Abstract
Context
Neuropathic pain is a common and debilitating condition following SCI. While treatments for neuropathic pain intensity have been reviewed, the impact on pain interference has not been summarized.
Objective
To systematically review the effect of neuropathic pain interventions on pain interference in individuals with spinal cord injury.
Methods
This systematic review included randomized controlled trials and quasi-experimental (non-randomized) studies which assessed the impact of an intervention on pain interference in individuals with spinal cord injury and neuropathic pain. Articles were identified by searching MEDLINE (1996 to April 11, 2022), EMBASE (1996 to April 11, 2022), PsycInfo (1987 to April, week 2, 2022). Studies were assessed for methodologic quality using a modified GRADE approach and were given quality of evidence (QOE) scores on a 4-point scale ranging from very low to high.
Results
Twenty studies met the inclusion criteria. These studies fell into the following categories: anticonvulsants (n = 2), antidepressants (n = 1), analgesics (n = 1), antispasmodics (n = 1), acupuncture (n = 2), transcranial direct current stimulation (n = 1), active cranial electrotherapy stimulation (n = 2), transcutaneous electrical nerve stimulation (n = 2), repetitive transcranial magnetic stimulation (n = 1), functional electrical stimulation (n = 1), meditation and imagery (n = 1), self-hypnosis and biofeedback (n = 1), and interdisciplinary pain programs (n = 4).
Conclusion
When considering studies of moderate to high quality, pregabalin, gabapentin, intrathecal baclofen, transcranial direct current stimulation, and transcutaneous electrical nerve stimulation (in 1 of 2 studies) were shown to have beneficial effects on pain interference. However, due to the low number of high-quality studies further research is required to confirm the efficacy of these interventions prior to recommending their use to reduce pain interference.
Keywords: Neuropathic pain, Pain interference, Spinal cord injury
Introduction
Chronic pain is a common comorbidity following spinal cord injury (SCI) effecting an estimated 68% of the population (1). Based on its etiology, chronic pain can be broadly categorized as either nociceptive or neuropathic pain (NP). While nociceptive pain results from damage to non-neural tissue, neuropathic pain results from a lesion or disease of the somatosensory nervous system itself. Damage to neurons may cause persistent or permanent changes to nociceptive thresholds resulting in unique pain states characterized by hyperalgesia and/or allodynia. While both nociceptive and neuropathic pain may negatively impact quality of life, the chronicity, intensity, and treatment resistance associated with neuropathic pain may make it a particularly debilitating pain state.
Neuropathic pain is notoriously difficult to treat due to an incomplete understanding of the underlying mechanisms (2). While both pharmacological and non-pharmacological treatment strategies have been assessed, pharmacotherapies have been largely dominant in clinical practice (3). No treatments, however, have been consistently proven to be universally effective, predictable, and safe for long-term use (4). Additionally, studies evaluating the efficacy of treatment strategies for neuropathic pain have largely focused on the effect on pain intensity, while neglecting the extent to which other quality of life domains are impacted. Neglecting such pain interference items negatively impacts the response to analgesic drugs (4).
Pain interference relates to the way in which pain impacts activity items (such as walking/mobility, work, and general activity) and affective items (such as mood, relationships with others, enjoyment of life, sleep) (5). Consideration of pain interference is therefore of particular importance following SCI as secondary health complications resulting from NP such as sleep disturbance (6), depression (6,7), and reduced quality of life (8) are common. A better understanding of not only the efficacy of treatment strategies to improve pain intensity, but also the way in which pain impacts one’s quality of life and activities of daily living may help to inform the development of more effective interventions.
In a recent systematic review (9) the efficacy of various treatment strategies for NP intensity following SCI have been summarized. This review did not however, include a thorough review of the impact on pain interference. The purpose of the present paper is therefore to provide summary of the effect of various treatment strategies on pain interference related to NP following SCI.
Materials and methods
Literature search strategy
Potentially relevant articles were identified by a literature search from 1987 to April 2022 using multiple databases (MEDLINE, EMBASE, PsycInfo). Keywords included Spinal cord injur*, neuropathic pain OR pain OR central pain, pain interference OR pain intrus* OR pain obtrus* OR pain imping*, BPI OR brief pain inventory OR SF-36 OR short form survey OR PROMIS OR Patient reported Outcome Measurement Information System (see appendix 1 for detailed search strategy). Among studies included for review, references were scanned to identify additional relevant articles missed in the original search.
Study selection
Studies which investigated how interventions for the treatment of neuropathic pain in individuals with spinal cord injury influence pain interference were included if the following criteria were met: (1) ≥ 50% SCI traumatic or non-traumatic SCI etiology; (2) human adult study participants ≥18 years old; (3) study population NP or mixed pain; (4) N ≥ 3 participants (SCI + NP/mixed pain); (5) outpatient, or community setting/non-acute setting; (6) any treatment intervention; (7) effect of treatment on pain interference assessed quantitatively. Studies were excluded for the following reasons: (1) Study participants <18 years old; (2) study population <50% SCI; (3) study <3 participants; (4) acute (inpatient) setting (5) participants with musculoskeletal pain only; (6) qualitative designs. The title, abstract, and full text screening was performed by 2 independent reviewers (DJA and MM). A third reviewer (EL) was consulted for any discrepancies regarding study eligibility. Figure 1 provides an outline of the identification, screening, eligibility, and inclusion of studies.
Figure 1.
Flow diagram for the identification, screening, eligibility, and inclusion of studies.
Data extraction
Two independent reviewers (DJA and MM) assessed the studies for methodologic quality using a modified GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach (10). Pain interference was the primary outcome assessed with GRADE for articles investigating treatment modalities. Studies which utilized tools specifically designed for the assessment of pain interference (e.g. Brief Pain Inventory, pain-related sleep interference, etc.) as well as studies which utilized tools for the more generic assessment of psychological health (e.g. CES-D, STAI-S, HAD scale) in individuals with NP were included. If agreement on an individual GRADE level assignment was not achieved, discrepancies were resolved by a third reviewer. Studies were given an initial grade rating based on study design (RCT = high, quasi experimental = moderate) and upgraded or downgraded based on risk of bias, inconsistency of results, indirectness of evidence, imprecision, and publication bias. Studies were given quality of evidence (QOE) scores on a 4-point scale ranging from very low to high. Data were extracted from studies using an electronic abstraction sheet which included author(s) / year, study title, study outcome, type of pain, intervention, comparator, population, and results. Investigations involving similar interventions were grouped and tabulated.
Results
The results related to identification, screening, eligibility and inclusion of studies are presented in Figure 1. Twenty studies including 13 RCTs and 7 quasi-experimental (non-randomized) met our inclusion criteria. Table 1 provides information on study characteristics and outcomes for all treatment types. Quality assessments are shown in Table 2.
Table 1.
Study characteristics and outcomes.
| Author | Type of Pain (N) | Intervention | Comparator | Outcome Measure | Outcome |
|---|---|---|---|---|---|
| Anticonvulsants | |||||
| Ahn et al. (11) | NP (31) | Gabapentin Dose: Maximum tolerable (3600 mg/day) |
NP <6-months vs >6-months | Pain-related sleep interference (Single item 11-point scale) |
+ |
| Pain Intensity (100 mm VAS) | + | ||||
| Cardenas et al. (12) | NP (220) | Pregabalin Dose: 150–600 mg/d |
Placebo | Pain-related sleep interference (Single item 11-point scale) |
+ |
| Pain Intensity (single item 11-point scale) | + | ||||
| Antidepressants | |||||
| Richards et al. (13) | NP (74) Mixed (39) |
Venlafaxine Dose: Maximum 300 mg/d |
Placebo | Pain Interference (7-item – BPI subscale) | − |
| Pain Intensity (0–10 scale) | − | ||||
| Analgesics | |||||
| Norrbrink et al. (14) | NP (36) | Tramadol Dose: Maximum 400 mg/d |
Placebo | Pain-related interference in everyday life (11-item MPI-S subscale) |
− |
| Anxiety & Depression (HADS scale) | + (Anxiety) |
||||
| Quality of Sleep (10-item sleep scale) | − | ||||
| Pain Intensity (CR-10 scale) | + | ||||
| Antispastics | |||||
| Kumru et al. (15) | NP (13) | Intrathecal Baclofen Dose: 50–100ug |
Placebo | Pain Interference (6-item BPI subscale) |
+ |
| Pain Intensity (NRS) | + | ||||
| Acupuncture | |||||
| Nayak et al. (16) | NP (12) MS (5) |
Acupuncture Dose: 15 sessions over 7.5 weeks |
Within-subject (7.5 week no treatment) | Pain interference with daily activities (single-item, 11- point scale) |
+ |
| Mood (CES-D, STAI-S) | − | ||||
| Pain Intensity (NRS) | + | ||||
| Norrbrink et al. (17) | NP (30) | Acupuncture Dose: Twice weekly for 6-weeks |
Massage | Psychological consequences of pain (MPI-S) |
− |
| Pain Intensity (VAS) | + | ||||
| Transcranial Direct Current Stimulation (tDCS) | |||||
| Soler et al. (18) | NP (39) | tDCS + visual illusion; sham tDCS + visual illusion; tDCS + control illusion; sham tDCS + control illusion Dose: 10, 20 min sessions over 2-weeks |
Pain Interference (7-item BPI) |
+ | |
| Anxiety (11-point NRS) | + | ||||
| Pain Intensity (NPSI) | + | ||||
| Active Cranial Electrotherapy Stimulation (CES) | |||||
| Tan et al. (19) | NP (23) MS (15) |
Active CES Dose: Daily, 1 h sessions for 21 days |
Sham CES | Pain interference (10-item BPI subscale) |
− |
| Pain Intensity (0–10 scale) | − | ||||
| Tan et al. (20) | NP (105) | Active CES Dose: Daily, 1 h sessions for 21 days |
Sham CES | Pain interference (10-item BPI subscale) |
+ (composite) |
| Pain Intensity (BPI pain intensity subscale) | − | ||||
| Transcutaneous Electrical Nerve Stimulation (TENS) | |||||
| Ozkul et al. (21) | NP (24) | Visual Illusion followed by TENS Dose: 10, 15 min sessions 5d/week for 2-weeks |
TENS followed by Visual Illusion | Pain interference (7-item BPI subscale) |
+ |
| Pain Intensity (VAS) | + | ||||
| Norrbrink et al. (14) | NP (24) | 2-weeks HF TENS followed by 2-weeks LF TENS Dose: 3, 30–40 min daily sessions |
2-weeks LF TENS followed by 2-weeks HF TENS Dose: 3, 30–40 min daily sessions |
Pain Interference (MPI-S) | − |
| Anxiety & Depression (HADS scale) | − | ||||
| Sleep (Nordic Basic Sleep Questionnaire) | − | ||||
| Life Satisfaction (LiSAT-9) | − | ||||
| Pain Intensity (Borg CR-10) | − | ||||
| Repetitive Transcranial Magnetic Stimulation (rTMS) | |||||
| Kang et al. (23) | NP (13) | rTMS Dose: 5 sessions of 20 trains (10 Hz – 5sec) |
Sham TMS | Pain interference (6-item BPI subscale) |
− |
| Pain Intensity (NRS) | − | ||||
| Functional Electrical Stimulation (FES) | |||||
| Calabro et al. (24) | NP (11) | FES cycling Dose: 6x per week over 6 weeks |
none | 36-item Short Form Survey (SF-36) | + |
| Pain Intensity (NRS) | + | ||||
| Meditation & Imagery | |||||
| Zanca et al. (25) | NP (16) | Clinical meditation and imagery Dose: 1x per week over 4-weeks |
Education on SCI health and function | Modified Multidimensional Pain Inventory Life Interference Subscale (MPI-LIS) |
− |
| Pain Intensity (NRS) | − | ||||
| Hypnosis & Biofeedback | |||||
| Jensen et al. (26) | NP (17) MS (20) |
Self-hypnosis Dose: 10 sessions over 2-weeks |
Biofeedback relaxation | Pain interference (10-item BPI subscale – composite score) | − |
| Depressive Symptoms (CES-D) | − | ||||
| Pain Intensity (NRS) | + (hypnosis only) |
||||
| Interdisciplinary Pain Programs | |||||
| Burns et al. (27) | NP (16) MS (1) |
patient ed., CBT, Self-management strategies, group discussion, exercise, guided relaxation Dose: biweekly 2.5 h session for 10-weeks |
None | Life Interference (50-item, MPI-SCI 7-point scale) |
+ |
| Pain Intensity (MPI-SCI subscale) | − | ||||
| Heutink et al. (28) | NP (61) | Multidisciplinary Cognitive Behavioural Program | Waitlist Control | Pain-related disability (2-item, 11-point Chronic Pain Grade Questionnaire) |
− |
| Depression & Anxiety (HADS) | + (anxiety) |
||||
| Pain Intensity (Chronic Pain Grade Questionnaire) | + | ||||
| Norrbrink et al. (29) | NP (38) | Pain Management Program | Control (no intervention) | Depression & Anxiety (14-item, 4-point HADS scale) |
+ (depression) |
| Pain Intensity (Borg CR-10 scale) | − | ||||
| Perry et al. (30) | NP (33) | Pain Management Program | Usual Care | Life Interference (MPI-SCI subscale) |
+ |
| Depression & Anxiety (HADS scale) |
− | ||||
| Pain Intensity (NRS) | − | ||||
Table 2.
Quality assessment.
| Quality Assessment | ||||||
|---|---|---|---|---|---|---|
| No of participants (studies) |
Risk of Bias | Inconsistency | Indirectness | Imprecision | Publication Bias | Overall Quality of Evidence |
| Are anticonvulsants effective in decreasing pain interference in individuals with SCI? | ||||||
| 251 (1 RCT, 1 Quasi-experimental) |
serious1 | not serious | not serious | not serious | none | ⊕OO Moderate |
| Are antidepressants effective in decreasing pain interference in individuals with SCI? | ||||||
| 74 (1 RCT) |
serious2 | not serious | not serious | serious3 | none | ⊕OO Moderate |
| Are analgesics effective in decreasing pain interference in individuals with SCI? | ||||||
| 36 (1 RCT) |
not serious | not serious | not serious | serious | none | ⊕OOO High |
| Are antispastics effective in decreasing pain interference in individuals with SCI? | ||||||
| 13 (1 RCT) |
serious2 | not serious | not serious | not serious | none | ⊕OO Moderate |
| Is acupuncture effective in decreasing pain interference in individuals with SCI? | ||||||
| 12 (2 Quasi-experimental) |
serious1 | not serious | not serious | not serious | none | ⊕⊕ Low |
| Is Transcranial DCS effective in decreasing pain interference in individuals with SCI? | ||||||
| 40 (1 RCT) |
not serious | not serious | not serious | not serious | none | ⊕OOO High |
| Is CES effective in decreasing pain interference in individuals with SCI? | ||||||
| 143 (2 RCT) |
not serious | serious | not serious | serious3 | none | ⊕⊕ Low |
| Is TENS effective in decreasing pain interference in individuals with SCI? | ||||||
| 48 (1 RCT, 1 Quasi-experimental) |
not serious | not serious | not serious | serious4 | none | ⊕OO Moderate |
| Is rTMS effective in decreasing pain interference in individuals with SCI? | ||||||
| 13 (1 RCT) |
serious | not serious | not serious | serious3 | none | ⊕⊕ Low |
| Is functional electrical stimulation effective in decreasing pain interference in individuals with SCI? | ||||||
| 11 (single-arm) | serious1 | not serious | serious5 | not serious | none | ⊕ Very Low |
| Is meditation and imagery effective in decreasing pain interference in individuals with SCI? | ||||||
| 16 1 (RCT) | serious2 | not serious | not serious | not serious | none | ⊕OO Moderate |
| Is self-hypnosis and biofeedback effective in decreasing pain interference in individuals with SCI? | ||||||
| 37 (1 RCT) | not serious | not serious | serious | not serious | none | ⊕OO Moderate |
| Is an interdisciplinary pain program effective in decreasing pain interference in individuals with SCI? | ||||||
| 152 (1 RCT, 3 Quasi-experimental) |
serious | not serious | not serious | serious3,4 | none | ⊕⊕ Low |
Note: 1. Trial not blinded, 2. Incomplete data not addressed, 3. CI not provided, 4. Wide CI’s, 5. No control group.
Anticonvulsants
Two moderate quality studies included assessments of pain interference following administration of anticonvulsants in individuals with SCI and NP (11,12). In a non-randomized trial, Ahn et al. (11) recruited 31 SCI participants (all with NP, time since injury unreported) and divided participants into 2 groups: duration of symptoms < 6 months (n = 13) vs duration of symptoms > 6 months (n = 18). Following an 18-day titration period, participants maintained a constant dose of gabapentin for 5 weeks. Pain severity and sleep interference were assessed via 100 mm VAS and 0–10 VAS, respectively. At the end of the study, pain and sleep interference scores were significantly reduced in both groups. Six adverse effects were reported including somnolence (n = 10), edema (n = 1), dizziness (n = 1), headache (n = 1), perioral numbness (n = 1), and worsening of preexisting renal insufficiency (n = 1).
Cardenas et al. (12) recruited 220 participants with chronic below-level NP due to SCI (≥ 12 months post-injury) and randomized them into 2 groups: pregabalin (150 mg/day to 600 mg/day) (n = 108), or placebo (n = 112). Following a 4-week optimization period, participants performed a 12-week maintenance period followed by a 1-week taper period. Pain-related sleep interference was assessed as a secondary outcome (11-point scale) and demonstrated a significant improvement over placebo at 1-week which was maintained throughout the trial. Adverse events reported in the treatment group were primarily mild to moderate and included somnolence (n = 37), dizziness (n = 20), peripheral edema (n = 13), dry mouth (n = 9), fatigue (n = 8), blurred vision (n = 7), and edema (n = 6). One serious adverse event of hypoglycemia was reported which resolved upon discontinuation of the pregabalin treatment.
Antidepressants
One moderate quality RCT included an assessment of pain interference following administration of the antidepressant venlaxafine XR (13). The study consisted of 123 individuals with SCI (10.9 ± 10.6 years post-injury) and major depression who also reported pain (89 of whom had NP). Participants were randomized into 1 of 2 groups: venlaxafine XR (n = 64) or placebo (n = 59). A flexible dosing plan was used over a 12-week treatment period with titrations at 1,3,6,8, and 10 weeks. Among the Venlaxafine and placebo group 74 and 77 pain sites were classified at neuropathic, respectively. There were no significant group x time interactions for any measure of pain interference as assessed via the Brief Pain Inventory (BPI). Reported serious adverse events in the Vanlaxafine group included urinary tract infection, pressure ulcer, heart palpitations, and suicide attempt.
Analgesics
One high quality RCT included an assessment of pain interference following the administration of the analgesic tramadol (14). The study included 35 individuals with SCI (14.6 ± 11.3 years post-injury) and NP who were randomized to receive either tramadol (n = 23) or placebo (n = 12). Study medication was taken over a period of 4-weeks with an initial dose of 50 mg/day. The dose was increased every 5-days by 50 mg until a maximum dose of 400 mg/day was reached (or until optimal pain relief was experienced and/or adverse events occurred). No between group differences were observed in pain interference as rated on the 11 pain-related interference items of the Multidimensional Pain Inventory (MPI). Between group differences were reported for sleep quality, however, this was driven by a deterioration in the placebo group while the treatment group showed no change. HADS scores showed between group differences for anxiety only. Reported adverse events were substantial in the treatment group resulting in a 43% dropout rate and included tiredness (n = 17), dry mouth (n = 12), dizziness (n = 12), sweating (n = 9), constipation (n = 8), nausea (n = 9), and voiding dysfunction (n = 1).
Antispasmodics
One moderate quality RCT included an assessment of pain interference following the administration of an antispasmodic in the form of intrathecal baclofen (ITB) (15). The study included 13 (11 after dropouts) individuals with SCI (range: 12–246 months post-injury) and NP who were randomized to receive either a single ITB bolus (n = 8) or placebo (n = 5). Measures of pain interference were assessed using a modified (sleep not assessed) 6-item version of the Brief Pain Inventory (BPI) subscale at baseline, 4, 8, and 24 h after application of ITB or placebo. Interference of pain with general activity, moving around, enjoyment of life, ability to work and perform daily tasks, and relationship with other people improved in the treatment group only, at all-time points (except for moving around at 8- and 24-hour post). Adverse events were reported as ‘minimal’.
Acupuncture
Two studies (one low and one very low quality) included an assessment of pain interference following the administration of acupuncture in individuals with SCI and NP (16,17). In a single-arm study, Nayak et al. (16) recruited 22 individuals with SCI (8.49 ± 7.47 years post-injury), of whom 12 were classified as having central or deafferentation pain. All participants completed a 7.5 week no-acupuncture baseline period followed by a 7.5-week active treatment period with acupuncture to allow for within-subjects comparisons. Pain interference was assessed via the 1-item pain impact and interference activity scale (11-point scale) and demonstrated a significant improvement from baseline. Depression and anxiety were assessed via the Centre for Epidemiological Studies Depression Scale (CES-D) and the Spielberger State Anxiety Inventory (STAI) respectively and showed no significant changes. With respect to adverse events, the authors stated a small group of participants reported a slight increase in pain after the course of the treatment and follow-up.
In a single-arm study, Norrbrink et al. (17) recruited 30 individuals with SCI (11.9 ± 12.3 years post-injury) and NP, using a sequential controlled design, to complete 6-weeks of either acupuncture or massage therapy. Pain interference was assessed as a secondary outcome using the MPI and improved in the massage group only. Adverse events included tiredness (n = 1) and acutely increased pain (n = 1) in the acupuncture group, and soreness (n = 2), increased pain (n = 1), and feeling cold (n = 1) in the massage group.
Transcranial direct current stimulation (tDCS)
One high quality RCT included an assessment of pain interference in response to transcranial direct current stimulation (tDCS) with and without visual illusion (18). Thirty-nine participants with SCI (range: 1–31 years post-injury) and NP were randomly assigned to one of four treatment groups: tDCS + visual illusion, tDCS + control illusion, tDCS sham + visual illusion, or tDCS sham + control illusion. Pain interference (general activity, mood, ability to work and perform daily tasks, sleep, enjoyment of life, ability to get around, relationships with other) was assessed with the BPI and in general, the combination of tDCS + visual illusion showed the highest improvement with significant changes in all categories except general activity and relationships with others. Anxiety was assessed via an 11-point NRS and showed a significant improvement in each treatment group. Adverse effects related to tDCS included mild headache (n = 3).
Active cranial electrotherapy stimulation (CES)
Two RCTs (one low and one moderate quality) included an assessment of pain interference in response to active cranial electrotherapy stimulation (CES) (19,20). The first was a pilot study by Tan et al. (19) whereby 38 males with SCI (19.9 ± 12.3 years post-injury) were randomly assigned to receive either 1-hour of active CES (n = 18, 12 with NP) or sham CES (n = 20, 11 with NP) per day for 21 days. Pain interference was assessed with a version of the 10-item pain interference subscale of the BPI modified for persons with physical disability. No significant difference between groups with regard to change in any pain interference item (pre to post) were shown. No adverse events were reported.
A larger scale clinical trial was then performed by Tan et al. (20) whereby 105 individuals with SCI (15.2 ± 14.1 years post-injury) and NP were randomly assigned to receive either 1-hour of active CES (n = 46) or sham CES (n = 59) per day for 21 days. Pain interference was assessed with a version of the 10-item pain interference subscale of the BPI modified for persons with physical disability. Only the composite pain interference score (10-items) showed a significant group x time interaction whereby the active CES group had larger improvements in pain interference. Reported adverse events in the active CES group were mild and included: tingling sensation (n = 13), spasms (n = 1), burning in buttocks (n = 1), ringing in ears (n = 1) drowsiness (n = 7), dizziness (n = 3), nausea (n = 1), headache (n = 2), metallic taste in mouth (n = 1), increase pain (n = 2).
Transcutaneous electrical nerve stimulation (TENS)
Two studies (1 moderate quality RCT and 1 low quality quasi-experimental study) included an assessment of pain interference in response to transcutaneous electrical nerve stimulation (TENS) (21,22). In a crossover design, Ozkul et al. (21) recruited twenty-four individuals with SCI (range 2–132 months post-injury) and NP. Participants were randomly assigned to first receive either 2-weeks of visual illusion therapy followed by 2-weeks of TENS (n = 12), or 2-weeks of TENS followed by 2-weeks of visual illusion therapy (n = 12). Pain interference was assessed with a 7-item version of the pain interference subscale of the BPI modified for persons with disability. Significant improvements following TENS were shown for 3 pain interference subscale items including: relationships with others, mood, and sleep. Adverse events were not reported.
A second crossover design by Norrbrink et al. (14) recruited twenty-four individuals with SCI (6.8 ± 8.4 years post-injury)and NP. Participants received 2-weeks of high frequency TENS, and 2-weeks of low frequency TENS (separated by a 2-week washout period). The order of treatment was determined based on recruitment order. No significant between group or within group differences were found for pain interference (as assessed by the MPI-S), anxiety and depression (as assessed by the HADS), quality of sleep (as assessed by the Nordic Basic Sleep Questionnaire), or life satisfaction (as assessed by the LiSAT-9). Adverse events were mild and included discomfort / increased pain during treatment (n = 3), and muscle spasms (n = 1).
Repetitive transcranial magnetic stimulation (rTMS)
One low quality RCT included an assessment of pain interference in response to repetitive transcranial magnetic stimulation (rTMS) (23). In this within-subjects cross-over design, individuals with SCI (range: 15–231 months post-injury) and NP were randomly assigned to first receive a single session of rTMS followed (12-weeks later) by a single session of sham-rTMS or begin with sham-rTMS followed by rTMS. Pain interference was assessed with a modified 6-item version (walking removed) of the BPI subscale of the BPI modified for persons with physical disability. Pain interference items did not differ between real and sham rTMS treatments. Adverse events were not reported.
Functional electrical stimulation
One very low quality study included an assessment of pain interference in response to functional electrical stimulation (FES) cycling (24). This single-arm trial included 16 individuals with SCI (11 of whom had NP, range: 4–14 months post-injury) who completed 6-weeks of FES cycling (2x daily, 6-times weekly) in addition to physiotherapy. Pain interference was assessed via the 36-item Short Form Survey (SF-36). SF-36 scores were shown to be significantly reduced from baseline to post, and baseline to 3-month follow-up. However, as participants also received physiotherapy and a control group was not included it is not possible to attribute these improvements to FES cycling. No adverse events were reported.
Meditation & imagery
One moderate quality RCT included an assessment of pain interference in response to meditation and imagery (25). This randomized controlled trial included 24 individuals with SCI (16 of whom had NP, range 1–21 years post-injury) who were randomized to receive either a 4-week (1x per week) clinical meditation and imagery program or an SCI health and function education control condition. Pain interference was assessed via the Modified Multidimensional Pain Inventory Life Interference Subscale (MPI-LIS). Significant between group differences were shown for pain interference, however, this was driven by a greater reduction in the control group suggesting no benefit for the meditation and imagery program. No adverse events were reported.
Hypnosis & biofeedback
One moderate quality RCT included an assessment of pain interference in response to hypnosis and biofeedback training (26). This trial included 37 individuals with SCI (17 of whom had NP, ≥ 6-months post-injury), who were randomized to receive either 10 sessions of hypnotic analgesia and self-hypnosis training (n = 23) or 10 session of EMG biofeedback training (n = 14). Pain interference was assessed via a version of the 10-item pain interference subscale of the BPI modified for persons with physical disability. No significant changes in pain interference were observed in either group. Depression as assessed by the CES-D showed a significant group x time interaction, however, this was driven by an increase in depressive symptoms in the biofeedback group. No adverse events were reported.
Interdisciplinary pain programs
Four studies (3 of low quality and 1 of moderate quality) included an assessment of pain interference in response to an interdisciplinary pain program (27–30). In a single-arm study, Burns et al. (27) recruited 22 individuals with SCI (8.9 ± 11 years post-injury), of which complete data was available for 17 (16 of whom had NP). Participants completed 10-weeks of biweekly sessions of CBT, patient education on chronic pain, self-management strategies, group discussions / activities, and either group exercise or guided relaxation. Pain interference was assessed via the Multidimensional Pain Inventory (MPI-SCI). ANOVA revealed a significant change for life interference. Post hoc analysis showed the decline in life interference was not significant immediately following the intervention but was significant 3 and 12-months after the intervention. Adverse events were not reported.
Heutink et al. (28) randomized 61 individuals with SCI (> 1-year post injury) and NP to receive either 10 sessions of a multidisciplinary cognitive behavioral program (CBT) or enter a waitlist control period. Pain-related disability was assessed via the Chronic Pain Grade Questionnaire (CPG) which assesses the degree of pain interference with daily activities, work/household activities, and recreational/social activities. No significant group x time interactions were shown for pain-related disability. Depression and anxiety were assessed as secondary outcomes via the Hospital Anxiety and Depression Scale (HADS). No changes were observed in scores of depression. A significant group x time interaction was shown for anxiety whereby the intervention group showed a significant reduction from baseline to 3-months post and from baseline to follow-up (6-months). No adverse events were reported. A follow-up to this study was performed including 29 of the 31 participants from the original treatment group at 9-months and 12-months post (the control group was not included in the follow-up analysis). Pain-related disability was significantly reduced from baseline to 9-months and baseline to 12-months in the treatment group. While HADS depression scores remained unchanged, HADS anxiety were significantly reduced from baseline to 12-months.
Norbrink et al. (29) performed a non-randomized trial on 38 individuals with SCI (9.9 ± 12.8 years post-injury) and NP undergoing a comprehensive pain management program vs control condition. The comprehensive pain management program (20 session over 10-weeks) consisted of patient education, CBT sessions, relaxation techniques, stretching / light exercise, and body awareness training. Quality of sleep was assessed using a 10-item questionnaire and depression was assessed via the HADS. A significant group x time interaction was found for depression whereby the treatment group had a significant reduction from baseline to 12-months. No group differences were found for quality of sleep. No adverse events were reported.
Perry et al. (30) performed a non-randomized trial on 36 individuals with SCI (33 of whom had NP, 70.5 ± 92.6 months post-injury) and underwent a 10-week pain management program (PMP) vs usual care. As an estimation of the perceived interference of pain on physical functioning, the Life Interference Subscale of the Multidemensional Pain Inventory-SCI (MPI-SCI) was assessed. The PMP treatment group showed a significantly greater improvement in life interference due to pain than the control group. Depression and anxiety were also assessed via the HADS, but no significant differences between groups were shown. No adverse events were reported.
Discussion
This review included a total of 20 studies which assessed the efficacy of various strategies for the treatment of pain interference in individuals with neuropathic pain following spinal cord injury. When considering treatment strategies assessed by studies of moderate to high quality (n = 9), gabapentin, pregabalin, intrathecal baclofen, transcranial direct current stimulation (tDCS), and transcutaneous electrical nerve stimulation (TENS) were shown to have beneficial effects concerning pain interference and were primarily associated with only mild to moderate adverse events.
The use of the anticonvulsants gabapentin (11) and pregabalin (12) were each shown to have a beneficial effect on sleep interference. These treatments were associated with several mild to moderate adverse events (with the exception of one severe event in the form of hypoglycemia following pregabalin treatment). These treatment strategies have also been shown previously to be front-line treatment options for neuropathic pain intensity (31). The use of these anticonvulsants for pain interference may therefore be warranted, however, as the findings pertain only to sleep interference, were based on a single study for each anticonvulsant, and lacked a true control group in the gabapentin study, further research is needed.
Intrathecal baclofen, an antispasmodic, was also shown to have an acute beneficial effect on pain interference in comparison to placebo (as assessed via the BPI) in the first 24 h following treatment (15). BPI items including general activity, moving around, enjoyment of life, ability to work and perform daily tasks, and relationships with other people were all shown to improve. Minimal adverse events were reported; however, long-term effects were not assessed. Further research is warranted to assess chronic effects on pain interference and potential adverse events.
Transcranial direct current stimulation (tDCS) was assessed as a sole treatment as well as in combination with visual illusion. Using a within subjects analysis, tDCS alone was shown to benefit several aspects of pain interference including general activity, mood, and ability to get around. However, the combination of tDCS and visual illusion was generally more effective. Further, while statistical comparisons between the tDCS and placebo group were not reported, the placebo group was also shown to have a significant improvement in mood. Thus, while tDCS may help improve pain interference (and is associated with only mild adverse events), further research is required to determine its efficacy as a standalone treatment.
Transcutaneous electrical nerve stimulation (TENS) was shown to improve 3 aspects of pain interference, (assessed via the modified BPI) including relationships with others, mood, and sleep following 2-weeks of treatment in a within-subjects analysis from a single study (21). However, a second study, also assessing 2-weeks of high-intensity and low-intensity TENS found no between or within group differences for pain interference. Future randomized controlled trials, which include a placebo group are warranted.
Other studies of moderate to high quality including those which assessed the use of antidepressants (13), analgesics (14), hypnosis/biofeedback (26), and meditation (25) were not shown to improve pain interference. Again, findings for each of these treatment strategies are based on a single study. The remaining 9 studies included in this review were deemed low quality due to issues related to blinding, incomplete data, lack of a control group and large or unreported variability and showed mixed results with regards to efficacy.
The current review has several limitations. The primary limitation relates to the limited number of studies which assess pain interference as an outcome following treatment for neuropathic pain in individuals with spinal cord injury. Findings were often based on a single study which demonstrates the need for further research to better establish which treatment strategies most effectively improve pain interference.
A second limitation relates to heterogeneity between studies due to the relatively broad definition of pain interference and the use of varying assessment tools. Pain interference encompasses several physical (e.g. sleep quality, mobility, etc.) and affective (mood, relationship with other, etc.) items. While some studies utilize a composite score which includes an average of both physical and affective items, others focus on one or more items in isolation. Among studies included in the current review, 9 unique assessment tools were utilized. In addition, common assessment tools, such as the BPI, were frequently modified by adding or removing items. Such heterogeneity makes it difficult to compare treatment effects across studies.
Finally, several studies included in this review were limited by study design and/or analysis/reporting of findings. Numerous studies either did not include a true control or reported only within group effects despite including a control. Given the subjective and highly variable nature of pain interference the inclusion of a control group and reporting of between group effects is highly valuable.
Despite these limitations, findings from quality studies will help to expand the relevance of the CanPain SCI recommendations for the treatment of neuropathic pain following SCI. To date, treatment recommendations from these guidelines have focused exclusively on the impact on pain intensity and have identified first-line treatment options based on the quality of evidence in the literature, and the strength of recommendations from experts (based on factors such as efficacy, side effects, cost, etc.). This has resulted in recommendations for the use of the anticonvulsants pregabalin and gabapentin, as well as the tricyclic antidepressant amitriptyline as first-line treatment options for the reduction of neuropathic pain intensity. While no studies assessing the efficacy of amitriptyline on pain interference were identified in the current review (and a single study on the SNRI Venlafaxine showed no benefit), the beneficial effect of pregabalin and gabapentin on sleep interference may help to further strengthen the recommendation for their use as first-line treatment options for NP.
Conclusion
The current review found that when considering treatment strategies from studies of moderate to high quality, pregabalin, gabapentin, intrathecal baclofen, transcranial direct current stimulation, and transcutaneous electrical nerve stimulation (in 1 of 2 studies) were beneficial for pain interference. However, due to the low number of high-quality studies there is a need for further research to provide stronger evidence regarding the efficacy of these interventions prior to recommending there use to benefit pain interference.
Disclaimer statements
Contributors None.
Conflicts of interest Authors have no conflict of interests to declare.
Supplementary Material
Appendix.
Appendix 1. Search Strategy
Date of Search: April 2022
Databases: MEDLINE (1996 to April 22 2022), EMBASE (1996 to April 22 2022), PsycInfo (1987 to April week 2 2022)
| # | Searches | Results |
|---|---|---|
| 1 | Spinal cord injur* | 99688 |
| 2 | neuropathic pain OR pain OR central pain | 1743444 |
| 3 | pain interference OR pain intrus* OR pain obtrus* OR pain imping* | 6045 |
| 4 | BPI or basic pain inventory or SF-36 or short form survey or PROMIS or Patient-Reported Outcome Measurement Information System | 74938 |
| 5 | 3 or 4 | 78893 |
| 6 | 1 and 2 and 5 | 448 |
| 7 | Remove duplicates from 6 | 269 |
Funding Statement
This work was supported by Ontario Neurotrauma Foundation [grant number 2018-RHI-GUIDE-1049].
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