Clinical Trial Demonstrates Efficacy of Transcranial Direct Current Stimulation (tDCS) in Improving Pain Management from Post-Laminectomy Syndrome ()
1. Introduction
Pain is defined as a multifaceted experience that affects not only sensory perception but also cognition and emotional well-being [1] . It exerts direct influences on quality of life whose individuals experiencing it [2] . According to International Association Study of Pain (IASP), chronic pain is characterized by continuous and recurrent symptoms persisting for a minimum of three months [3] [4] , often associated with central sensitization [5] . Post-laminectomy syndrome, also referred as surgical failure syndrome, which is defined as “low back spinal pain of undetermined origin persisting in the same location as original pain despite surgical interventions or developing after surgeries” [6] [7] . Several clinical presentations of post-laminectomy syndrome frequently overlap, with low back pain being the predominant manifestation [7] [8] . When it persists, it leads to significant physical disability, increased use of analgesics, and heightened utilization of emergency services [8] .
Also, disability resulting from chronic pain is a matter of great societal concern [9] , with physiological, emotional, behavioral, and socio-cultural factors significantly influencing the progression, severity, and persistence of pain. In this regard, chronic pain is considered multidimensional [3] [10] [11] .
Despite substantial advancements in pain management over recent decades, including pharmaceutical interventions and incorporation of patients into multidisciplinary therapies, chronic pain remains a formidable therapeutic challenge [2] . In this context, therapies directly modulating cortical activity, such as non-invasive brain stimulation, have gained increasing attention in treatments [2] [12] .
Some researches appointed the efficacy of Transcrananial Direct Current Stimulation (tDCS) in chronic pain treatment [1] [2] [9] [13] , such as the Pain Management Program at The Menninger Clinic in Houston, Texas. Eighty-four participants were randomized (1:1) into a single-blind, 2 × 12 (group × time) controlled trial. A battery-powered direct and constant current stimulator (Soterix Medical Inc. 2014) delivered anodal stimulation over the left dorsolateral prefrontal cortex (DLPFC) and cathodal stimulation over the right DLPFC. Active tDCS is applied by supplying a 2 mA current for 20 min/session over 10 sessions. This study proves the efficacy of a minimally invasive neuromodulation technique as an adjunctive treatment for chronic pain among individuals with significant psychiatric comorbidity. A meta-analyses [13] included from 2 to 16 clinical trials demonstrates positive and larger effects on pain relief, quality of life, depression and anxiety by combining tDCS with aerobic exercise or even in intervention alone.
Despite several studies involving tDCS in chronic pain, to our knowledge, there is limited literature supporting the potential benefits of adjunctive tDCS a in pain management in post-laminectomy syndrome patients. This study aims to provide that (tDCS) shall improve as a efficacy treatment in this cases. Furthermore, this technique’s low cost, ease of use, and high tolerability make it a promising adjuvant therapy for chronic pain conditions like post-laminectomy syndrome.
2. Methods
2.1. Design
This is a randomized, controlled, double-blind clinical trial. Approval for this study was granted by Research Ethics Committee of Faculdade de Medicina de São José do Rio Preto (FAMERP) under opinion number 1.291.038, in 2019.
Twenty-four individuals suffering from chronic pain due to post-laminectomy syndrome were enrolled in this study. Participants were recruited from Chronic Pain Clinic of Faculdade de Medicina de São José do Rio Preto and Centro Traumatológico Ortopédico de São José do Rio Preto. The patients completed a form for selection or exclusion, attached in Appendix 1. As a limitation of the study, a small sample size was chosen due to difficulties in patient transportation (most of them came from other cities) and their refusal to participate in the study due to worsened pain and discomfort during transportation. To standardize the study, the maximum number of patients that could be selected was divided into three groups with an equal number of individuals.
Transcranial direct current stimulation instrument used was TCT (Trans Cranial Technologies (TCT) Research Limited) (28). Participants were divided into three distinct groups. Group 1 underwent sham stimulation, while active stimulation was administered over primary motor cortex (M1) for Group 2 (M1) and dorsolateral prefrontal cortex (CDLPF) for Group 3.
Stimulation occurred over five consecutive days, with each session lasting 20 minutes, delivering a current of 1.5 mA via 25 cm2 electrodes. Electrodes soaked in a saline solution facilitated passage of electric current. Cathode electrode was positioned in extraball region, over deltoid muscle. Choice of hemisphere for stimulation was determined by lateralization of pain. For patients with asymmetric pain, contralateral hemisphere was stimulated, whereas for those with symmetric pain, right-handed patients received stimulation in left hemisphere, and left-handed patients received it in right hemisphere. Regarding sham stimulation, electrodes were placed in the same position as the anodic stimulation in M1. Sham stimulation consisted of a 30-second application followed by discontinuation. The 30-second ramp-up period allowed patients in control group to experience initial sensations of current passage, such as local discomfort and itching.
Each group comprised eight individuals. Randomization of patients involved pre-determining a specific type of stimulation in week. Thus, patients in each week received the same type of stimulation, considering possibility that these patients shared the same environment while awaiting treatment.
In the end of each session, patients were asked which type of stimulation they believed had received to evaluate blinding. Adverse events were also assessed through open-ended questions, with sleep quality also being evaluated.
Pain assessment employed by Brief Pain Inventory (33) (BPI) and Visual Analog Scale (VAS) Additionally, World Health Organization Brief Quality of Life Questionnaire (WHOQoL-Bref) (29), Short Form Health Survey (SF-12) (30), Beck’s Depression and Anxiety Inventories (BDI and BAI) (31, 32), and Clinical Global Impression Scale (34) (CGI) were applied. All instruments were administered in initial evaluation before intervention, except for CGI (disease improvement) and VAS. CGI was applied after five days of stimulation, while VAS was used at eight different time points: 1) before stimulation (baseline VAS); 2) after fifth day stimulation (post-intervention); 3) in the first; 4) second; 5) third; 6) and fourth weeks after the end of stimulation (VAS 1, 2, 3, 4 weeks); 7) in the second month; and 8) in the third month after sessions (VAS 1 and 2 months). Clinical improvement was defined as a reduction at least 1 point on post-intervention VAS compared to baseline VAS.
Exclusion criteria encompassed: a) individuals taking carbamazepine, based on previous studies suggesting attenuation of tDCS effects in individuals using this medication; b) patients with metallic objects above neck, as they could interfere with electrical current direction.
2.2. Statistical Analysis
Data normality distribution and homoscedasticity were assessed using Shapiro-Wilk and Levene tests, respectively. Comparisons between groups were conducted using the following methods: ANOVA-one way (for normally distributed and homoscedastic data), ANOVA-Welch (for heteroscedastic data), Kruskal-Wallis (for data with no assumed normal distribution, comparing three groups), and Mann-Whitney (for data with no assumed normal distribution, comparing two groups). Fisher’s test was employed for qualitative variables. The threshold for statistical significance was set at 5%.
3. Results
The sample comprised 24 subjects, evenly distributed between three groups with 8 subjects in each group (n = 8). Table 1 presents the sample characterization based on clinical intervention groups, with no statistically significant differences observed between them (p > 0.05).
Overall, participants provided positive evaluations for items related to their quality of life, as average scores for most items exceeded 2.5. The items that received lowest ratings were satisfaction with health (WHOQoL: 2), ability to perform daily activities without pain (WHOQoL: 3), need for treatment to lead a normal life (WHOQoL: 4), availability of leisure opportunities (WHOQoL: 14), and ability to work (WHOQoL: 18).
The sample had a mean total score (standard deviation) of 16.42 (10.39) on Beck Depression Inventory (BDI). None of items received a high average response, i.e., above midpoint of response scale (1.50). Concerning the distribution of individuals based on severity of depression, 14 had no depression, 3 had mild depression, 4 had moderate depression, and 3 had severe depression.
For the Beck Anxiety Inventory (BAI), the sample had a mean total score (standard deviation) of 16.58 (13.28). Notably, the mean responses for items BAI 4 (inability to relax) and BAI 10 (feeling nervous) exceeded midpoint of response scale (1.5). Regarding distribution of individuals according to severity of anxiety, 8 had no anxiety, 5 had mild anxiety, 8 had moderate anxiety, and 3 had severe anxiety.
Participants reported experiencing moderate to severe pain levels, with pain affecting general activities, mood, walking, and work the most.
Most individuals (n = 15, 62.5%) were undergoing some form of pain treatment (BPI 7), with an average pain relief percentage of 39.0% (sd = 23.1) (BPI 8).
The distribution of variables such as quality of life, degree of depression and anxiety, pain intensity, pain interference with activities and mood, and overall clinical impression of severity and improvement among individuals is presented in Table 2, broken down by intervention groups.
Concerning characteristics detailed in Table 2, the distribution of individuals across the groups remained uniform. There was a notable positive association between improvement of individuals, as assessed by Clinical Global Impression scale, and intervention group, with a significant improvement observed in individuals allocated to Group M1.
Additionally, regarding the effects after clinical intervention, presence of side effects and improvements in sleep were documented.
Reported side effects included headache (n = 8), pruritus (n = 5), and tingling (n = 1). Headaches were exclusively reported in active stimulation groups (M1 and CDLFP). In contrast, the sham group only reported pruritus.
Regarding improvements in sleep, there were more subjects who reported enhanced sleep quality in Group M1. However, these differences between groups did not achieve statistical significance.
Correlation study examining relationships between variables such as quality of life, depression, anxiety, and pain is presented in Table 3.
It is noted that patient’s initial report of intensity of their pain is positively correlated to severity of their depression. The states of depression and anxiety are inversely correlated to all aspects of quality of life. Quality of life shows a higher correlation (inversely proportional) with interference of pain in individual’s daily life than with reported pain intensity. The effect of tDCS on the assessment of pain intensity, based on VAS, is shown in Table 4. The minimum pain reported on VAS by participants at beginning of study was 6.38 ± 0.92.
As it is notable in Table 4, there was improvement in pain intensity following tDCS in Group M1, mainly after a week intervention (3.88 ± 1.55), with statistically significant improvement (F(7, 285) = 12.292; p < 0.001; Power = 1.000; η2p = 0.534). However, the degree of improvement among individuals depends on the interaction between time and the stimulation group. This improvement
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Table 2. Comparison of variables according to intervention groups.
*statistically significant (= 5%) difference; †ANOVA-one way; ††ANOVA-Welch; ††††Kruskal-Wallis.
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Table 3. Correlation between the variables quality of life, depression, anxiety and pain.
*statistically significant difference (p < 0.05); **statistically significant difference (p < 0.001).
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Table 4. Effect of intervention on pain intensity assessment using VAS.
A, b Different letters indicate statistically significant differences, capital letters indicate differences between lines, lower case letters indicate differences between row.
persisted for four weeks after conclusion of care protocol. However, beginning the third week, the average pain intensity reported by participants in this group started to resemble reports of individuals in other groups (6.00 ± 1.69).
Regarding improvement of participants, Table 5 provides the profile of individuals who experienced either improvement or not in pain intensity following clinical intervention.
As it is mentioned in Table 5, there was a statistically significant difference in how individuals assess their quality of life WHOQoL-item 1 (p = 0.04), considering statistical significant difference p < 0.05. Those who reported improvement in pain intensity tended to rate their quality of life higher than those who did not experience improvement. However, it’s important to note that these differences, while clinically meaningful, did not achieve statistical significance. For instance, among individuals who reported improvement (n = 14), 86% (n = 12) had no or mild depression. It is worth mentioning that the relatively small sample size may have limited statistical power of these findings.
Among individuals who exhibited some degree of anxiety and/or depression (n = 17), we investigated whether there was an association between pain
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Table 5. Profile of individuals according to improvement or not in pain intensity (baseline VAS-after intervention).
*statistical significant difference (= 5%); †ANOVA-one way; †††Man-Whitney.
improvement (baseline VAS - after intervention) and the intervention group (Table 6).
4. Discussion
Transcranial Direct Current Stimulation (tDCS) is a promising neuromodulation technique that has garnered extensive attention as a therapeutic option for various neuropsychiatric disorders as well as cognitive and physical rehabilitation [10] . Recent clinical trials have yielded satisfactory responses in treatment of a wide range of pain disorders, including headache, fibromyalgia, chronic pelvic pain, neuropathic pain, and chronic low back pain [2] [5] [14] - [20] . To our knowledge, this clinical trial represents one of few investigations into application of tDCS in post-laminectomy syndrome as an adjunctive treatment for pain control.
Post-laminectomy syndrome is a condition that arises subsequent to surgeries that did not meet the initial expectations of both patient and surgeon, affecting approximately 10% to 40% of individuals undergoing such procedures [18] . Pain constitutes one of primary consequences, leading to patient dissatisfaction, often being reported as more severe following surgical intervention [18] [21] .
As noted by Teixeira et al. [21] the evaluation and treatment of this syndrome pose a challenge for medical team, given low success rate of reoperations. Consequently, complementary therapies have emerged as alternatives for pain
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Table 6. Association study between improvement in pain intensity (VAS) and intervention group in patients with some degree of depression and anxiety.
management in this patient population. Among these therapeutic approaches for pain modulation, non-invasive techniques like tDCS have gained prominence. This clinical trial has demonstrated the effectiveness of tDCS in reducing pain intensity in Group M1, mainly after a week intervention (3.88 ± 1.55), with statistically significant (F (7, 285) = 12.292; p < 0.001; Power = 1.000; η2p = 0.534).
The analgesic effects of Transcranial Direct Current Stimulation (tDCS) are believed to originate from modulation of excitability in brain regions associated with medial system and descending inhibitory pain system [10] [11] . Valle et al. [22] propose that anodic stimulation in the primary motor cortex (M1) produces analgesic effects through modulation of thalamic inhibitory pathways, among other cortico-cortical and cortico-subcortical projections involved in pain processing. In a study investigating the application of transcranial magnetic stimulation, de Andrade et al. [22] demonstrated that stimulation of M1 induces analgesic effects and involves opioid system as one of the circuits modulated.
Regarding various targets for pain modulation through stimulation, the existing literature suggests that stimulating M1 is effective in pain control. Some studies have also shown pain improvement after dorsolateral prefrontal cortex (DLPFC) stimulation, with these effects often accompanied by enhancements in cognition and emotional symptoms. Consequently, this region has been identified as a promising target for modulating emotional aspects of pain, as well as for addressing depressive and anxious symptoms [18] [20] [23] . Interestingly, in our study, the application of tDCS to CPFDL did not lead to significant improvements in pain control.
It is important to highlight that post-laminectomy syndrome is a chronic pain condition. Individuals dealing with chronic pain often present with psychiatric comorbidities, such as depression and anxiety [20] [24] [25] . Approximately 30% to 45% of chronic pain patients receive a diagnosis of these psychiatric conditions.
This study provides valuable insights into potential application of Transcranial Direct Current Stimulation (tDCS) as a neuromodulation technique in management of post-laminectomy syndrome. It is clear from literature that this condition, which develops after surgeries that do not meet initial expectations, is associated with chronic pain and often presents with comorbidities such as depression and anxiety, making it a complex challenge for medical teams [6] [20] [24] [25] .
The study results reveal several positive aspects:
4.1. Association between Depression and Pain
There is a significant association between depression and pain intensity and improvement. The relationship between depression and chronic pain is complex, with both conditions possibly contributing to each other due to shared biological substrates. Chronic pain can increase substances like P-substance and cytokines while decreasing catecholamine action, potentially predisposing individuals to depression. Conversely, depression can impact pain perception and sensitivity by affecting substance P levels and inhibitory mechanisms [5] . This study demonstrates reduction in depression and anxiety according to Beck’s Depression and Anxiety Inventories (BDI and BAI), p < 0.05 in M1 group.
4.2. Safety Profile
tDCS appears to have a generally safe profile, with reported adverse events such as tingling, headache, pruritus, and nausea being of minor severity [6] [26] [27] [28] .
Blinding: The study’s sham technique effectively blinded participants, with some believing they were receiving active stimulation despite being in the sham group. This blinding technique, which provides initial sensations of active stimulation through a brief (30 seconds) period, contributes to maintaining the double-blind design. The study underscores the feasibility of tDCS in clinical practice, given its significant impact on pain control, safety, and device accessibility.
4.3. Quality of Life
A substantial proportion of the patients reported impaired quality of life, consistent with existing literature [5] [6] [29] [30] . There was a clear association between patients’ assessment of their quality of life and their pain improvement. Quality of life also inversely correlated with pain intensity, underlining the multidimensional nature of pain. After stimulation in M1 group, a significant improvement was observed in WHOQoL-Bref Quality of life item 1 (p = 0.04), considering statistical significant difference p < 0.05. It highlights the importance of evaluating pain from multiple aspects beyond just intensity, considering factors like pain interference with daily activities and affectivity.
Despite these valuable findings, the study has some limitations. The sample size, while sufficient to demonstrate the efficacy of tDCS with high power and effect size, may not have allowed for an in-depth examination of the impact of various patient characteristics on treatment outcomes. Additionally, the study focused solely on pain intensity measured by the VAS, while future research should explore tDCS’s effects on other dimensions of pain and related aspects such as quality of life and psychiatric comorbidities. Further clinical trials with comprehensive protocols are recommended to investigate the broader impact of tDCS in individuals with post-laminectomy syndrome.
5. Conclusions
The application of Transcranial Direct Current Stimulation (tDCS) to the primary motor cortex has demonstrated its effectiveness in pain management for patients with post-laminectomy syndrome. Interestingly, the comorbidities present in the patients did not appear to have a significant association with the observed pain improvement. This suggests that tDCS may be a promising adjuvant therapy for modulating chronic pain in conditions like post-laminectomy syndrome.
Furthermore, tDCS appears to offer several advantages, including its cost-effectiveness, high tolerability, and ease of management. These characteristics make it a feasible and attractive option for inclusion in the treatment regimen for individuals dealing with chronic pain.
The study’s findings highlight the potential of tDCS as a valuable addition to the therapeutic toolkit for managing chronic pain, particularly in cases like post-laminectomy syndrome. Further research and clinical trials are encouraged to explore and validate the broader applications of tDCS in pain management and its potential benefits for patients with various chronic pain disorders.
Acknowledgements
We would like to extend our gratitude to all patients who participated and consented to the publication of this report.
Appendix 1
Pre-screening form