Tired of living with painful arthritic knees, 54-year-old Deborah Brown’s interest was piqued when she saw a recruitment flyer for a clinical trial on an innovative pain treatment at The University of Texas Health Science Center at Houston (UTHealth).
“My knees feel like bone on bone,” said Brown, who works at a blood donation center. “It’s a shooting pain and it has been getting worse.”
That joint pain that Brown and other osteoarthritis patients experience has been traced to a part of the brain called the primary motor cortex.
Hyochol “Brian” Ahn, PhD, ANP-BC, the study’s principal investigator and an associate professor with Cizik School of Nursing at UTHealth, believes he can stop knee pain by administering tiny electrical charges to this area in the brain.
“This study has the potential to significantly improve the self-management of pain, decrease public health expenditures, and improve the quality of life for older adults,” said Ahn, the Theodore J. and Mary E. Trumble Professor in Aging Research at Cizik School of Nursing.
Ahn said the brain is an electrochemical organ that processes pain and that his team is trying to desensitize the areas tied to knee pain.
Study participants wear a cap powered with three AAA batteries that relays a weak current between a positive and negative electrode. There are 15, 20-minute sessions over a three-week period.
To see if the brain stimulation works, participants are asked to rate their pain on a scale of 1 to 100 before and after the treatment to complete a questionnaire.
Researchers will also review medical images of the brains of participants for possible changes.
Knee pain sufferer Deborah Brown is helping UTHealth’s Hyochol “Brian” Ahn, PhD, ANP-BC, and his colleague Lindsey Park evaluate an innovative pain relief treatment. Image is credited to Maricruz Kwon/UTHealth.
To establish the validity of the experiment, Ahn is creating a control group comprised of volunteers who do not receive enough brain stimulation to make a difference. “They’re our baseline and their scores will be compared to the people receiving full treatment,” Ahn said.
“Knee osteoarthritis pain is one of the most common pain conditions among people more than 45 years of age, and pharmacological interventions do not adequately address this common condition,” Ahn said.
The clinical trial, Self-Administered Transcranial Direct Current Stimulation for Pain in Older Adults With Knee Osteoarthritis: A Phase II Randomized Sham-Controlled Trial, runs through July 31, 2022, and is designed to test the efficacy of the device.
The study is funded by National Institutes of Health (R15NR018050) and Ahn hopes to recruit 120 volunteers.
To be eligible, volunteers must be 50 to 85 years of age, have no serious medical conditions (e.g., brain tumor, seizure, or stroke) and be able to attend four sessions in the Texas Medical Center. For more information, call 713-500-2179.
Said Brown, “I feel a little tingling when I wear the cap. I hope it works. I’m tired of the pain pills.”
The management of chronic pain syndromes is currently a challenging task, since only 40-60% of patients experience a favorable outcome from pharmacological treatments1. Several studies have shown that the majority of currently available treatments including antidepressants, opioids and topical anesthetics have limited long-term effectiveness and are often associated with moderate, or in some cases, severe adverse effects2.
One of the main reasons for the lack of efficacy is that current pharmacological approaches have limited or no effect on the mechanisms underlying chronic pain3–5. For instance, central sensitization is one of the main neural mechanisms associated with chronic pain. Opioid analgesics may increase, rather than decrease, central sensitization6.
Over the years, alternative therapies such as acupuncture, mirror therapy and thermotherapy, as well as different procedures (i.e. Botox injections) have been performed in an attempt to decrease pain levels. However, behavioral therapies have limited effects on brain plasticity and treatment effectiveness in chronic pain patients. In this context, recent alternative approaches such as neuromodulation techniques have been used not only to alleviate pain but also to revert maladaptive plasticity and may also be used to enhance the effects of behavioral therapies6.
Transcranial Direct Current Stimulation (tDCS) has significantly advanced in the past 15 years as a treatment tool7–9. TDCS has a theoretical advantage when compared with traditional chronic pain treatments since it directly affects central neural targets, thus having a potential stronger effect on central sensitization10. On the other hand, its effects may take longer to appear (i.e., only after 5-10 sessions, may subjects notice pain decrease)11.
The accepted neural mechanism of tDCS is the modulation of spontaneous neuronal firing: decrease or increase according to the polarity of stimulation that results in a change in neural excitability. Cathodal stimulation generally results in reduced excitability (“inhibition”) and anodal stimulation generally results in increased excitability of neurons in the area underneath the tDCS scalp electrodes12.
The final effect of tDCS depends on parameters of stimulation and also ongoing neural activity12. Although all the mechanisms and neural circuits involved with tDCS are not completely known, tDCS of the motor cortex contralateral to the site of pain has been suggested to activate inhibitory systems, thus reducing overactivation of thalamic nuclei2,13.
Several preliminary studies have demonstrated initial efficacy of tDCS for pain control7,8,14. The effects of tDCS on pain control are not limited to cortical structures only as its effects can be seen in the thalamus and also on descending pain control mechanisms15–17.
Due to its relatively low cost, ease of use and safety profile, tDCS may be a suitable alternative treatment for pain in different disorders18. However, as the field moves towards larger clinical trials, new questions arise regarding its effectiveness, safety, methodology and specifically optimal approaches. In this review, we will discuss the current knowledge of tDCS and possible mechanism to enhance its effects for the treatment of chronic pain.
tDCS CURRENT EVIDENCE
The efficacy of tDCS treating chronic pain, including neuropathic pain, has been investigated through multiple clinical trials in the past years8,9,11,19–28. In this manuscript, we have reviewed the meta-analyses published in the past 5 years through a PubMed (table 1) database search that estimated the effect sizes of tDCS treatment for pain. Table 1 presents summarized characteristics of the six included meta-analyses in chronic pain conditions, including the subgroups analysis of each one. We excluded two meta-analyses due to methodological discrepancies related to mean effect size calculation29,30. Only the comparison between active and sham groups was included in this analysis.
Meta-analysis of tDCS in chronic pain.
|Author/Date||Clinical Condition||Sample Size||Total Sample Size||Clinical Condition||Group 1||Group 2||Effect Size||P Value|
|Zhu et al.; 201733||Fibromyalgia||6 studies||168||pain intensity||Anodal tDCS over M1||sham tDCS||pooled SMD for pain was −0.59 (95% CI: −0.90 to −0.27)**||p = 0.0002|
|2 studies*||48||pain intensity||Cathodal tDCS over M1||sham tDCS||pooled SMD for pain was −0.17 (95% CI: −0.74 to 0.40)**||p > 0.05|
|2 studies*||48||pain intensity||Anodal tDCS over DLPFC||sham tDCS||pooled SMD for pain was −0.32 (95% CI: −0.89 to 0.26)**||p = 0.28.|
|Shirahige et al.;201634||Migraine||6 studies||130||pain intensity||active NIBS (TMS and tDCS; M1 and DLPFC)||sham NIBS||pooled SMD for pain was −0.61 (95% CI: −1.35 to 0.13)**||p = 0.11|
|3 studies||78||pain intensity||Cathodal tDCS over visual cortex and anodal tDCS over M1||sham tDCS||pooled SMD for pain was −0.91; (95% CI: −1.79 to −0.03)**||p = 0.04|
|Hou et al.; 201632||Fibromyalgia||16 studies||572||pain intensity||active NIBS (TMS and tDCS; M1 and DLPFC)||sham tDCS||pooled SMD for pain 0.66 (95% CI: 0.44 to 0.88)||p > 0.001|
|5 studies*||179||pain intensity||tDCS over M1 and DLPFC||sham tDCS||pooled SMD for pain 0.56 (95% CI: 0.26 to 0.87)||p > 0.001|
|Mehta et al.; 201521||SCI pain||5 studies||83||pain intensity||anodal tDCS over M1||sham tDCS||pooled SMD for pain 0.51 (95% CI: 0.11 to 0.90)||p=0.012|
|Boldt et al.;201431||SCI pain||2 studies||57||pain intensity||anodal tDCS over M1 area||sham tDCS||pooled SMD for pain −1.90 (95% CI: −3.48 to −0.33)||p = 0.018|
|O’Connell et al.;201428||Chronic Pain||10 studies||183||pain intensity||anodal tDCS over M1||sham tDCS||pooled SMD for pain −0.18, (95% CI −0.46 to 0.09)||p = 0.19|
tDCS: transcranial direct current stimulation; NIBS: non-invasive brain stimulation; TMS: transcranial magnetic stimulation; SMD: standardized mean difference; M1: primary motor area; DLPFC: dorsolateral prefrontal cortex; SO: supraorbital area; VMC: visual motor cortex; SCI: spinal cord injury; ABM: abdutor digiti minimi.*Subgroups analysis with different sample sizes in the same study (different tDCS montages).**The negative results favor active tDCS compared to sham for relieving pain.
p= p value; bold p values represents significant ones.
These meta-analyses included from 231 to 16 clinical trials32 with moderate sample sizes (up to 572 subjects included in the largest meta-analysis); however, for the majority of studies, the sample sizes were relatively small including around 50 subjects31,33.
Five meta-analyses presented statistically significant results, with the effect size ranging from 0.51 to 1.924,31–34. From these, only one study evaluated the effects of tDCS in overall chronic pain, showing a small effect size and no significant diference35.
Most of the studies estimated the effects of tDCS in specific chronic pain conditions such as fibromyalgia, migraine, low back pain and spinal cord injury pain. The majority of these meta-analyses have positive results24,31–34.
Another point to be considered is the large variability between the tDCS protocols, such as differences in electrode placement (M1 or DLPFC) and polarity of the stimulation (anodal or cathodal) that can contribute to the significant heterogeneity between the tDCS trials. Most of the tDCS studies used anodal stimulation over the primary motor cortex (M1 area:C3/C4 – International 10-20 system for the electroencephalography (EEG) electrode) of the hemisphere contralateral to the location of pain (Table 1).
Other montages have been tested including anodal/cathodal over the left dorsolateral pre-frontal cortex (DLPFC) for fibromyalgia and migraine33,34; and primary visual cortex (V1) for migraine36–38. In most of the studies, the cathode was placed over the contralateral supraorbital region.
The majority of clinical trials included in the meta-analyses used protocols with five and 10 consecutive 20-min tDCS sessions (mostly with an intensity of 2mA with an electrode size of 35 cm2). The analgesic after-effect has been demonstrated to be cumulative and last for 2-6 weeks8,19,39,40. Moreover, in the last 2 years, there was a clear trend towards increasing session duration and number of sessions (15 to 20) with a positive impact in pain improvement after the end of the treatment and in the follow up sessions11,23.
Even though positive results of tDCS on chronic pain have been shown in several studies, to date, clinical recommendation has only been given for two pain conditions: fibromyalgia [level B of evidence (probable efficacy)] and lower limb pain due to spinal cord injury [level C of evidence (possible efficacy)]23.
Therefore, the need for more clinical trials evaluating the effects of tDCS in chronic pain is evident. A better understanding of tDCS mechanism and the standardization of the main parameters are critical for achieving clinical meaningful effects on reducing pain levels. Besides that, so far most of the tDCS clinical trials are phase II studies which have typically small sample sizes and show small to moderate effects on pain levels. There is still a need for phase III pivotal clinical trials evaluating tDCS effects in a larger sample size; however, these studies should take into consideration all the parameters and different population aspects discussed here.
The Food and Drug Administration (FDA), Health Canada and other international agencies consider tDCS as a non-significant-risk therapy, meaning it is a technique without reasonable expectation of any Serious Adverse Effect9,18.
A recent review updated the evidence on the safety of tDCS based on the published serious adverse effects seen in human trials and brain damage seen in animal tests. There was no record of serious adverse effects related to repetitive tDCS across more than 32,000 sessions over 1000 subjects using a conventional tDCS protocol: 40 min, 4 milliamperes, 7.2 Coulombs.
In animal models, the finding of brain injury by direct current stimulation occurred at intensities over an order of magnitude above that used in conventional tDCS trials18. In addition, there have been hundreds of more subjects treated with tDCS that were not analyzed due to unpublished pilot research41.
Overall, tDCS is a safe technique with adequate tolerability and acceptability. Safety has been tested in several research centers and in different protocols42–45 which stated that the adverse effects experienced by subjects were mild and slowly disappeared after the tDCS session ended.
The latest systematic review published to date reinforced that the most common adverse effects are: mild tingling, burning sensation, itching, transient headaches and skin redness46. Recently, authors investigated whether adverse effects become more prevalent and dangerous with increased exposure to tDCS and a larger number of treated subjects.
For this analysis, 158 studies (total 4130 participants) were reviewed, taking into consideration tDCS exposure (cumulative charge), revealing that there was no evidence in regards of tDCS as a trigger of maladaptive plasticity or a negative influence for cognitive function18,47–50. Moreover, higher cumulative currents were not related to serious adverse effects; however, both erythema and paresthesia were more likely to occur in active conditions as compared to sham46.
These findings reinforce the notion that tDCS is overall safe and well tolerable in healthy subjects and patients with different conditions18,47–50. In the specific case of chronic pain, several sessions of tDCS have proven to be safe in fibromyalgia, spinal cord injury, low back pain and phantom limb pain (PLP)7,35,43,51,52.
Considering other diagnoses, this technique had no severe harm in epileptic subjects53,54, or in stroke patients regardless of those with large vessel occlusion55. Only transient adverse effects, such mild headache, have been reported. Nevertheless, additional monitoring is required when including these at-risk populations55.
Pre-existing implants such as metal in the head or neck (e.g., plates or pins) as well as any electronic medical devices in the head or neck (e.g., cochlear implants, vagus nerve stimulator) remain as exclusion criteria for most of clinical trials using tDCS. However, theory based on modeling and limited clinical experience does not show an increase in serious adverse effects in participants with pre-existing implants18.
Regarding special populations such as children, tDCS treatment for several conditions including: cerebral palsy, encephalitis, and epilepsy have been investigated with no report of serious adverse effects18. Nevertheless, there is relatively limited tDCS experience across pediatric populations compared to adults, and extra caution is required. On the other hand, in elderly populations, tDCS proved to be safe and there were no reports of severe adverse events in over 40 studies with more than 600 older adults with a variety of diagnoses18.
Notwithstanding, the safety of tDCS has been demonstrated primarily for short-term use. So far, to our knowledge, in chronic pain, Castillo-Saavedra et al. tested the longest protocol regimen with 30 consecutive sessions but with a small sample size11. This study also showed no evidence of moderate nor severe adverse effects. Further data collection is required to understand the effects of continued tDCS over longer periods56.
So far, the chronic use of tDCS did not lead to any serious adverse event and some examples to the literature can confirm it: a) a patient with schizophrenia that received two 30 minutes sessions daily over a 3-year period57; b) depressive patients that received multiple courses of tDCS (>100 sessions in total)58 and c) the longest acute treatment trial to date that delivered about six weeks of tDCS, with up to 30 sessions.59,60.
In summary, the increasing amount of literature on tDCS reinforces its safety and the unlikelihood of it causing serious adverse effects. However, it is important to keep investigating and collecting data on this matter in order to better understand tDCS effects over long term brain plasticity and the manipulation of physical properties of neural tissue.
This manuscript reviewed the main aspects of tDCS in chronic pain. TDCS has become a potential candidate for the treatment of chronic pain; however, there is a lack of confirmatory pivotal clinical trials and most pilot-feasibility trials show a small to moderate effect size reducing pain. Besides that, the results of these trials are heterogeneous due to large variability within protocols and parameters as well as between chronic pain subjects. Further work needs to be done to develop optimized protocols to increase its effects sizes. Recent literature describes the advantages of combining tDCS with behavioral therapies such as exercise and mirror therapy. This combination strategy offers a unique perspective combining a top-down strategy (tDCS) with a bottom up intervention (for instance, mirror therapy). The initial clinical trials testing combined interventions as compared to single interventions show positive results. Besides that, the clinical effects of tDCS in chronic pain varies significantly depending on the specific parameters of stimulation, including polarity, size and position of electrodes and number of sessions. In addition, specific population characteristics, such as presence or absence of neurophysiological markers can be a good strategy to enhance tDCS effects and identify better responders. Therefore, choosing optimum doses, patients and the best combination therapies is required to reach clinically significant results, especially in chronic pain. To date, it is still not possible to conclude whether tDCS is associated with a meaningful clinical effect for the treatment of chronic pain. Hence, further studies should explore these mechanisms and better define the optimal protocols to enhance tDCS’ effects.
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