Neuropathic Pain Post Spinal Cord Injury Part 1: Systematic Review of Physical and Behavioral Treatment

Abstract

Background:

Neuropathic pain has various physiologic and psychosocial aspects. Hence, there is a growing use of adjunct nonpharmacological therapy with traditional pharmacotherapy to reduce neuropathic pain post spinal cord injury (SCI).

Objective:

The purpose of this study was to conduct a systematic review of published research on nonpharmacological treatment of neuropathic pain after SCI.

Methods:

MEDLINE, CINAHL, EMBASE, and PsycINFO databases were searched for articles addressing nonpharmacological treatment of pain post SCI. Articles were restricted to the English language. Article selection was conducted by 2 independent reviewers with the following inclusion criteria: the subjects participated in a treatment or intervention for neuropathic pain; at least 50% of the subjects had an SCI; at least 3 subjects had an SCI; and a definable intervention was being studied. Data extracted included study design, study type, subject demographics, inclusion and exclusion criteria, sample size, outcome measures, and study results. Randomized controlled trials (RCTs) were assessed for quality using the Physiotherapy Evidence Database (PEDro) assessment scale. Levels of evidence were assigned to each intervention using a modified Sackett scale.

Results:

The 16 articles selected for this review fell into 1 of 2 categories of nonpharmacological management of pain after SCI: physical and behavioral treatments. The pooled sample size of all studies included 433 participants. Of the 16 studies included, 7 were level 1, 3 were level 2, and 6 were level 4 studies.

Conclusions:

Physical interventions demonstrated the strongest evidence based on quality of studies and numbers of RCTs in the nonpharmacological treatment of post-SCI pain. Of these interventions, transcranial electrical stimulation had the strongest evidence of reducing pain. Despite a growing body of literature, there is still a significant lack of research on the use of nonpharmacological therapies for SCI pain.

Pain is a common complaint among individuals who have experienced a spinal cord injury (SCI), and its persistence can have a negative impact on their quality of life. The International Association for the Study of Pain (IASP)¹ defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage.” According to research by Siddall et al,² at least 80% of people with an SCI experience chronic pain, and at least 40% of these people are affected by neuropathic pain. Neuropathic pain is defined by the IASP¹ as “pain caused by a lesion or disease of the somatosensory nervous system,” and it can be categorized as central or peripheral neuropathic pain. Neuropathic pain usually has its onset shortly after the injury and can persist for the rest of the patient’s life.³ Neuropathic pain associated with SCI negatively affects quality of life (QOL) including cognitive, emotional, and physical functioning, and ultimately, rehabilitation outcomes.⁴

Neuropathic pain can occur above, at, or below the level of injury. Neuropathic pain above the level of SCI is uncommon. Diagnosis of neuropathic pain can be difficult because of the lack of “validated diagnostic criteria.”⁵ Hallstrom and Norrbrink⁶ found that a variety of screening tools are available to assist in the diagnosis of neuropathic pain; the most popular and validated tools include the Doleur Neuropathique (DN4), Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), Neuropathic Pain Questionnaire (NPQ), and PainDETECT (PD-Q). These tools assist clinicians in screening their patients; however, an assessment should also include the patient’s pain history and somatosensory testing.⁶ A number of pain symptoms and sensory impairments localized to the same area remain the basis for the diagnosis of neuropathic pain.⁷

Neuropathic pain is unique to each individual and is a persistent problem for many people with SCI; it is typically managed with a range of pharmacological and nonpharmacological treatments. A great deal of research has been conducted on the efficacy of pharmacological interventions to treat neuropathic pain; these interventions are not without adverse effects, and many individuals are concerned about the consequences of long-term use of these medications. As a result, there is growing interest in nonpharmacological interventions for neuropathic pain. Nonpharmacological treatments can be used as an effective adjunct to pharmacological interventions, enhancing the overall impact of pain-relieving interventions for the individual with an SCI. There is some evidence that physical modalities may be used effectively in conjunction with pharmacological treatment.⁸ Psychological approaches such as visual imagery, cognitive behavioral therapy (CBT), and body awareness training are also often applied in pain management and are used alone or in conjunction with pharmacological and physical therapies. The use of psychological approaches and alternative treatments (eg, cranial electrotherapy [CES], transcranial direct current stimulation [tDCS], and acupuncture) alone or in conjunction with pharmacological intervention may be useful in helping patients manage neuropathic pain while limiting unwanted side effects.

This systematic review was conducted to assess the effectiveness of physical and behavioral therapies on neuropathic pain in people with SCI.

Methods

Literature search strategy

A systematic review of all relevant literature, published from 1980 to April 2011, was conducted using multiple databases (MEDLINE, CINAHL, EMBASE, PsycINFO). Key words included spinal cord injuries, pain, pain treatment, pain management, massage, heat, exercise, hypnotic, hypnosis, acupuncture, transmagnetic stimulation, transcranial electrical stimulation, and transcutaneous electrical nerve stimulation. Retrieved references were scanned for relevant citations.

Study selection

Studies were selected for analysis if the following criteria were met: (1) at least 50% of the subjects had an SCI; (2) at least 3 subjects had an SCI; (3) the study included individuals with neuropathic pain; and (4) a definable intervention was being studied. Study design was not an exclusion criterion. Studies were excluded if there was insufficient reporting detail to enable data synthesis or if the study was a nonclinical trial (ie, reviews, epidemiology, or basic sciences research).

Study appraisal

A quality assessment was conducted for each study by 2 reviewers using the Physiotherapy Evidence Database (PEDro) scoring system⁹ for randomized controlled trials (RCTs). Any disagreements were resolved through consensus. The PEDro tool consists of 11 questions with a maximum score of 10. In the present methodology, a PEDro score of 5 or lower was used to designate a “poor” quality RCT, which corresponds to a marginally lower score than the approximate mean value over all RCTs in the PEDro database conducted over the latest reported periods (ie, 1995-2002).¹⁰ The Downs and Black (D&B) tool was used in the assessment of non-RCTs. The D&B tool contains 27 items with a maximum score of 28; higher scores reflect a higher methodological quality of the rated study.¹¹

Data synthesis

Studies involving similar interventions were grouped and tabulated. Summary tables were developed indicating the quality of the study, the type of study, a brief summary of intervention outcomes, and study results. The strength of the evidence for each intervention was rated using a modified Sackett scale.¹² The evaluation of the data led to the conclusion that a meta-analysis would be inappropriate to summarize the evidence because of the heterogeneity of the studies, inconsistency in the use of specific types of outcome measures, low methodological quality, and insufficient data reporting.

Results

Study size and quality

Power calculations were not reported in any of the included studies. Pooled size of all included studies was 433 subjects. Sample sizes of each study ranged from 5 to 47 with a mean of 27.6 subjects. Seven of the 16 studies included were level 1 RCTs,^13–19 1 was a level 2 RCT,²⁰ 2 were level 2 prospective controlled trials,^21,22 and 6 were level 4 studies.^23–28

Neuropathic pain assessment

Most of the studies reviewed included only participants with neuropathic pain. However, 6 studies comprised a heterogeneous population, which included both individuals with musculoskeletal and individuals with neuropathic pain.^{13,17,20,24,26} Assessment of neuropathic pain was conducted by means of clinical interview in most studies,^{13–18,20,25,26,28} while Arienti et al¹⁹ used the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale to assess neuropathic pain and Rapson²⁷ used patient characteristics from a chart review to identify pain type. Neuropathic pain was identified based on a number of clinical features in all the studies including the following descriptions: sharp, burning, “at level,” “below level,” shooting, and central pain.

Combined pharmacological treatment

All studies included in the review also reported use of various pharmacotherapeutic agents by participants including opiates, tricyclic antidepressants, anticonvulsants, nonsteroidal antiinflammatory drugs, and analgesics. Participants in most studies were required to continue using their pharmacological treatment and maintain their specific dosage. Capel¹⁷ asked participants to try to reduce their use of medication, if possible, 24 hours before the intervention. The study by Arienti et al¹⁹ involved prescription of pregabalin, 600 mg per day, to the pharmacological group and the combined pharmacological and osteopathic group. Gustin et al²⁴ included patients receiving stable analgesic medications including gabapentin, amitriptyline, oxycodone, escitalopram, naproxen, and paracetamol.

Physical treatments

Transcranial electrical stimulation

Despite the fact that transcranial electrical stimulation (TES) is a relatively new treatment for post-SCI pain, 4 RCTs^13,15–17 indicate that it may be useful, which has spurred increasing interest in its use for the reduction of neuropathic pain in SCI. Tan et al¹³ conducted a double-blind RCT with participants receiving either active TES or inactive TES (sham control) over 21 days. The electrical stimulation was set at a subthreshold level, ensuring that patients were blinded to their treatment group. The study demonstrated that patients with SCI receiving TES (n=18) experienced a significant reduction in post-SCI neuropathic pain according to their reported average daily rating of pain intensity (P = .03); however, there was no significant reduction in pain as noted on the Brief Pain Inventory (BPI) when compared to controls.

Capel et al¹⁷ reported that TES resulted in lower pain scores on the McGill Pain Questionnaire for those in the treatment group (n=15), while those in the control group (n=15) reported no change. No statistical differences were noted across different pain types, although the authors did comment on greater relief of visceral pain after each active 4-day treatment phase of the study. TES was associated with a reduction in the use of analgesics and antidepressants.

Fregni et al¹⁵ reported similar results after examining the effects of transcranial direct current stimulation (tDCS) on central neuropathic pain. The treatment group (n=11) received active tDCS for 5 consecutive days and experienced a significant reduction in pain over time (P <.0001) compared with those receiving sham treatments (n=6).¹⁵ Furthermore, 7 of the 11 participants reported a reduction of greater than 50% in pain intensity.

Soler et al¹⁶ divided participants into 4 groups: the tDCS group, visual illusion group, combined tDCS and visual illusion group, and the control group. The tDCS group received direct current simulation over C3 or C4 at a constant intensity of 2 MA for 20 minutes along with a control visual illusion, which involved watching a video of faces or landscapes. The actual visual illusion group was provided with a sham tDCS treatment; after 5 minutes, they were shown a video of someone walking in front of a vertical mirror so patients would perceive themselves walking for 15 minutes. The combined tDCS and visual illusion group received active tDCS treatment and viewed an actual visual illusion, and the control group received sham tDCS treatment and viewed a control visual illusion. Each participant received a total of 10 sessions of therapy, 20 minutes each, for 2 weeks. The study demonstrated significant improvement in numeric rating scale (NRS) pain perception, pain reduction, ability to work, ability to perform daily tasks, enjoyment, and less interference of pain with sleep (P <.05) in the combined tDCS and visual illusion group compared with the other groups. A clinically significant reduction in pain intensity of 30% was observed in 30% of participants in the combined group.

Level 1 evidence from 4 RCTs^13,15–17 supports a beneficial effect of TES in reducing post-SCI neuropathic pain.

Transcranial magnetic stimulation

Defrin et al¹⁸ conducted an RCT examining the treatment effect of 10 daily motor transcranial magnetic stimulation (TMS) treatments for 2 weeks. Twelve patients were randomly assigned to either a sham control group or a TMS treatment group. Coils with identical shape and background noise were used in both groups, but only the active TMS group received magnetic stimulation. A significant change in pain threshold was found between the active and sham TMS groups after treatment (P <.05). Both groups reported similar decreases in pain scores immediately after treatment, but only the active TMS group reported improved pain and depression scores at follow-up (2-6 weeks). Participants also experienced clinically significant reduction in pain intensity (30%) after TMS treatment.

Kang, Shin, and Bang¹⁴ provided participants with either active repetitive TMS (rTMS) or sham rTMS in an RCT. The active rTMS group received 20 trains of 10-Hz stimuli over 5 seconds, repeated for 5 days, while the sham group received a similar setup but with no stimulations. The authors reported no significant difference between the 2 groups in NRS score for average pain. Worst pain decreased in the active rTMS group compared with the sham group (P = .05).

The results of 2 small RCTs^14,18 provide level 1 evidence that TMS treatment may reduce pain threshold and worst pain. However, no reduction of pain intensity was seen as a result of TMS treatment.

Transcutaneous electrical nerve stimulation

Norrbrink²¹ in a crossover study, examined the effect of low-frequency (2 Hz) or high-frequency (80 Hz) TENS. Patients received either low- or high-frequency stimulation for 30 to 40 minutes, 3 times a day, for 2 weeks, followed by a 2-week washout period. They then switched stimulation frequency groups. The authors reported no significant difference between the 2 treatments in relieving neuropathic pain. However, the authors did find clinically significant reductions of pain intensity, worst pain intensity, and pain unpleasantness after treatment when compared with baseline scores. In 70% of participants, there was a decrease of greater than 2 points in pain intensity from baseline, where clinical significance was defined as having a reduction of greater than 1.8 points.

Davis and Lentini²⁵ reported on an uncontrolled study of a series of patients (n=31) in whom transcutaneous nerve stimulation was applied to painful areas. Among those with a thoracic (n=11) or caudal level injury (n=16), only 36% reported that the treatment was successful in reducing neuropathic pain at the injury site; meanwhile, none of those with a cervical injury (n=4) experienced any reduction in pain. In general, TENS was not deemed effective for radicular or below-level injury site pain.

In summary, there is conflicting evidence that TENS treatment reduces neuropathic pain post SCI. Results of one level 2 study²¹ demonstrated reduction in general pain intensity, worst pain intensity, and pain unpleasantness after TENS treatment. However, a level 4 study²⁵ provided evidence that TENS reduced pain at the site of injury in a minority of patients with thoracic or cauda equina SCI, but not in those with cervical SCI.

Osteopathy

In 1 RCT, the use of osteopathic treatment in reducing neuropathic pain post SCI was examined.¹⁹ Participants were randomly assigned to 1 of 3 groups: the pharmacological group received 600 mg of pregabalin per day; the combined pharmacological and osteopathy group received osteopathic treatment once a week for the first month, once every fortnight for the second month, and once during the third month for 45 minutes along with the pharmacological treatment; the osteopathic group received only the osteopathic treatment schedule described; and the combined group received both active treatments. The study revealed that verbal numeric scale (VNS) ratings were not significantly different among the groups from baseline to 8 weeks. However, the combined treatment group had the greatest pain relief, compared with the pharmacological treatment alone (P = .05) and the osteopathic treatment alone (P = .001) groups, from 13 to 24 weeks.

Based on the results of 1 RCT,¹⁹ combined osteopathic treatment and administration of pregabalin provide significant neuropathic pain relief, which is significantly greater than relief provided by either of the 2 treatments alone.

Acupuncture

Two studies examined the effect of acupuncture on chronic central neuropathic pain. Rapson et al²⁷ conducted a retrospective chart review of 36 patients with SCI who had undergone at least 1 therapy session involving electroacupuncture for below-level central neuropathic pain. Two-thirds (24/36) of the patients reported improvement, based on a subjective retrospective assessment of overall results reported in the chart, with improvement greatest among those with bilateral, symmetric, constant, burning pain.

In a pre-post study involving 31 patients with SCI, Nayak et al²⁶ investigated the effect of 15 acupuncture treatments over a 7.5-week period on various types of SCI-related chronic pain, the most predominant types being central or deafferentation pain (54.5%) and musculoskeletal pain (22.7%). Pain intensity and pain interference with activities of daily living decreased from pre to post treatment. Pain relief was reported by 46% of the sample post treatment, and this relief was also maintained in 35% at 3 months. Despite these results, 6 patients (19%) reported a worsening of pain after treatment. Those that reported pain above their level of injury were more likely to respond to treatment (P <.05), as were those with incomplete versus complete injuries (60% vs 33%) and those with musculoskeletal versus neuropathic pain (80% vs 42%), although these latter differences were not statistically significant. At the 3-month follow-up visit, 18% of participants reported a decrease in pain intensity of greater than 3 points, whereas 27% reported more moderate levels of pain intensity decrease (between 2 and 3 points) (P <.01).

In conclusion, there is limited (level 4)^26,27 evidence that acupuncture reduces neuropathic pain in some patients with SCI.

Effectiveness of behavioral treatments

Behavioral management

Common behavioral management approaches include CBT, relaxation, and body awareness training (see Table 2).

Table 1.

Physical treatments

Study, study type, and scale score	No. of participants, type of pain, and diagnostic tool	Intervention and pain scale	Results
Transcranial electrical stimulation
Tan et al, 200613/USA RCT PEDro = 10	N = 38 Pain: Mixed (musculoskeletal and neuropathic)	Treatment: Subjects received TES or sham TES for 1 hr for 21 days to treat neuropathic or musculoskeletal pain. Following this, the control group was offered the opportunity to participate in an open-label TES study. Pain scale: BPI	No significant difference between TES and sham groups for BPI pain intensity or interference subscales. However, several individual interference items were significantly reduced, from pre to post intervention, in the TES group only. For active TES, average daily pain intensity from pre to post assessment decreased significantly (P = .03) compared with the sham (control) group. Significant reduction in daily pain intensity noted in treatment group (pre-post) (P = .02) but not in control group (P = .34).
Fregni et al, 200615/USA RCT PEDro = 9	N = 17 Pain: Neuropathic	Treatment: Subjects received either sham (10 sec of stimulation with same procedure but then turned off) or active tDCS (2 mA, 20 min for 5 consecutive days). Pain scale: VAS	Treatment produced significant decrease in pain scores over time (P <.0001). There was no significant effect of treatment on either anxiety or depression scores in either group.
Soler et al, 201016/Spain RCT PEDro=8	N = 39 Pain: Neuropathic Tool: Clinical interview	Treatment: Patients were randomly divided into 4 groups: tDCS and visual illusion group received direct current stimulation over C3 or 4 at a constant 2 mA intensity for 20 min and after 5 min of tDCS, video with someone walking was shown and the legs of person for 15 min with a vertical mirror so patients could see themselves walking; tDCS group with control visual illusion received the above-mentioned tDCS; however, for the visual illusion they only received a video of faces or landscapes; visual illusion group and sham tDCS had electrodes placed on the same area as the treatment group; however, the stimulator was turned off after 30 sec of stimulation; placebo group consisted of both the control visual illusion and the sham tDCS. Pain scale: NRS	The most significant reduction in NRS of pain perception was seen in the combined tDCS and visual illusion group compared with the visual illusion group (P = .008) or the placebo group (P = .004). Pain reduction was also greater in the tDCS and visual illusion group than in the other 3 groups at first and last follow-up; however, no difference was seen at second follow-up. Visual illusion group was shown to have significant reduction in neuropathic pain intensity on last day of treatment (P = .02); however, this effect was not maintained over the long term.
Capel et al, 200317/Canada RCT PEDro = 8	N = 30 Pain: Mixed group	Treatment: Subjects with SCI were randomly assigned to 1 of 2 groups. Treatment group received TES twice daily for 4 days, while control group received sham treatment. After an 8-wk washout period, treatments were reversed for sham treatment group only; thus, during the second half of the observation period, all received active treatment. Three subjects left the study early, 2 of whom because of interactions between TES and medications. Pain scale: SF-MPQ, PPI, VAS	During first part of the study, those receiving TES reported less severe pain vs baseline (P = .0016); control subjects reported no change. During phase 2 of study, control group (now receiving TES) also reported significantly less pain (P <.005).
Transcranial magnetic stimulation
Defrin et al, 200718/Israel RCT PEDro = 10	N = 12 Pain: Neuropathic	Treatment: Patients were randomly placed into 2 groups: real or sham 10 daily motor rTMS treatments (500 trains at 5 Hz for 10 sec; total of 5000 pulses at intensity of 115% of motor threshold) over a 2 wk period, using figure-of-8 coil over the vertex. Pain scale: VAS; MPQ	The real and sham TMS stimulated similar, significant decreases in VAS scores (P <.001) after all 10 treatment sessions and in VAS and MPQ scores after the final treatment series. The reduction in MPQ scores in the real rTMS group continued during the follow-up period (2 to 6 wk). There was no significant between-group difference in the magnitude of pain reduction. At follow-up, patients in the rTMS group reported a 30% reduction in chronic pain intensity, compared with a 10% pain reduction reported by patients in the sham TMS group. A significant increase in heat-pain threshold was found only for patients in the real rTMS group (4°C; P <.05) at the end of the series. There was a significant difference in the magnitude of change in pain threshold between the real and sham TMS groups (P <.05).
Kang et al, 200914/Korea RCT PEDro = 9	N = 11 Pain: Neuropathic Tool: Clinical interview	Treatment: Individuals received 2 sessions, either the real rTMS or the sham rTMS. Individuals in the real rTMS group received 20 trains of 10 Hz stimuli over 5 sec repeated for 5 consecutive days. While in the sham group, the setup was similar but no stimulations were provided. Pain scale: NRS	No significant change was seen between the 2 treatments in the NRS score for average pain. There was a trend toward decrease in the NRS score for worst pain between the real rTMS and the sham at 3 wk (P = .05).
Transcutaneous electrical nerve stimulation
Norrbrink, 200921/Sweden Prospective controlled trial	N = 24 Pain: Neuropathic Tool: Not stated	Treatment: Patients were provided with either low-frequency (2 Hz) or high-frequency (80 Hz) TENS stimulation for 30 to 40 min 3 times a day for 2 wk, followed by a 2-wk washout period and switched stimulation frequency. Pain scale: Borg CR-10, NRS	No significant difference was found between the 2 modes of stimulation. 21% reported reduction of greater than or equal to 2 units of general pain intensity (more than 1.8 is considered significant clinical reduction), 29% in worst pain intensity, and 33% in pain unpleasantness. 29% reported a favorable effect on the global pain relief scale from HF and 38% from LF stimulation.
Davis & Lentini, 197525/USA Case series D&B = 4	N = 31 Pain: Neuropathic	Treatment: Patients were tested with TENS Pain scale: Subjective patient report	Those with a cervical injury (n=4) were not successfully treated with TENS. About one-third (n=11) felt that treatment was a success, with those experiencing at-injury site pain most effectively treated.
Osteopathy
Arienti et al, 201119/Italy RCT PEDro = 6	N=47 Pain: Neuropathic Tool: LANSS Scale	Treatment: Patients were randomly placed into 3 groups: pharmacologic group received pregabalin (600 mg/day). The pharmacological and osteopathic group received pregabalin (600 mg/day) and osteopathic treatment once a week for the first month, once every fortnight for the second month, once during the third month—all for 45 min by an osteopathic physician. The osteopathic group received only the osteopathic treatment described above. Pain scale: VNS	Rates of improvement based on VNS scores were similar across the 2 treatments (P = .26). The greatest pain relief was seen in the combined pharmacologic and osteopathic group compared with the pharmacologic alone (P = .05) and the osteopathic alone (P = .001).
Acupuncture
Nayak et al, 200126/USA Pre-Post D&B = 21	N = 31 Pain: Mixed group	Treatment: 31 patients were offered 15 acupuncture treatments administered over a 7.5-wk period using a specific set of acupuncture points; additional points were selected based on individual history and clinical examination. Pain scale: NRS	Pain intensity decreased over time (posttreatment vs pretreatment) for worst pain (P <.01), average pain (P <.01), and present pain (P <.01). Posttreatment decline in pain intensity was maintained at 3-month follow-up (follow-up vs pretreatment: P <.01). Those who reported pain relief at 3-month follow-up reported more moderate levels of pain intensity on the NRS at baseline (7.83 ± .75) than those who did not report pain relief (9.67 ± .58; P <.01).
Rapson et al, 200327/Canada Pre-Post D&B = 14	N = 36 Pain: Neuropathic	Treatment: 36 SCI patients were given acupuncture treatments. Pain scale: Investigator impression of pain improvement, based largely on pain VAS from chart	24 participants improved in response to electro-acupuncture, while 12 exhibited no improvement. Bilateral pain (n=21) was more likely to respond to electro-acupuncture than unilateral pain (n=3) (P = .014). Those with symmetric pain had a greater response to treatment than those with asymmetric pain (P = .26). Those experiencing burning pain (bilateral and symmetric) and those experiencing bilateral and symmetric constant burning pain (P = .006 and P =.005) were more likely to improve after electro-acupuncture.

Note: ADL = activity of daily living; BDI = Beck Depression Inventory; BPI = Brief Pain Inventory; D&B = Downs and Black quality assessment scale score; EPQ = Eysenck Personality Inventory; HF = high frequency; LANSS = Leeds Assessment of Neuropathic Symptoms and Signs; NRS = Numeric Rating Scale; LF = low frequency; PEDro = Physiotherapy Evidence Database rating scale score; PPI = Present Pain Index; rTMS = repetitive transcranial magnetic stimulation; SF-MPQ = Short Form McGill Pain Questionnaire; STAI = Speilberger State and Trait Anxiety Inventory; tDCS = transcranial direct current stimulation; TENS = transcutaneous electrical nerve stimulation; TES = transcranial electrical stimulation; TMS = transcranial magnetic stimulation; VAS = Visual Analog Scale; VNS = verbal numeric scale; VRS = verbal rating scale; WUSPI = Wheelchair User’s Shoulder Pain Index.

Table 2.

Behavioral treatments

Study, study type, and scale score	No. of participants, type of pain, and diagnostic tool	Intervention and pain scale	Results
Behavioral management
Norrbrink et al,200622/Sweden Prospective controlled trial D&B = 19	N = 38 Pain: Neuropathic pain Tool: not stated	Treatment: 27 patients participated in a 10-wk twice weekly treatment program (20 sessions) vs 11 controls receiving regular care. Each treatment session consisted of 1.5 hr of education, 1.5 hr of CBT, and 1 hr each of stretching & relaxation and body awareness training. Pain scale: Borg CR10 scale	Pain intensity and unpleasantness, health-related QOL, and life satisfaction did not change over time for either group. Treatment group: anxiety and depression were reduced from baseline to 12-mo evaluation, with a significant difference between treatment vs controls. Sleep improved in the treatment group. When assessing QOL scores (Nottingham Health Profile), a significant improvement was noted for the Emotional Reaction subscale only (P <.01). A significant decrease in the number of visits between baseline and the 12-mo assessment was noted for the treatment group (from 15 to 5; P <.03), along with a reduction in the median number of visits to physicians (from 3 to 1; P <.03). Significant decreases in health care visits were also seen for the control group.
Hypnosis
Jensen et al, 200920/USA RCT PEDro = 5	N = 37 Pain: Mixed Tool: Not stated	Treatment: Participants were randomly assigned to receive either hypnosis or biofeedback. Individuals receiving hypnosis underwent 10 sessions of training daily or weekly. The biofeedback group received 10 sessions of EMG biofeedback. Pain scale: NRS	For individuals with neuropathic pain, a significant decrease in daily pain intensity was seen in the hypnosis group post session (P <.01) but not in the biofeedback group. Neither treatment was effective in reducing pain for individuals without neuropathic pain.
Jensen et al, 200023/USA Pre-Post D&B = 16	N = 22 Pain: Mixed Tool: Not stated	Treatment: Hypnotic suggestions were provided to individuals for pain relief. Pain scale: Self-report	86% reported decrease in pain intensity and unpleasantness from before induction to just after induction. A significant time effect emerged for both pain intensity (P <.001) and pain unpleasantness (P <.001). Significant effect for analgesic suggestion on pain intensity over and above the effects of the induction alone was observed, with a significant decrease occurring in reported pain intensity before and after the analgesic suggestion (P <.05). Pre-induction, post-induction, and post-analgesia suggestion pain intensity ratings were all significantly lower than average pain during the previous 6 mo (P <.01, P <.0001, P <.0001, respectively). Statistical significance was noted for 2 of the associations: effect of pain plus analgesia suggestion on pain intensity (P <.01) and effect of induction alone relative to least pain (P <.05).
Soler et al, 201016/Spain RCT PEDro = 8	N = 39 Pain: Neuropathic Tool: Clinical interview	Treatment: Patients were randomly divided into 4 groups: tDCS and visual illusion group received direct current stimulation over C3 or C4 at a constant 2-mA intensity for 20 min and after 5 min of tDCS, video with someone walking was shown and the legs of person for 15 min with a vertical mirror so patients could see themselves walking; tDCS group with control visual illusion received the above-mentioned tDCS; the visual illusion only group received a video of faces or landscapes; visual illusion group and sham tDCS had electrodes placed on the same area as the treatment group but the stimulator was turned off after 30 sec of stimulation; placebo group consisted of both the control visual illusion and the sham tDCS. Pain scale: NRS	The most significant reduction in NRS of pain perception was seen in the combined tDCS and visual illusion group compared with the visual illusion group (P = .008) or the placebo group (P = .004). Pain reduction was also greater in the tDCS and visual illusion group than in the other 3 groups at first and last follow-up; however, no difference was seen at second follow-up. Visual illusion group was shown to have significant reduction in neuropathic pain intensity on last day of treatment (P = .02); however, this effect was not maintained over the long term. Combined tDCS and visual illusion group also showed significant improvement in ability to work, perform daily tasks, enjoyment, and interference of pain with sleep (P <.05). tDCS sessions were found to be safe with minor side effects including mild headache.
Gustin et al,200824/Australia Pre-Post D&B = 18	N = 15 Pain: Mixed Tool: Not stated	Treatment: All participants were trained in movement imagery for 7 days. Each participant was asked to imagine right ankle plantar flexion and dorsiflexion for 8 min. Pain scale: VAS	Individuals with neuropathic pain reported a significant increase in pain intensity during movement imagery (P <.01). Individuals without neuropathic pain reported a significant increase in non-pain intensity during movement imagery (P <.01).
Moseley,200728/UK Pre-Post D&B = 11	N = 5 Pain: Neuropathic pain Tool: Not stated	Treatment: Individuals with SCI (n=5) engaged in (1) virtual walking exercise; (2) guided imagery with a psychologist who took them through a scene in which they were pain free and doing something they liked; (3) watching an animated film. During the second part of the study, participants performed 10 min of virtual walking on 15 consecutive weekdays. Pain scale: MPQ; VAS	Pain decreased by approximately 65% with virtual walking; less so for guided visual imagery and film viewing. The amount of time to return to pre-task pain VAS after virtual walking was 34.9 min; after guided imagery, 13.9 min; and after watching a film, 16.3 min. The decrease in perceived foreignness of the legs was 43 mm during virtual walking, 4 mm during guided imagery, and 3 mm while watching the film. Change in foreignness was related to change in pain during virtual walking (P = .04). During the 3-wk trial of virtual walking, overall pre-task pain gradually decreased, and pain relief gradually increased; these effects persisted at 3-mo follow-up.

Note: B = Downs and Black quality assessment scale score; MPQ = McGill Pain Questionnaire; NRS = numeric rating scale; PEDro = Physiotherapy Evidence Database rating scale score; QOL = Quality of Life; VAS = Visual Analogue Scale; VRS = verbal rating scale.

Norrbrink, Kowalski, and Lundeberg²² compared a 10-week multidisciplinary pain management program (which included educational sessions, behavioral therapy, relaxation techniques, and body awareness training) (n = 27) with standard care (n = 11) in patients with neuropathic pain. They found that those individuals assigned to the pain management program exhibited a significant decrease in their anxiety and depression scores and had an increased sense of coherence (used to measure successful coping with stressors) (see Table 2) when compared with those receiving standard care. However, those in the treatment group did not experience significant reductions in their pain intensity or unpleasantness scores and had no improvements in health-related quality of life (QOL) or life satisfaction. Both groups had fewer health care visits. Overall, the multidisciplinary pain management program was noted to be of value in improving mood, coping, and quality of sleep in patients with SCI pain but not in relieving post-SCI pain.

Based on a single study,²² there is moderate (level 2) evidence that a behavioral pain management program can be of value in relieving certain secondary sequelae, such as depression and anxiety, but does not reduce the level of neuropathic pain.

Hypnosis

Two studies evaluated the effectiveness of hypnosis on pain after SCI. Jensen et al²⁰ randomly allocated participants to a hypnosis or a biofeedback treatment group. Participants in the hypnosis group reported a significant decrease in neuropathic pain intensity compared with those in the biofeedback group (P <.01). However, no such effect was seen between the 2 groups in individuals without neuropathic pain. In the second study, Jensen et al²³ also found a significant decrease in pain intensity after treatment (P <.05). Based on these 2 studies, there is level 2²⁰ and 4²³ evidence that hypnosis is effective in reducing neuropathic pain post SCI.

Visual imagery

Soler et al¹⁶ examined the effectiveness of visual imagery for neuropathic pain post SCI. As mentioned previously, the investigators found the greatest improvement in scores related to pain perception, pain reduction, ability to work, ability to perform daily tasks, enjoyment, and interference of sleep in the combined tDCS and visual illusion group (P <.05). Thirty percent of participants in this combined group also reported a reduction of 30% or more in pain intensity. The visual illusion group reported significant improvement in neuropathic pain intensity on the last day of treatment (P = .02); however, the effect was not maintained over 12 weeks.

Moseley²⁸ reported on 5 individuals with T12-L3 paraplegia (American Spinal Injury Association Impairment Scale [AIS] B) with neuropathic pain who engaged in a virtual activity. These individuals were led through a guided walking exercise in which they visualized themselves walking pain free. For the 4 subjects who completed the trial (1 patient withdrew from the study because of distress), there was a mean 42 mm reduction in neuropathic pain after individual treatments, based on a 100 mm visual analog scale. Additionally, immediately and 3 months after the daily virtual walking, 53 mm and 42 mm reductions were observed, respectively. Control treatments were visual imagery alone and watching a movie, both of which resulted in less dramatic pain reductions; however, no statistical comparisons were done.

Gustin et al²⁴ asked study participants to imagine right ankle plantar flexion and dorsiflexion for a duration of 8 minutes. In contrast to the studies described previously, a significant increase in neuropathic pain intensity was reported after guided visual imagery (P <.01).

Three studies^16,24,28 provide conflicting evidence that visual imagery may reduce at-level neuropathic pain post SCI for a short period.

Discussion

In this systematic review of nonpharmacological interventions used to treat neuropathic pain post SCI, 16 studies met the inclusion criteria. Ten studies examined physical treatments, 5 studies examined behavioral treatments, and 1 study examined both physical and behavioral treatments. In terms of physical treatments, there was level 1 evidence from 2 small RCTs that suggests neuropathic pain post SCI may be ameliorated using either TENS or TMS. There is conflicting evidence that TENS can reduce general pain intensity, worst pain intensity, and pain unpleasantness after SCI. A level 1 RCT has provided evidence that a combination of osteopathy and pregabalin treatment is effective in reducing neuropathic pain and that the combination is more effective than either treatment given individually. Acupuncture has been suggested as a modality to reduce neuropathic pain post SCI, but the level 4 evidence is not sufficient to make firm conclusions. There is limited evidence that CBT is not effective in reducing neuropathic pain. Two studies, a level 2 study and a level 4 quality study, demonstrated that hypnosis may be effective in reducing neuropathic pain. There is conflicting evidence that visual imagery may reduce neuropathic pain post SCI over the short term.

Physical interventions

Transcranial electrical stimulation

Four level 1 RCT studies assessing the efficacy of TES provided strong evidence of its efficacy in reducing neuropathic pain.^13,15–17 However, although all of the studies indicated that TES reduces average pain intensity, worst pain intensity, and pain unpleasantness, half of the studies included patients who had ambiguous pain of both neuropathic and musculocutaneous origin.^13,17 Dividing patients into categories of musculocutaneous or neuropathic pain remains a challenge in this research. A careful subgroup analysis would have helped resolve this issue. Because none of the studies included power calculations, we are unsure whether there were a sufficient number of participants to demonstrate clinically significant effects in pain reduction.

Pain outcome measures varied across studies and included 5 different tools, only 2 of which were repeated between studies. Because we cannot directly compare scores among all of the study participants, we cannot determine with certainty that all of the groups were similar at baseline. In the future, clinical research into the assessment and management of neuropathic pain in individuals with SCI would be enhanced through the use of common, objective, and reliable outcome tools to measure pain.

Finally, most of the treatment sessions were quite long (eg, 4 hours),¹⁷ but the duration of the protocol for some of the studies was quite short (eg, 5 days)¹⁵; in 1 study, the protocol lasted 3 weeks (21 days).¹³ Despite variability in study design, all 4 studies showed that pain was reduced from pretreatment to posttreatment phases in the treatment groups. The ideal SCI patient for this type of treatment would have low to moderate levels of neuropathic pain and a low-level and incomplete SCI. To date, the relationship between treatment intensity and pain relief has not been elucidated.

Transcranial magnetic stimulation

Two small level 1 RCTs offered limited evidence that TMS can provide a reduction in worst pain intensity and pain threshold, but not in mean pain intensity.^14,18 Both studies included subjects with SCI in whom pain was only neuropathic in origin. Unfortunately, both studies had small sample sizes.^14,18 Although the same treatment was used in both studies, the authors provided the therapeutic intervention at different rates and for different lengths of time. Subjects in the study by Defrin et al¹⁸ received 20 impulses of 10 Hz over 5 seconds, repeated for 5 days. Subjects in the study by Kang et al¹⁴ received 500 impulses of 5 Hz over 10 seconds, repeated for 14 days. Despite an observed reduction in pain, there was so much variability of treatment in the 2 studies that it is impossible to determine which timing and intensity of impulses is necessary to elicit the best outcome. The technique appears to be promising, but further research is necessary to clarify these optimal parameters of treatment.

Transcutaneous electrical nerve stimulation

Two studies met inclusion criteria for TENS: one was a prospective controlled study (level 2),²¹ and the other was a case series (level 4).²⁵ Norrbrink et al²¹ used a modern, robust approach to observe the effect of TENS on neuropathic pain, whereas the study by Davis and Lentini²⁵ was less sophisticated. The authors failed to provide demographic information on the study participants beyond an age range and general injury characterization such as location of nerve damage. Although 3 stimulators were used to offer pain relief, details of how each stimulator was used were not provided in terms of timing or intensity of impulses. Additionally, it was not known who or how many participants used each type of stimulator, and results for pain reduction were not stratified according to stimulator type. Therefore, it was impossible to know exactly which stimulators worked best at reducing pain. Finally, when describing how effective the stimulators were in providing pain relief, the authors used the terms “successes,” “partial successes,” and “failures.” The means by which the authors assessed pain reduction remains unknown. Given the severe methodological limitations in the study by Davis and Lentini,²⁵ the conclusion that pain is reduced by TENS must be viewed with caution. Nevertheless, Norrbrink et al²¹ have provided good evidence that TENS can help reduce pain for some people with SCI. Both studies are lacking in that there was no control group and there was no mention of how participants were diagnosed for neuropathic pain.

Osteopathy

Only a single (level 1) study met inclusion criteria for osteopathic treatment to reduce neuropathic pain in people with SCI. Arienti et al¹⁹ examined the effects of osteopathic treatment alone, pregabalin therapy alone, and a combination of the 2 treatments on pain. They found that the best outcome occurred when both treatments were used together, so a combination of physical and pharmacological therapies offers the most benefit according to this study. Although the scientific basis of osteopathic manipulative treatment is largely unknown, it has been suggested that it may result in a reduction in pain through the release of endogenous neurotransmitters, such as endorphins and serotonin.²⁹

Acupuncture

Two studies, one retrospective²⁷ and one prospective,²⁶ provided limited evidence that acupuncture may reduce neuropathic pain in people with SCI. The retrospective study demonstrated that a significant number of participants reported a positive outcome after the treatment. However, the authors considered an “improvement” as a positive report in the medical chart. This method of assessment is likely to have a high degree of unreliability, given the subjective interpretations on the part of the health care professional and the reviewers interpreting the notes. Additionally, the inclusion criteria stipulated that participants had to undergo a minimum of only 1 therapy session. Although Nayak et al²⁶ used a pre-post (noncontrolled) study design, they failed to differentiate patients according to origin of pain. Participants were included in the study regardless of whether the pain was musculocutaneous or neuropathic in origin; again, this may have confounded the results. Results suggested that this type of physical modality offered relief for several aspects of pain; however, the lack of a control group makes it difficult to exclude the possibility of the placebo effect. Definitive conclusions are impossible to make given these scenarios. It is recommended that future research assessing the effect of acupuncture on neuropathic pain in individuals with SCI involve rigorously controlled clinical trials.

Behavioral treatments

Three types of behavioral treatments were evaluated in this review: behavioral pain management, hypnosis, and visual imagery.

Behavioral management

According to a single level 2 study,²² there is moderate evidence that behavioral pain management programs do not improve neuropathic pain but may improve other outcomes such as sleep quality and relief of depression and anxiety. Behavioral pain management in this case consisted of a 4-part program implemented by a multidisciplinary team of clinicians. Because several clinicians were responsible for providing the treatment, the responsibility for accurately providing behavioral management was spread across many people instead of being focused on a single individual often delivering a single therapeutic modality. Because of the small number of participants in this study, the authors were not able to randomly assign the participants to different conditions; therefore, it is not known how much of the effect of the intervention was due to the behavioral pain management and how much could be attributed to a placebo effect. The primary goal of CBT is to improve coping by decreasing anxiety associated with pain. Because anxiety and pain may involve similar neural circuits, a secondary outcome may be a reduction in the intensity of neuropathic pain.³⁰ Cairns, Adkins, and Scott³¹ suggested that although a reduction in pain intensity moderates mood, an improvement in mood had only a weak effect on pain intensity. This observation would account for the fact that the intervention used in the study by Norrbrink and colleagues²² did not reduce neuropathic pain. The high compliance rate with the program and the high satisfaction scores suggest that the participants believed the behavioral management therapy was subjectively beneficial and meaningful. The purpose of behavioral therapies appears more to reduce psychological symptoms associated with neuropathic pain, which in turn assists individuals with SCI in managing and coping with their pain.³² Behavioral management to reduce neuropathic pain after SCI has not been supported by the scientific evidence. Further RCTs are needed to determine the benefits associated with CBT and the subsequent effects of decreased psychological strain on the neuropathic pain experience in patients with an SCI.

Hypnosis

Two studies included reports on the effectiveness of hypnosis on neuropathic pain. The pre-post study showed that some participants continued using self-hypnosis techniques even at 1-year follow-up.²³ Jensen et al³³ supported this finding in a study involving patients with SCI and multiple sclerosis. The study indicated that although 81% of the participants continued the use of hypnosis at 1-year follow-up, only 23% had a clinically significant reduction in pain intensity. These data indicate that hypnosis may not directly reduce pain intensity but instead may be involved in reducing the experience of pain. More research on the mechanism of action of hypnosis on neuropathic pain needs to be completed.

Visual imagery

In 2 studies, investigators examined visual imagery of virtual pain-free walking to assess neuropathic pain reduction after SCI. In the study by Moseley,²⁸ virtual pain-free walking was shown to decrease neuropathic pain, and the positive effects of visual imagery persisted 3 months after the end of the 3-week intervention. A level 1 RCT indicated that neuropathic pain was most significantly reduced in the group that received direct cranial stimulation along with visual illusion treatment.¹⁶ The group that received only visual illusion treatment had a significant reduction in neuropathic pain on the last day of treatment, but this effect did not last for an extended period. Although both studies had the same protocol for visual imagery, they differed in a number of aspects, including the number of treatment sessions, length of treatment, outcome measures, location of lesion, and time since injury. Long-term benefits of visual imagery alone were experienced primarily by patients with cauda equina injuries, suggesting that the combination of visual imagery and transcranial stimulation may be more effective for patients with lower motor neuron lesions. The heterogeneous nature of neuropathic pain suggests that the different types of neuropathic pain and different lesion levels may need to be treated with therapeutic techniques specific to the pain subtype. This idea is further supported by the findings of Gustin et al²⁴: Individuals with complete injuries and below-level pain reported an increase in pain intensity after visual imagery. Another explanation for the increase in pain intensity observed by Gustin et al²⁴ may be the lack of a mirror used in this study. Because visual imagery may involve cognitive strategies for reducing pain intensity, the difference in treatment protocol may have had an impact on effectiveness. More research on the difference between the 2 treatment protocols is needed.

In the future, studies should assess which combination of treatment strategies would be best for different types of SCI to optimize neuropathic pain outcomes. Because the 2 studies used different outcome measures, it is difficult to assess whether they are measuring the same aspect of pain (eg, pain intensity, pain unpleasantness, pain tolerance, subjective or objective pain). Harris³⁴ suggests that neuropathic pain is a result of a mismatch between sensory feedback and motor output. Theoretically, virtual walking attempts to compensate by providing false visual feedback, which is in agreement with the theory that motor output is produced neurologically. In eliminating the differences between output and feedback, neuropathic pain is subsequently reduced. Research in this area should focus on determining why certain individuals experience pain relief as a result of visual imagery and others experience increased pain. Furthermore, RCTs in the future should address the interaction between treatment methods and lesion location.

Limitations

Limitations of this systematic review study should be considered. Because of the relatively strict inclusion criteria, only 13 studies were reviewed. Only articles written in English were included, so some studies may have been missed. Given the tremendous variability in the quality and quantity of studies on this topic, quick and easy conclusions cannot easily be made.

Conclusion

This systematic review was conducted to assess the effectiveness of physical and behavioral therapies in relieving neuropathic pain in people with SCI. It has been demonstrated that there are very few good controlled studies that provide sufficient evidence for efficacy. Of the studies included, only 5 reported a clinically significant improvement in pain intensity. Hence, in future studies it is important to incorporate a measure of clinically significant reduction in pain and not just statistically significant changes. TMS and TENS are 2 noninvasive techniques that are very promising in both short- and long-term pain management. Researchers have demonstrated that there is a favorable risk-to-benefit ratio and that the therapies are cost effective.³⁵ Osteopathy management therapy may be a feasible treatment for regular use in pain control for individuals who cannot tolerate pharmacological treatments such as nonsteroidal antiinflammatory drugs. Osteopathy in combination with pharmacological agents has proven useful in reducing pain for varying ailments, including postoperative pain in women who had recently undergone hysterectomy.³⁶ Combining any physical and behavioral treatment with a pharmacological agent is likely going to result in a cumulative benefit of multiple treatments.

Acupuncture has been extensively studied as an analgesic modality. The technique is considered relatively safe and has been used extensively throughout history, particularly in Chinese medicine.³⁷ Adverse events such as bleeding, infection, or autonomic dysreflexia were not reported in the studies reviewed. Acupuncture may be proposed as a secondary therapy to individuals with low-level neuropathic pain. Long-term pain-relieving effects have not been formally studied.

Behavioral techniques such as CBT, which alleviate psychologic distress associated with pain, are multidisciplinary treatments requiring a variety of health care professionals. Although CBT has not been proven to be effective in reducing pain, it has been observed that those undergoing behavioral pain therapy have a greater ability to cope with and manage their pain. Visual imagery is a unique method of therapy that has been used for maintaining skill during recovery from a sports injury, reducing phantom limb pain, and developing empathy and for injuries requiring rehabilitation.^38–40 The use of mental imagery by people with SCI stimulates activation in the motor cortex, as well as in individuals without SCI.⁴¹ Visual imagery appears to be particularly useful for patients with cauda equina injuries. The type of SCI needs to be considered when treatment is planned.

Frequent methodological limitations affect many of the study conclusions for nonpharmacological interventions. For example, in many studies, investigators failed to differentiate between types of pain, included a small and heterogeneous sample of participants with different times to follow-up after SCI, used variable outcome measurement tools, included no control groups, and combined physical and pharmacological treatment concurrently. This underlies the need for more and better research in this area. With adequate evidence substantiating the treatment, osteopathic and acupuncture therapies may prove favorable in the future, especially since they are associated with fewer adverse reactions.