Article Text
PDF
Abstract
Background The efficacy of spinal cord stimulation (SCS) in chronic pain studies is traditionally assessed by pain scores, which do not reflect the multidimensional nature of pain perception. Despite the evidence of SCS’s influence on emotional functioning comprehensive assessments of its effect remain lacking.
Objective To assess changes in emotional and psychosocial functioning in patients who underwent SCS implantation for chronic pain.
Evidence review Ovid MEDLINE, EMBASE, PsychINFO, Cochrane CENTRAL and Scopus databases were searched for original peer-reviewed publications reporting emotional functioning after SCS. The primary outcomes were a pooled mean difference (MD) in anxiety, depression, global functioning, mental well-being and pain catastrophizing at 12 months. The Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) was used to determine the quality of evidence.
Findings Thirty-two studies were included in the primary analysis. Statistically significant improvements were observed in anxiety (MD −2.16; 95% CI −2.84 to −1.49; p<0.001), depression (MD −4.66; 95% CI −6.26 to −3.06; p<0.001), global functioning (MD 20.30; 95% CI 14.69 to 25.90; p<0.001), mental well-being (MD 4.95; 95% CI 3.60 to 6.31; p<0.001), and pain catastrophizing (MD −12.09; 95% CI −14.94 to −9.23; p<0.001). Subgroup analyses revealed differences in Global Assessment of Functioning and mental well-being based on study design and in depression based on waveform paradigm.
Conclusion The results highlight the statistically and clinically significant improvements in emotional and psychosocial outcomes in patients with chronic pain undergoing SCS therapy. However, these results need to be interpreted with caution due to the very low certainty of evidence per the GRADE criteria.
PROSPERO registration CRD42023446326.
- Spinal Cord Stimulation
- Back Pain
- CHRONIC PAIN
- Pain Management
- Complex Regional Pain Syndromes
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, an indication of whether changes were made, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
INTRODUCTION
Chronic pain poses a significant public health challenge, affecting 20% of the US population with 10.6 million persons suffering from high impact chronic pain.1 2 Despite significant advances in our understanding of pain pathophysiology, a substantial cohort of patients continue to experience inadequate pain relief with ramifications on their quality of life, daily functioning, and mental health.3 To address refractory chronic pain unresponsive to conventional treatments, spinal cord stimulation (SCS) has emerged as a pivotal opioid-sparing therapeutic approach.4 Its capacity to improve pain intensity is widely acknowledged and remains the primary outcome in the majority of SCS studies.5 6 However, in this population, traditional pain intensity scores may not reflect the multidimensional pain experience, notable emotional functioning and psychosocial outcomes.7 8 Failure to evaluate these components may result in an inadequate assessment of the complete therapeutic impact of SCS therapy.9
SCS involves the implantation of electrical leads in the epidural space, delivering patterned electrical impulses to the dorsal column of the spinal cord.10 11 Explained by the gate control theory, SCS inhibits transmission of noxious stimuli by depolarizing non-nociceptive Aβ neurons and modulating inhibitory interneurons.12 However, the gate control theory has been challenged by the advent of novel stimulation waveforms that do not rely on paresthesia-based paradigms, such as 10 kHz SCS and burst SCS (B-SCS).13 14
In the biopsychosocial model of pain, pain catastrophizing may amplify pain intensity in patients lacking effective coping strategies. The perceived suffering is associated with negative cognitive, emotional, and autonomic impact, resulting in increased pain intensity, functional disability, behavioral changes, and poor mental health.15 Recognizing suffering and physical pain as two separate entities underscores the importance of assessing both aspects as major outcomes from SCS treatment.16 This is concordant with the criteria supported by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group and the Centers for Disease Control and Prevention, which recommend measuring multiple components of the pain experience such as pain intensity, emotional suffering, and physical functioning.17 18
There is a paucity of research focusing on the effects of SCS on emotional and psychosocial functioning. Thus, the primary objective of this systematic review was to assess the change in emotional and psychosocial functioning after SCS therapy for patients with chronic pain. This systematic review and meta-analysis will assess scales that measure anxiety, depression, global functioning, mental well-being, and pain catastrophizing. We hypothesize that compared with baseline, SCS therapy will be associated with statistically and clinically significant improvements in all outcomes that reflect emotional and psychosocial functioning.
Materials and methods
We reported the systematic review and meta-analysis per the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.19 We also adhered to the guidelines for publishing systematic reviews and meta-analyses in regional anesthesia and pain medicine.20 The study protocol was prospectively registered in the International Prospective Register of Systematic Reviews.
Search strategy
A systematic search strategy was designed and conducted by a medical librarian experienced in systematic review methods with input from the principal investigator (RSD). The search spanned from database inception to July 7, 2023 with additional update on December 20 and was limited to English language. We queried the following databases: Ovid Medline and Epub Ahead of Print, Ovid Embase, Ovid Cochrane Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, APA PsychINFO, and Scopus via Elsevier. Additionally, we screened the references of included publications for additional eligible studies. The search strategy employed controlled vocabulary supplemented with keywords to identify studies describing emotional and psychosocial outcomes following SCS therapy for patients with chronic pain. The complete search strategy is detailed in online supplemental material 1.
Supplemental material
Study selection criteria
Peer-reviewed original research publications were considered for inclusion based on the following eligibility criteria, described below using the Patient, Intervention, Comparison, Outcome and Time (PICOT) format:
Population: adult patients (>18 years old) with any chronic pain condition.
Intervention: dorsal column SCS implantation.
Comparison: comparisons were made with baseline patient metrics before SCS implantation.
Outcomes: we included outcomes that measured emotional functioning, including anxiety, depression, mental well-being, pain catastrophizing, and psychological distress by validated questionnaires. These included the Beck Depression Inventory (BDI), Global Assessment of Functioning (GAF), Hospital Anxiety and Depression Scale (HADS-A and HADS-D), emotional component of health-related quality of life (EQ-5D), Pain Catastrophizing Scale (PCS), Patient Health Questionnaire (PHQ-9), Profile of Mood States (POMS), State-Trait Anxiety Inventory (STAI), mental component of Short Form-36 Item Health Survey (SF-36 MCS) or Short Form-12 (SF-12 MCS), Sickness Impact Profile (SIP). A list of potential questionnaires reflecting emotional functioning were decided a priori to study selection.
Time: study eligibility was not restricted by the follow-up duration, but the primary outcome was measured at 12 months after SCS implantation. The authors determined that the minimal follow-up time of 3 months was required for study eligibility and considered this as sufficient time for changes in emotional function to manifest.
Exclusion criteria included publications only available in abstract form, non-original studies, systematic reviews, non-human studies, SCS trials, dorsal root ganglion stimulation, case reports, and case series with less than 10 patients. Studies were not restricted by the type of lead, implantation technique, indication, or stimulation mode. To facilitate a comprehensive capture of studies, we did not mandate emotional functioning to be the primary outcome of the studies.
Study screening and assessment
While four authors were involved in the screening phase, each title and abstract was independently screened by two of four authors (JK, IU, ME, SL) using Rayyan online software (Rayyan System, Cambridge, Massachusetts).21 Similarly, all potentially eligible citations had their full-text versions independently reviewed by two reviewers for final inclusion (JK, IU, ME). Any discrepancies were resolved by an adjudicating author (RSD).
Primary and secondary outcome
The primary outcome was a change in measures of emotional functioning (anxiety, depression, GAF, mental well-being, pain catastrophizing) from baseline to 12 months after SCS implantation. The secondary outcomes included changes in these aforementioned outcomes at 3 and 6 months after SCS implantation.
Measurement of outcome data
Studies reporting mental health (anxiety and depression) or psychosocial function (GAF, PCS, mental health related quality of life) prior to and after SCS implantation were included. We anticipated that several different instruments would be used to evaluate the same outcome (ie, depression). Thus, we elected to convert all instruments that measured the same construct to the most commonly used instrument in clinical practice.22 Specifically, all evaluations for (1) depression were converted to a BDI; (2) anxiety was converted to a HADS-A; (3) mental health-related quality of life to SF-36. Prior to conversion, we ensured that all the scales shared the same direction. In instances where the scale reported results in the opposite direction, we first performed a scale inversion (SIP-68). A detailed description of the conversion method is provided in online supplemental material 2. The minimal clinically important difference (MCID) was utilized to interpret the clinical significance of these changes.23 If MCID was not previously published, an arbitrary 20% change from baseline was determined a priori as clinically significant.
The BDI evaluates the severity of depression across characteristic attitudes and symptoms.24 The range of possible scores is 0–63 with higher scores indicating more depressive symptoms. A 5-point change is deemed as the MCID threshold for chronic pain patients.25–27
The HADS assesses mood disorders in non-psychiatric patients.28 It separately assesses the depression subscale (HADS-D) and anxiety subscale (HADS-A) with each subscore ranging from 0 to 21, where higher scores indicate more severe symptoms.29 The MCID for HADS-A was determined to range from 1.4 to 3.8 points based on the computation method used.30
GAF evaluates an individual’s psychological, social, and occupational functioning on the scale from 0 to 100 with higher score representing better functioning.31
The PCS measures the degree of catastrophizing thoughts and cognitive responses to the pain experience and is a predictor of pain-related disability.32–34 It consists of three subdomains: helplessness, magnification, and rumination, which are combined into composite score (scale ranging 0–52). Scores above 30 indicate clinically significant pain catastrophizing. A recent study estimated the MCID for PCS in patients with SCS to be 1.9–13.6 points.25
The SF-36 and SF-12 Item Health Survey assess health-related quality of life through eight domains and two overall summary scores: physical and emotional components, each scored from 0 to 100, with higher scores indicating better health.35 36 We postulated that SF-12 equals SF-36 based on the identical score range. The MCID for the mental component score (MCS) domain was established at four points for SF-36.37
Additional information on the included questionnaires is found in online supplemental table 1.
Data extraction
Data from each included study were independently extracted into a spreadsheet (Microsoft Excel V.2016) by two reviewers from a group of three authors who were involved in data extraction (JK, AA-H and IU). The extracted data included study characteristics (study design, study funding source, sample size, waveform, subgroups, indication for SCS implantation) and outcomes. Any discrepancies were resolved through discussion with an adjudicator (RSD). Data that were only reported in graphical form were extracted using a graph analyzing online tool (Plot Digitizer V.3.1.5, 2024; Available from plotdigitizer.com).
Risk of bias and quality assessment
Two groups of paired authors (JK/IU and ME/AA-H) independently assessed the quality of included studies, while the principal investigator (RSD) resolved any discrepancies. Randomized controlled trials (RCTs) were assessed using the Cochrane Risk of Bias Tool for Randomized Trials V.2 (RoB 2 tool).38 RoB2 tool assesses bias in five domains: randomization (D1), deviation from intended intervention (D2), missing outcome data (D3), measurement of outcome (D4), and selection of reported results (D5). Each domain may receive a designation of low risk, high risk, or some concerns of bias assessment. The overall risk of bias was classified as high if any one of the domains had a high risk of bias and some concern if at least one domain had some risk of bias. Observational studies were evaluated using the Newcastle-Ottawa Quality Assessment Scale (NOS).39 The NOS scale was implemented by using a star grading system to appraise the studies across three categories: study group selection, comparability, and outcome. A maximum of four, two, and three stars could be obtained, respectively, with a greater number of stars indicating lower risk of bias.
For quality appraisal, the GRADEpro GDT software (McMaster University and Evidence Prime, 2024; Available from gradepro.org) was used by two reviewers (JK and IU) who independently assessed the evidence for each primary outcome across the included studies using Grading of Recommendation, Assessment, Development and Evaluation (GRADE) quality assessment criteria.
Statistical analysis
It was determined a priori that a meta-analysis would be conducted for outcomes reported in two or more studies. The analysis was performed with Review Manager software (RevMan V.5.4.1.; Nordic Cochrane Center, Cochrane Collaboration). Quantitative variables were presented as mean difference (MD) and SE. For studies reporting other metrics (SD, 95% CI, median and IQRs), the Cochrane Collaboration Guidelines were followed to estimate SE and the median was used to approximate the mean.40 We performed a meta-analysis for the outcome MD after treatment compared with baseline, utilizing a generic inverse variance method with a random effects model to generate a pooled effect estimate with a 95% CI.41 Statistical heterogeneity between studies was assessed using the I2 statistic according to Cochrane Handbook recommendations. An outcome was considered to have substantial heterogeneity when the value was >50%. A significance was set at p<0.05. Publication bias was assessed for primary outcomes with funnel plot asymmetry and the Egger’s test. A sensitivity analysis was conducted with the leave-one-out method. Outcomes that could not be included in quantitative synthesis were summarized qualitatively.
Subgroup analysis
Subgroup analysis was performed for all primary outcomes that had two or more studies per subgroup in the following categories: funding source, study design, and type of stimulation. For the subgroup analysis based on funding, studies receiving any form of industry support were classified as industry-funded studies; studies receiving funding from a non-industry source such as academic or national grants or non-funded studies were classified as non-industry-funded studies. Those without a funding statement were excluded from the subgroup analysis. We also performed subgroup analysis based on study design (RCT vs observational studies) and stimulation type (paresthesia-based vs non-paresthesia-based). We performed additional post hoc subgroup analysis comparing retrospective and prospective studies.
Protocol deviations
Given the inconsistency in reported outcomes, the list of included questionnaires was revised during the initial phase of the study and the comprehensive list is provided as online supplemental table 1. Additionally, it was decided post hoc to convert the instruments reporting the same construct to natural units of the most commonly used assessment.22 The statistical analysis method was amended to inverse variance model following the peer-review process for the journal.
Results
Study characteristics
Of 1277 eligible studies, 85 studies42–126 met the final inclusion criteria. The selection process and reasons for exclusion are depicted in the PRISMA flowchart (figure 1 and online supplemental table 2). Among the included studies, there were 20 RCTs,45 57 60–62 65 68 69 80 81 87 93–95 100 101 106–108 116 50 prospective observational studies,43 44 46–48 50–55 58 59 63 64 66 67 71–75 77–79 82 83 85 86 88 96 97 99 102 104 109–114 117–123 125 126 and 15 retrospective observational studies.42 49 56 70 76 84 89–92 98 103 105 115 124 Seven studies46 53 63 64 68 71 106 were conducted in multiple countries. Most studies received industry support,42–46 48 50–54 61–68 70–72 74 77 79 85 87 92–95 97 99–101 106 108 110 112–114 116 118–120 122 125 126 21 studies reported either no funding or academic/government funding,49 55–60 67 69 78 80–82 88 89 91 98 107 115 117 124 and 15 studies did not include a funding statement into the final manuscript.47 73 75 76 84 86 90 96 103–105 109 111 121 122 Participants underwent 10 kHz SCS in 17 studies,42–45 48 53 57 60 72 74 77 79 83 100 101 120 126 B-SCS in 12 studies,61–64 66 67 71 82 83 87 89 108 and subthreshold stimulation waveform in eight studies.50 81 85 97 99 107 108 112 The duration of follow-up varied from 3 months up to 10 years. Nineteen studies included patients experiencing back and leg pain of mixed etiology.45 47 51 52 56 62–64 66 71 87 93–95 105 110 112 115 126 Other investigated indications encompassed persistent spinal pain syndrome type 2 (PSPS-T2) in 16 studies,50 60 68 77 78 82 83 99 106–109 113 114 118 119 complex regional pain syndrome in seven studies,57 65 70 80 84 86 96 peripheral neuropathy in six studies,72 100–102 116 125 refractory angina pectoris in four studies,46 69 121 123 persistent spinal pain syndrome type 1 (PSPS-T1) in three studies,43 44 61 postsurgical pain48 74 and upper limb pain53 120 each in two studies and critical limb ischemia,81 abdominal pain79 and scoliosis89 each in one study.
PRISMA diagram. Flowchart demonstrates the study selection process. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses
The prospective studies consisted of 3899 participants who underwent permanent implantation. The most commonly used questionnaires were the BDI in 29 studies,49 51 52 54 56 58 59 62 73 75 76 78 82–85 90 96–98 102 103 111 113 115 116 120 122 125 GAF in 9 studies,45 48 53 72 74 79 100 101 120 HADS in 9 studies,60 77 91 99 108 109 117 119 124 PCS in 28 studies,42 48 49 54 56 61–64 66 67 70 71 73 74 76 77 85 87 90 97 98 103 104 110 111 115 126 SF-36 in 26 studies,43 44 46 50 55 58 62 65 68–70 81 86 88 89 92 102 106 110 112 114 116 119 121 125 127 and SF-12 in 10 studies.45 48 53 57 60 74 79 93 94 120 Other self-reported questionnaires used in at least one study were the Brief Anxiety Scale,107 Center for Epidemiologic Studies Depression Scale and its German version,89 123 EQ-5D depression subscale,64 68 Hamilton Anxiety Rating Scale,58 59 Montgomery and Asberg Depression Rating,107 Major Depression Inventory,70 PHQ-9,64 71 POMS,65 93–95 SIP,47 51 52 80 96 118 STAI,64 71 110 and the Zung Self-Rating Depression Scale.80 Data from each study are summarized in online supplemental table 3. Fifty studies42 44 45 47–49 51–54 56 59–61 63 65–68 71–75 77–79 82–85 87 89 93 100–102 104 106–111 116 117 119 120 122 123 underwent quantitative synthesis, of which 3244 45 47–49 51 53 56 60 65 67 68 71–75 77 79 84 93 100 102 107 109–111 117 119 120 122 123 provided data for the primary outcome.
Primary outcome
Pooled analysis with 872 patients at baseline revealed an improvement in anxiety (HADS-A) at 12 months after SCS implantation60 71 77 107 109 110 117 119 with a MD of −2.16 (95% CI −2.84 to −1.49; p<0.001, figure 2A), which surpassed the MCID. This finding had high statistical heterogeneity (χ2=29.43, df=8 (p<0.001), I2=73%). Pooled analysis with 1127 patients at baseline revealed an improvement in depression scores (BDI) at 12 months after SCS implantation49 51 56 60 71 73 75 77 84 102 107 109 111 117 119 120 122 123 with a MD of −4.66 (95% CI −6.26 to −3.06; p<0.001, figure 2B), which did not reach the MCID threshold of 5 points. This finding had high statistical heterogeneity (χ2=189.71, df=22 (p<0.001), I2=88%). Pooled analysis with 372 patients at baseline revealed an improvement in global functioning45 48 53 72 79 100 120 at 12 months after SCS implantation with an MD in the GAF scale of 20.30 (95% CI 14.69 to 25.90, p<0.001, figure 2C). This finding had high statistical heterogeneity (χ2=221.22, df=7 (p<0.001), I2=97%). The GAF scale does not have a defined MCID threshold in the literature; however, the MD surpassed the 20% score reduction threshold determined a priori. Pooled analysis with 990 patients at baseline revealed an improvement in mental well-being (SF-36 MCS) at 12 months after SCS implantation with a MD of 4.95 (95% CI 3.60 to 6.31, p<0.001, figure 2D) exceeding the MCID threshold of 4 points.44 45 47 48 53 65 68 79 93 102 110 120 There was substantial statistical heterogeneity in this finding (χ2=45.19, df=13 (p=0.001), I2=71%). Pooled analysis with 1067 patients at baseline revealed an improvement in pain catastrophizing at 12 months after SCS implantation48 49 56 67 71 73 74 77 110 111 with a MD of −12.09 (95% CI −14.94 to −9.23, p<0.001, figure 2E). This finding had high statistical heterogeneity (χ2=140.33, df=12 (p<0.001), I2=91%). The MD for pain catastrophizing surpassed the MCID threshold determined by 3 out of 4 computation methods. The outcomes of the included studies are summarized in online supplemental table 4. Sensitivity analysis using the leave-one-out method did not reveal any significant changes in the MD for all primary outcomes, suggesting the robustness of data.
(A) Forest plot representing the change in anxiety (HADS-A) scores at 12 months after the SCS implantation. The score reduction indicates the decrease in anxiety. (B) Forest plot representing the change in depression (BDI) scores at 12 months after the SCS implantation. The score reduction indicates a decrease in depression. (C) Forest plot representing the change in global functioning (GAF) scores at 12 months after the SCS implantation. The score increase indicates better global functioning. (D) Forest plot representing the change in mental well-being (SF-36 MCS) scores 12 months after the SCS implantation. The score increase indicates better mental well-being. (E) Forest plot representing the change in pain catastrophizing (PCS) scores at 12 months after the SCS implantation. The score reduction indicates the decrease in pain catastrophizing. The change is represented as MD. The diamond represents the pooled estimated effect size, and the diamond width reflects the 95% CI. (Amirdelfan 2018 Group 1: tonic SCS; Amiderlfan 2018 Group 2: 10 kHz SCS; Campwala 2021 Group 1: PSPS-T2; Campwala 2021 Group 2: PSPS-T1; De Andres 2017 Group 1: Tonic SCS; De Andres 2017 Group 2:10 kHz SCS; Gee 2019 Group 1: decreased opioids; Gee 2019 Group 2: increased opioids/no change; Gee 2019 Group 3: no opioids; Haider 2017 Group 1: cervical SCS; Haider 2017 Group 2: thoracic SCS; Mekhail 2020 Group 1: closed loop SCS; Mekhail 2020 Group 2: open loop SCS). GAF, Global Assessment of Functioning; HADS-A, Hospital Anxiety and Depression Scale; MD, mean difference; PSPS-T1, chronic low back pain without previous surgery; PSPS-T2, chronic low back pain with previous surgery; SCS, spinal cord stimulation; SF-36 MCS, mental component of Short Form-36 Item Health Survey.
Secondary outcome
Meta-analysis of emotional functioning outcomes was performed at 3 months and 6 months after SCS implantation, if sufficient studies were available to pool outcomes. Compared with baseline, we identified an improvement in anxiety59 60 71 77 107 108 110 117 at 6 months (MD −2.01; 95% CI −2.26 to −1.77; p<0.001); an improvement in depression at 6 months59 60 71 75 77 89 102 107 108 111 116 117 120 (MD −4.77; 95% CI −6.11 to −3.43; p<0.001) and at 3 months52 54 60 78 82–84 89 102 116 117 120 123 (MD −5.86; 95% CI −7.77 to −3.95; p<0.001); an improvement in global functioning48 53 72 79 100 101 120 at 6 months (MD 19.44; 95% CI 13.48 to 25.41; p<0.001) and at 3 months48 53 72 79 100 101 120 (MD 18.95; 95% CI 16.33 to 21.56; p<0.001); an improvement in mental well-being at 6 months (MD 4.71; 95% CI 3.91 to 5.52; p<0.001)44 47 65 68 89 102 106 110 116 120 and at 3 months (MD 6.34; 95% CI 4.90 to 7.77; p<0.001)44 48 65 68 79 89 93 102 116 120; and an improvement in pain catastrophizing at 6 months42 48 61 63 66 71 74 77 87 104 110 111 (MD −14.20; 95% CI −16.64 to −11.76, p<0.001) and at 3 months42 48 54 61 66 74 85 87 (MD −14.33; 95% CI −18.51 to −10.14; p<0.001). All secondary outcomes are presented in online supplemental figures 1−9.
Subgroup analysis
Subgroup analysis based on study design (RCT vs observational studies) revealed no subgroup differences for anxiety (RCTs: MD −1.88; 95% CI −2.42 to −1.35 vs observational: MD-2.33; 95% CI −3.33 to −1.32; p=0.45) and depression (RCTs: MD −5.57; 95% CI −7.45 to −3.69 vs observational: MD −4.64; 95% CI −6.42 to −2.86; p=0.48). However, subgroup analysis of global functioning and mental well-being showed statistically significant higher improvement in observational studies compared to RCTs (GAF RCTs: MD 13.63; 95% CI 6.56 to 20.70 vs GAF observational: MD 24.52; 95% CI 18.17 to 30.87 (p=0.02); SF-36 MCS RCTs: MD 3.40; 95% CI 1.11 to 5.68 vs SF-36 MCS observational: 6.07; 95% CI 4.88 to 7.25 (p=0.04)). There was insufficient data to perform subgroup analysis based on the study design for pain catastrophizing. Additional post hoc subgroup analysis of prospective versus retrospective studies revealed significant difference for pain catastrophizing (prospective: MD −13.43; 95% CI −16.52 to −10.34 vs retrospective: MD −7.29, 95%–9.72 to −4.85, p=0.002). There was insufficient data to perform a subgroup analysis for anxiety, global functioning, and mental well-being.
Subgroup analysis based on funding source (industry vs non-industry) revealed no subgroup differences for anxiety (industry funded: MD −2.09, 95% CI −2.70 to −1.48 vs non-industry funded: MD −1.73, 95%–2.22 to −1.25; p=0.37), depression (industry funded: MD −5.14, 95% CI −7.51 to −2.77 vs non-industry funded: MD −3.50, 95%–5.38 to −1.62; p=0.29), and pain catastrophizing (industry funded: MD −15.26, 95% CI −19.16 to −11.37 vs non-industry funded: MD −9.82, 95%–14.35 to −5.28; p=0.07). Insufficient data were available to perform subgroup analysis based on study funding for global functioning and mental well-being.
Subgroup analysis based on stimulation waveform (paresthesia-based vs non-paresthesia-based) revealed no significant subgroup differences for anxiety (non-paresthesia-based: MD −1.86; 95%–2.43 to −1.29 vs paresthesia-based: MD −1.69; 95% CI −2.18 to −1.19; p=0.66), mental well-being (non-paresthesia-based: MD 5.38; 95% 4.20 to 6.55; paresthesia-based: MD 3.77; 95% CI 1.29 to 6.25; p=0.25) and pain catastrophizing (non-paresthesia-based: MD −16.78; 95%–21.97 to −11.60 vs paresthesia-based: MD −9.36; 95% CI −14.80 to −3.92; p=0.05). However, significant improvement was observed for depression in those who received non-paresthesia-based stimulation (non-paresthesia-based: MD −7.17; 95%–9.03 to −5.32 vs paresthesia-based: MD −3.76; 95% CI −5.02 to −2.50; p=0.003). The subgroup analysis is displayed in online supplemental figures 10−13.
Risk of bias and quality appraisal
Risk of bias assessment of meta-analyzed studies is summarized in figure 3128 and online supplemental table 5. Overall, all RCTs demonstrated a low risk of bias in D1 (randomization process), D2 (deviations from intended intervention) and D3 (missing outcome data) domain with the exception of 3 RCTs.45 57 80 The majority of studies demonstrated some concerns or high risk of bias for D4 (measurement of the outcome) and D5 (reporting bias) due to an open-label, non-blinded study design, which could potentially be associated with overestimation of the treatment effect. Only four RCTs implemented blinding of the study assessors.60 93–95 107 108 Three RCTs implemented a cross-over design with low risk of bias in domain S.62 87 108 Only two RCTs showed low risk of bias in the overall RoB2 assessment.93–95 107 Bias assessment of the observational studies using the NOS tool revealed that all studies have an overall fair quality due to lack of control groups. Most studies had low to moderate risk in the selection and outcome domains of the NOS criteria.
Risk of bias assessment for included RCTs. Green circle indicates a ‘low risk of bias’, yellow indicated ‘some risk of bias’ and red circle represents ‘high risk of bias’. Star (*) identifies RCTs with multiple follow-up publications. RCT, randomized controlled trial.
Funnel plot symmetry (online supplemental figures 14−18) was assessed with Egger’s test for primary outcomes, which did not suggest publication bias based on p value in anxiety (p=0.59), depression (p=0.35), GAF (p=0.07), mental well-being (p=0.26) and pain catastrophizing outcome (p=0.23). However, visual assessment of the Funnel plot suggested a presence of publication bias in depression, global functioning, and pain catastrophizing.
The GRADE Evidence profile and summary of findings are displayed in tables 1 and 2. The certainly (or quality) of GRADE evidence for improvements in anxiety, depression, global functioning, mental well-being and pain catastrophizing after 12 months of SCS therapy was rated as very low. The very low certainty (or quality) of GRADE evidence was attributed to predominance of observational studies, high risk of bias, and inconsistency of included studies.
GRADE Evidence profile: studies report anxiety, depression, global functioning, and mental well-being at 12 months SCS postimplantation
GRADE summary of findings: studies report anxiety, depression, global functioning, and mental well-being at 12 months SCS postimplantation
Discussion
This meta-analysis revealed clinically and statistically significant improvements in anxiety, global functioning, pain catastrophizing and mental well-being after 12 months of SCS therapy for chronic pain. Furthermore, we observed a statistically significant improvement in depression scores after 12 months of SCS therapy, although this change did not meet the MCID threshold for clinical significance. Concordantly, significant improvements in all emotional and psychosocial functioning outcomes were also demonstrated at 3 and 6 months after SCS implantation. However, our findings should be interpreted with caution due to a very low certainty of evidence per the GRADE framework as well as substantial statistical, clinical, and methodological heterogeneity.
One potential explanation for the positive mental health benefits of SCS therapy is that pain intensity and mental health are strongly associated.129 Therefore, it is plausible that improvements in emotional functioning after SCS therapy may be mediated by improvements in pain intensity. Another explanation may be related to the stimulation of medial pathways in the central nervous system. There is evidence from preclinical models that certain non-paresthesia-based waveforms including B-SCS may attenuate the affective component of the pain experience through modulation of the medial pain pathway, which projects to brain centers that are involved in emotional processing (eg, dorsal anterior cingulate cortex, anterior insula, limbic system, and prefrontal cortex).10 130 This proposed mechanism of action aligns with the results of the subgroup analysis based on stimulation paradigm. The stimulation paradigm-based subgroup analysis not only addressed the heterogeneity for the outcome of depression but also revealed significantly greater alleviation of depression among patients treated with non-paresthesia-based SCS.
Clinical and methodological heterogeneity are persisting challenges in SCS research, stemming from the various pain conditions treated and personalized SCS parameters tailored to individual patients’ needs. The necessity to address the latter has been advocated in IMMPACT of Neuromodulation/International Neuromodulation Society recommendations, which suggested reporting SCS-specific measures in RCTs.131 However, as demonstrated in online supplemental table 3, inconsistent and inadequate reporting of these measures introduces significant methodological heterogeneity. Additionally, the inclusion of patients with diverse pain conditions across the majority of studies results in a heterogeneous study population, making subgroup analysis based on indication unfeasible. We also identified subgroup differences in global functioning and mental well-being based on study design. Interestingly, our results showed more favorable outcomes for patients in observational studies, which contradicts the clinical experience from real-world observational studies. These typically demonstrate smaller effect sizes in participants compared with RCTs that select for ideal participants.45 132 While prior literature suggests that industry-sponsored trials are associated with larger effect sizes compared with non-industry sponsored studies,133 134 we did not observe this in our subgroup analysis. However, we note that emotional and psychosocial functioning metrics were abstracted as a secondary outcome in most studies. Further, only 16 of 29 included studies were funded by industry, implying that industry-funded studies may either under-report emotional and psychosocial functioning outcomes or present their findings in a manner that precludes meta-analysis. Furthermore, the distinction between industry funding and sponsoring, which signifies different levels of industry involvement, is often not clearly reported. The complexity of industry funding was underscored in a recent systematic review on the impact of industry funding in SCS RCTs, which similarly found no statistically significant difference between industry-funded and industry-independent studies.135
Taken together, our findings are important because emotional and psychosocial components of the pain experience are a cornerstone of successful pain treatment. Although emotional and psychosocial functioning are under-reported outcomes in pain trials, research suggests a strong bi-directional relationship between mental health and chronic pain. Thus, while chronic pain may lead to poor mental health, the bidirectional relation suggests that poor mental health may also predispose individuals to chronic pain.136 Therefore, incorporating assessment of emotional and psychosocial outcomes after SCS implantation can facilitate optimization of patient outcomes and treatment success.
In this meta-analysis, substantial inconsistency was noted. For instance, reported outcomes included various combinations of scales measuring anxiety, depression, global functioning, mental well-being, pain catastrophizing and other emotional constructs (online supplemental table 3). There is lack of consensus in the literature regarding which measures should be considered most important in the assessment of emotional and psychosocial functioning. The available guidance comes from IMMPACT group recommendation, which identified the BDI and POMS scales as core outcomes for pain clinical trials.24 However, as demonstrated in our systematic review, only a minority of studies reported the POMS scale.65 93 Conversely, pain catastrophizing was frequently measured in many included studies, however it was not included in the IMMPACT criteria. In response to the need for integrating multiple measures into one composite score, a novel holistic response framework has been developed. This framework combines the baseline measures across various domains with MCID to capture the multidimensional nature of the pain experience.137 However, it lacks specificity regarding recommended scales for integration and has not yet gained widespread use.
We note several strengths in this meta-analysis. First, we did not limit our review by a specific scale, but rather included all emotional and psychosocial functioning domains. In addition, by converting outcomes to natural units of the most common instrument, our analysis can be easily understood by clinicians and can be interpreted in comparison to previously published MCID thresholds.
There are several notable limitations. First, emotional functioning was often assessed as a secondary outcome in included studies. Second, we did not analyzed long-term emotional outcomes beyond 12 months due to the scarcity of published studies and variability in emotional outcome constructs utilized. Future research should investigate the long-term change (>12 months) in emotional functioning after SCS therapy and consider measuring this metric as a primary outcome. Third, some studies presented data only graphically which necessitated the use of a graph analyzer tool to extract our outcomes of interest. Fourth, methodological heterogeneity was notable among studies including trial pain reduction threshold, duration of SCS trial, and trial stimulation waveform, all of which may influence results. Fifth, although the MCID serves as a valuable tool for interpretation for clinical significance, this threshold may vary depending on the population and disease being studied. Sixth, the close association between SCS research and industry funding raises concerns about potential underreporting of unfavorable results, although our subgroup analysis did not reveal any subgroup differences in outcomes based on funding source. Seventh, the gray literature was not considered for inclusion due to lack of a rigorous peer-review process, which could introduce bias into our results. However, that decision may have potentially increased the risk for publication bias and may led to overestimation of the true effect size. Additionally, it is important to note that we focused exclusively on the change in emotional and psychosocial outcomes in the SCS treatment arm, which allowed us to include prevalent single-arm studies. However, the absence of a control group may result in the attribution of non-SCS-related improvements to the SCS treatment. Finally, reporting results in natural units of the common instrument required conversion, which may have introduced some degree of statistical error.
Conclusion
The results of this meta-analysis suggest that there may be clinically relevant improvements in emotional and psychosocial functioning after SCS implantation for chronic pain. However, these findings should be interpreted with caution due to very low certainty of evidence as per the GRADE framework as well as high statistical, clinical, and methodological heterogeneity.
Ethics statements
Patient consent for publication
Ethics approval
Not applicable.
Acknowledgments
The authors thank Larry Prokop MLS from Mayo Library System, Mayo Clinic, Rochester, MN for his contribution with the literature search.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
X @JohanaKlasova, @@Ryan_S_DSouzaMD
Contributors JK, RSD'S: responsible for study design, protocol registration, screening, data extraction, data analysis/interpretation, drafting the manuscript, final manuscript approval. NH: responsible for study design, data analysis/interpretation, drafting the manuscript, final manuscript approval. IU: responsible for screening, data extraction, data analysis/interpretation, final manuscript approval. AA-H: responsible for data extraction, data analysis/interpretation, final manuscript approval. ME: responsible for study design, screening, data analysis/interpretation, final manuscript approval. SL: responsible for screening, final manuscript approval.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests RDS received investigator-initiated grant funding pain to his institution from Nevro Corp and Saol Therapeutics.
Provenance and peer review Not commissioned; externally peer-reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.