming (In the first week: 5 consecutive sessions of tDCS after non-invasive intervention)	Anode: C3 Cathode: C4	2 mA	20 min	-	5 consecutive sessions (in the first week)	15 min	2×/wk (3 wk)	10 sessions	4 wk
Riberto et al³³	Group 1: Active tDCS + Rehabilitation Program for Pain Group 2: Sham tDCS + Rehabilitation Program for Pain	During the first hour: educative interventions or cognitive behavior group therapy focused in pain; orientations on posture and ergonomics by physical and occupational therapists and in behavioral modulation by psychologists and social workers. During second hour: cardiovascular and strengthening training or stretching exercises.	tDCS priming	Anode: C3 Cathode: Fp2	2 mA	20 min	35 cm²	10 sessions 1×/wk (10 wk)	120 min	3×/wk	10 sessions	4 mo
Sakrajai et al¹⁵	Group 1: Active tDCS + standard care Group 2: Sham tDCS + standard care	After the trigger points were identified, patients were taught active stretching exercises. Exercise program: slow-sustained stretching of the group of muscles throughout the available range of motion. Stretching stops at the point of pain, and then moves slowly and gently just a little further with the goal of decreasing muscle tightness. Patients were asked to perform daily stretching activities of both shoulder throughout the study period. Treatment also included ultrasound therapy for 5-10 min followed by the application of hot packs over the affected part for 20 min 3 times/week for 2 wk. All participants also received the instructions to assume and maintain good posture.	tDCS priming (In the first week: 5 consecutive sessions of tDCS and non-invasive intervention)	Anode: C3 or C4 (contralateral to the most painful shoulder) Cathode: Fp1 or Fp2 (contralateral to the anode electrode)	1 mA	20 min	35 cm²	5 consecutive sessions (in the first week)	-	3×/wk (2 wk)	11 sessions	3 wk
tDCS priming
Study ID	Treatment received (all groups)	Protocol of the non-invasive non-pharmacological therapies associated	tDCS application time	tDCS parameters					Total time each session	Non-invasive non-pharmacological therapies sessions frequency	Total number sessions	Total duration of interventions
Study ID	Treatment received (all groups)		tDCS application time	Allocation	Intensity	Time	Total area	No. of tDCS sessions	Total time each session		Total number sessions	Total duration of interventions
Straudi et al³⁴	Group 1: Active tDCS + exercise Group 2: Sham tDCS + exercise	In the first study moment: only 1 h of the explain pain neurophysiology and advised on posture at work with ergonomics information. The exercises applied until the end of the study were: Instructions of the patients on specific muscle stabilization and mobilization exercises for the trunk	tDCS priming (Only tDCS for 5 session)	Anode: C3 or C4 (pain central in the back or bilateral: anode was placed on the of the dominant hemisphere; pain irradiated to 1 side: anode contralateral of pain) Cathode: Fp1 or Fp2 (contralateral to the anode electrode)	2 mA	20 min	35 cm²	5 consecutive sessions (in the first week)	60 min	2-3×/wk	15 sessions	4 wk
tDCS additive
Study ID	Treatment received (all groups)	Protocol of the non-invasive non-pharmacological therapies associated	tDCS application time	tDCS parameters					Total time each session	Non-invasive non-pharmacological therapies sessions frequency	Total number sessions	Total duration of interventions
Study ID	Treatment received (all groups)		tDCS application time	Allocation	Intensity	Time	Total area	Nº tDCS sessions	Total time each session		Total number sessions	Total duration of interventions
Arroyo-Fernández et al³⁵	Group 1: Active tDCS + exercise Group 2: Sham tDCS + exercise Group 3: no intervention	Aerobic exercise (at the same time the tDCS) and muscle strengthening (after tDCS)	tDCS additive	Anode: C3 Cathode: Fp2	2 mA	20 min	25 cm²	5 alternated sessions	60 min	Alternate days	5 sessions	2 wk
Jafarzadeh et al³⁶	Group 1: Active tDCS + progressive postural training Group 2: Sham tDCS + progressive postural training Group 3: training only group	Progressive postural training on the Biodex Balance System (at the same time the tDCS)	tDCS additive	Anode: C3 Cathode: Fp2	2 mA	20 min	25 cm²	6 alternated sessions	20 min	3×/wk	6 sessions	2 wk
Ramasawmy et al³⁷	Group 1: Active tDCS + mindfulness meditation Group 2: Sham tDCS + mindfulness meditation Group 3: not receive any intervention	The participants meditated to a pre-recorded guided meditation audio. The meditation sessions during both training and stimulation weeks included a 5-min body scan meditation exercise (focus on the present-moment awareness of different sensations and feelings within various body parts, and all parts of the body) and a 20-min Mindfulness Meditation exercise (focused attention on the breathing). Additionally, a 5-min nature sound audio was played to relax the participants.	tDCS additive	Anode: C3 Cathode: Fp2	2 mA	20 min	Anode 16 cm² Cathode 50 cm²	10 consecutive sessions	25 min	Consecutive days	15 sessions	3 wk

Abbreviations: tDCS additive, non-invasive non-pharmacological therapies at the same time the tDCS; tDCS priming, tDCS applied before other non-invasive non-pharmacological therapies; C3, primary motor area on the left side; C4, primary motor area on the right side; Fp1, supraorbital region on the left side; Fp2, supraorbital region on the right side; F3, left dorsolateral frontal cortex; F4, right dorsolateral frontal cortex; CBM, Cognitive Behavioral Management.

Figure 2.

Hierarchical representation of the characteristics of the studies. The order of significance from inside to outside is the timing of tDCS application (additive or priming), followed by the sample’s diagnostic subcategory. The outermost layer is the study itself.

Risk of Bias

Table 4 details the risk of bias assessment for each included study. Within this assessment, only 1 study was identified as having reasonable methodological quality.³⁶ The rest of the studies were classified under higher quality categories, being categorized either as “good” or “excellent” in terms of their methodological rigor. This classification indicates a generally high standard of research quality across the majority of the studies included in the analysis.

Table 4.

Physiotherapy Evidence Database (PEDro) Scale Scores.

PEDro Scale	Arroyo-Fernández et al³⁵	Jafarzadeh et al³⁶	Kim et al¹³	Luedtke et al²⁹	Matias et al³⁰	Mendonca et al³¹	Oliveira et al³²	Ramasawmy et al³⁷	Riberto et al³³	Sakrajai et al¹⁵	Straudi et al³⁴
1. Eligibility criteria were specified (no points awarded)	No	No	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	No
2. Subjects were randomly allocated to groups	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
3. Allocation was concealed	Yes	No	No	Yes	Yes	Yes	Yes	No	No	No	Yes
4. The groups were similar at baseline regarding the most important prognostic indicators	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
5. There was blinding of all subjects	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
6. There was blinding of all therapists who administered the therapy	Yes	No	No	Yes	No	No	No	No	No	No	Yes
7. There was blinding of all assessors who measured at least 1 key outcome	Yes	Yes	No	No	Yes	Yes	Yes	No	Yes	No	Yes
8. Measures of at least 1 key outcome were obtained from more than 85% of the subjects initially allocated to groups	Yes	Yes	Yes	No	No	No	Yes	No	Yes	Yes	Yes
9. All subjects for whom outcome measures were available received the treatment or control condition as allocated or, where this was not the case, data for at least 1 key outcome was analyzed by “intention to treat”	Yes	No	No	Yes	No	Yes	Yes	No	Yes	Yes	Yes
10. The results of between-group statistical comparisons are reported for at least 1 key outcome	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
11. The study provides both point measures and measures of variability for at least 1 key outcome	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Total score	10	7	6	8	7	8	9	5	8	7	10

Pain Intensity

The analysis focused on the impact of combining tDCS with other types of NINPT on pain intensity. Results indicated a significant reduction in pain intensity, demonstrating a large effect size, when both interventions were actively used, irrespective of the tDCS application timing. The statistical outcomes were: Standard Mean Difference (SMD): −0.73; 95% Confidence Interval (CI): −1.18 to −0.27; Z-value = 3.12; P = .002; Tau² = .45; Chi² = 48.99 with a P = .001, and I² = 80% (as illustrated in Figure 3).

Figure 3.

Forest plot of comparison: active tDCS associated non-invasive non-pharmacological therapies versus sham tDCS associated non-invasive non-pharmacological therapies for intensity of pain.

Subgroup analyses based on the timing of tDCS application yielded further insights. When tDCS was applied prior to another NINPT (referred to as “tDCS priming”), there was a notable reduction in pain intensity, also with a large effect size. The relevant statistics were: SMD: −0.79; 95% CI: −1.42 to −0.15; Z = 2.44; P = .01; Tau² = .68; Chi² = 45.84 with a P = .001, and I² = 85%.

Additionally, when tDCS was applied simultaneously with another NINPT (termed “tDCS additive”), there was a significant reduction in pain intensity, but with a moderate effect size. The statistical results for this scenario were: SMD: −0.57; 95% CI: −1.06 to −0.08; Z = 2.28; P = .02; Tau² = .07; Chi² = 2.96 with a P = .23, and I² = 33% (refer to Figure 3 for details).

Quality of Life

Eight studies were reviewed to compare quality of life across various groups. Among these, 3 studies utilized the SF-36. However, the inconsistency in data presentation hindered a meta-analysis. Specifically, 2 studies provided the mean and standard deviation for the overall SF-36 score. Only the study by Mendonca et al³¹ detailed results for the recommended subcategories,³¹ as per guidelines.³⁸ In contrast, 2 other studies employed distinct questionnaires. Additionally, a meta-analysis was conducted on 3 studies that used the FIQ. This analysis revealed no significant impact of combining tDCS with other non-invasive interventions on quality of life. The statistical results were as follows: Standard Mean Difference (SMD): −1.17; 95% Confidence Interval (CI): −8.06 to 5.72; Z-value = 0.33; P = .74; Tau² = .001; Chi² = .82 with a P = .66, and I² = 0% (refer to Figure 4 for more details).

Figure 4.

Forest plot of comparison: active tDCS associated non-invasive non-pharmacological therapies versus sham tDCS associated non-invasive non-pharmacological therapies for quality of life.

Patient-Reported Symptoms and Adverse Effects of tDCS

Out of the 11 studies reviewed, only 6^{15,30,31,34,36,37} provided detailed accounts of the adverse effects observed in participants. The study by Jafarzadeh et al³⁶ found itching as a frequent side effect. They found that 20 minutes of active-tDCS applied over the primary motor cortex (M1) was generally well-tolerated, with only minimal adverse effects reported.³⁶ Matias et al³⁰ identified headache and tingling as the most common adverse effects in their study. In the research conducted by Mendonca et al,³¹ participants experienced skin redness, drowsiness, and mild headaches, with these symptoms present in both active and sham groups.³¹

The study by Ramasawmy et al³⁷ revealed that mild headache was a prevalent adverse effect, affecting 80% of participants in the active-tDCS group and 70% in the sham-tDCS group. This was followed by fatigue, reported by 70% of the active group and 50% of the sham group.³⁷ In Sakrajai et al,¹⁵ a transient erythematous rash without itching or pain under the anode was observed in 2 patients from the active group. This adverse reaction resolved on its own within an hour, and no other adverse events were noted in the intervention groups.¹⁵ Finally, the study by Straudi et al³⁴ reported that skin redness and tingling were the most commonly observed adverse effects in both treatment groups.³⁵

GRADE Analysis

Table 5 illustrates the evidence found in this review, providing the quality of this evidence considering 8 aspects suggested by GRADE. The quality of evidence was considered moderate for the effect of tDCS associated with another type of NINPT on pain intensity in CPP.

Table 5.

Active tDCS Associated With Non-Invasive Interventions Compared to Sham tDCS Associated Non-Invasive Interventions for CPP.

Certainty assessment							No. of participants		Effect		Certainty	Importance
No. of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	active tDCS + non-invasive non-pharmacological therapies	sham tDCS + non-invasive non-pharmacological therapies	Relative (95% CI)	Absolute (95% CI)	Certainty	Importance
Self-reported pain (severity; evaluated by: VAS/NRS/VNS)
11	Randomized trials	Not serius^a	Serious^b	Not serious^c	Not serious^d	None	228	221	—	SMD 0.73 SD lower (1.18 lower to 0.27 lower)	⨁⨁⨁◯ Moderate	CRITICAL

Abbreviations: CI, confidence interval; SMD, standardized mean difference.

Five studies did not adequately report allocation concealment. However, only Ramasawmy et al³⁷ achieved a bias risk considered reasonable according to the PEDro scale criteria. Therefore, most of the information comes from studies with a low risk of bias. It is unlikely that potential limitations will reduce confidence in the effect estimate. Final decision: not downgraded.

We observed significant heterogeneity among the studies (Tau² = .45; Chi² = 48.99; I² = 80%). Several factors may account for this observation: the inclusion of populations with diverse primary chronic pain diagnosis subcategories, variations in tDCS parameters, differences in the types of combined non-invasive non-pharmacological therapies, and disparities in the timing of tDCS application (priming or additive). However, there was no variation in the effect estimate, and the studies were consistent in their results, demonstrating a favorable effect of active-tDCS when associated with other non-invasive non-pharmacological therapies. Consequently, our final decision was to downgrade the rating by 1 level due to inconsistency.

The studies by Matias et al,³⁰ Mendonca et al,³¹ and Riberto et al³³ included only women, which may not fully represent the broader population experiencing primary chronic pain. Nonetheless, it is noteworthy that these studies focused on individuals diagnosed with fibromyalgia, a condition where females are more prevalent.^39,40 We observed a wide variation in the interventions conducted in the studies. However, the main objective of our study was to evaluate the summative effect of tDCS associated with other types of non-invasive non-pharmacological therapies. Only the study by Kim et al,¹³ allocated the anode to the region of the dorsolateral prefrontal cortex and, therefore, we do not consider it a serious implication on the quality of our findings. Final decision: not downgraded.

The sample size was 449 individuals (+ 200 per group). We consider the optimal information size acceptable. We observed a significant effect of active tDCS combined with other types of non-invasive non-pharmacological therapies in reducing the level of pain severity in patients with primary chronic pain (SMD: −0.73; 95% CI: −1.18 to 0.27; Z = 3.12; P = .002). Final decision: not downgraded.

Discussion

This study conducted a systematic review and meta-analysis to assess the effectiveness of the tDCS combined with another NINPT in reducing pain severity in patients with CPP. We hypothesized that patients with CPP receiving active-tDCS in conjunction with another NINPT would experience a more significant reduction in pain intensity than those receiving sham-tDCS with an NINPT. In total, 11 studies were carefully analyzed, encompassing a combined sample of 449 subjects.

Our meta-analysis revealed a notable reduction in pain intensity when active-tDCS was paired with other NINPT, whether applied as a priming or additive technique, in patients with various forms of CPP. This finding aligns with those of a prior systematic review focused on chronic pain patients, which demonstrated enhanced pain reduction in groups receiving combined tDCS and NINPT treatments compared to control or solo intervention groups.⁴¹ However, those earlier findings were not subjected to meta-analysis. Additionally, other existing systematic reviews have not fully explored the range of NINPT used in conjunction with tDCS, nor have they comprehensively addressed all subcategories of CPP.^9,10 They typically evaluated different types of diagnoses separately and included secondary chronic pain subcategories in some cases. Our study, therefore, provides a more inclusive examination of tDCS and NINPT protocols employed in the treatment of various CPP types.

Timing of tDCS Application in Chronic Pain

The present review indicates that active-tDCS, irrespective of its timing (priming or additive), significantly reduces pain intensity. Non-invasive and non-pharmacological interventions, targeting various mechanisms, can normalize pain processing and act on central sensitization, effectively reducing pain intensity in patients with nociplastic pain.^3,34 tDCS, particularly, modulates spontaneous neuronal activity leading to long-term neuroplastic changes.^41,41 The therapeutic outcomes were significantly enhanced when interventions focused on the ascending (bottom–up) pathway were integrated with those influencing the descending (top–down) pathway.^43,44

In our subgroup analysis, active-tDCS used as priming in combination with another NINPT significantly reduced pain intensity in various types of CPP. This could be attributed to tDCS priming protocols modulating cortical excitability, neural network connectivity, and synaptic input cooperation, influencing subsequent tDCS effects.^42,45 These changes suggest metaplastic interactions, where the brain’s state at 1 moment can influence future outcomes, with synaptic plasticity depending on timing, presynaptic synchronization, and postsynaptic activity levels.^43,46 This provides a unique opportunity for tDCS application at optimal times for synaptic activity modification.⁴⁶ The included studies showing superior pain reduction effects when tDCS priming is combined with physiotherapy for chronic musculoskeletal pain,¹³ aerobic exercises in fibromyalgia,³¹ manual therapy and exercises in temporomandibular disorders,³² and various treatments in chronic myofascial shoulder pain.¹⁵

However, some studies, like Matias et al³⁰ and Riberto et al,³³ observed no significant difference in pain reduction between groups with different tDCS applications, potentially influenced by factors like the tDCS repetition rate. Daily tDCS applications over a short period have shown cumulative effects on neuronal excitability.⁴⁷

The study also explored tDCS in conjunction with NINPT for non-specific chronic low back pain (CLBP). While standalone tDCS showed limited effects in CLBP patients,^48,49 combinations with other bottom-up NINPT, like Transcutaneous Electrical Nerve Stimulation, yielded positive responses.^50,51 However, results varied depending on the types of NINPT used, as seen in studies by Luedtke et al²⁹ and Straudi et al³⁴ suggesting the need for further research to identify optimal NINPT combinations with tDCS in CLBP treatment.

Regarding additive tDCS, used simultaneously with other interventions, a moderate effect was noted. This finding is supported by studies demonstrating pain intensity reduction in chronic pain patients when tDCS is combined with physiotherapy,⁵² exercises,⁴⁴ manual therapy,^53,54 cognitive-behavioral therapy,⁵⁵ mindfulness,³⁷ and biofeedback.⁵⁶

Our review highlights a gap in research regarding tDCS combined with various NINPT across different CPP diagnoses. Despite this, existing studies show good methodological quality and indicate that the association of active-tDCS with other NINPT has moderate evidence supporting its efficacy.

Locus of Stimulation for Chronic Pain

Among the studies reviewed, only the study by Kim et al¹³ employed tDCS targeting the dorsolateral prefrontal cortex (DLPFC). This limited representation makes it challenging to compare the efficacy of different tDCS protocols. The primary motor cortex (M1) and the prefrontal cortex, including the DLPFC, are frequently chosen targets in brain stimulation for chronic pain management.⁵⁷ There is emerging evidence suggesting that stimulation of the DLPFC region may effectively reduce pain severity in CPP.^58-60 Contrastingly, tDCS targeting the M1 region is more commonly used in CPP treatments,⁶¹ with studies indicating its short, medium, and long-term effects on pain intensity.⁶²

A recent study highlighted the superior effectiveness of tDCS when applied to the M1 region over the DLPFC in patients with fibromyalgia.⁶³ However, another robust study showed no superiority of tDCS effects when applied to the M1, DLPFC, or operculo-insular cortex compared to the placebo group.⁶⁴ Determining the optimal site for stimulation in chronic pain treatment remains an open question.⁶¹ This gap underscores the need for more research to directly compare the effects of stimulating between brain regions in individuals with chronic pain. Additionally, it is crucial to explore other types of NINPT that enhance the effects of tDCS.

Evidence of Intervention Associations in Quality of Life in CPP

In evaluating quality of life outcomes, we encountered notable inconsistencies in the presentation of SF-36 results, and only 3 studies^30,33,35 could be statistically analyzed. The limited sample size in our analysis may have affected our ability to detect a significant impact of tDCS, combined with other NINPT, on the quality of life in CPP patients. For instance, a clinical trial involving 130 fibromyalgia patients reported a nonspecific effect, possibly attributable to a placebo response. In this trial, active tDCS did not demonstrate superiority over sham stimulation in enhancing quality of life.⁶⁵ However, it’s worth noting that tDCS, when applied to either the M1 or DLPFC regions, has shown to improve short-term quality of life. Specifically, stimulation of the M1 region was found to have medium-term effects on quality of life in fibromyalgia patients.⁶²

Adverse Effects of tDCS

Our findings regarding adverse effects are consistent with previous studies.^66,67 We observed no severe adverse events linked to tDCS. The most common side effects were sensations of tingling, burning, and itching, with no significant difference in frequency between the active-tDCS and sham-tDCS groups.⁶⁷

Limitations and Perspectives

This systematic review and meta-analysis should be considered in light of certain limitations. Firstly, the subcategory of chronic primary visceral pain was not included due to diagnostic uncertainty based on the involved pathophysiological mechanisms.⁶⁸ Thus, we selected only CPP subcategories with well-established diagnostic criteria, ensuring more reliable results due to the similarity in the pathophysiological mechanisms of the chosen categories. Secondly, there was significant heterogeneity among the included studies, necessitating cautious interpretation of our results. This heterogeneity was anticipated, given the diverse types of NINPT assessed, in line with our objective to evaluate the impact of tDCS in conjunction with conventional CPP interventions. Another factor that may explain this heterogeneity could be the variability among tDCS protocols or the initial state of brain activation. Thirdly, our analysis was confined to the immediate effects post-intervention, omitting long-term outcomes. Future research should explore these long-term effects and also include an evaluation of other important outcomes, such as anxiety and depression. Finally, not including other types of non-invasive transcranial stimulation, such as transcranial magnetic stimulation, was another limitation of our study. We suggest that future studies include other types of non-invasive brain stimulation. Further, we recommend that subsequent studies strive to identify the most effective type of NINPT to be paired with tDCS for different CPP diagnoses.

Conclusion

Our study concludes that the combination of active-tDCS with other non-invasive interventions, regardless of application timing, is effective in reducing pain intensity in patients diagnosed with primary chronic pain, primarily when targeting the primary motor cortex. However, the impact of this combined approach on quality of life remains inconclusive.

Footnotes

Author Contributions

Renata Emanuela Lyra de Brito Aranha: Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Software; Validation; Writing—original draft; and Writing—review & editing. José Diego Sales do Nascimento: Conceptualization; Supervision; Validation; Visualization; and Writing—review & editing. Danielle Dorand Amorim Sampaio: Data curation; Investigation; and Resources. Nelson Torro-Alves: Supervision; Validation; and Writing—review & editing.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part by funding from Coordination for the Improvement of Higher Education Personnel—CAPES; Brazilian National Council for Scientific and Technological Development—CNPq (313414/2021-1, 404988/2021-0), and Grant 008/2019, Pronex, Paraíba State Research Foundation—FAPESQ.

ORCID iD

Renata Emanuela Lyra de Brito Aranha

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