A Systematic Review of the Interventions for Management of Pain in Patients After Spinal Cord Injury

Chronic pain is a very common problem in patients with spinal cord injury (SCI) as it affects 80% of these patients, which negatively affects their quality of life. Despite many advantages that exist in the management of any type of pain (neuropathic, nociceptive, mixed) in these patients, there is no cure, and the analgesic effect of some treatments is inadequate. This study aims to conduct an evidence-based systematic review regarding the various interventions used for the management of pain after SCI. The PubMed, Physiotherapy Evidence Database (PEDro), and Cochrane Library databases were searched from 1969 to 2023. The risk of bias was assessed using the PEDro scoring system. A total of 57 studies met the inclusion criteria and were included in this systematic review. Among the different interventions at present, 18 studies examined the role of oral medications, 11 studies examined the role of minimally invasive methods (injection and infusion), 16 studies investigated physiotherapy and alternative treatments, and 12 studies examined the role of repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and cranial electrotherapy stimulation (CES) in the management of pain in patients after SCI. Gabapentin and pregabalin are very effective in managing chronic neuropathic pain after SCI, and pregabalin also seems to reduce anxiety and sleep disturbances in the patients. It is noteworthy that lamotrigine, valproate, and carbamazepine do not have an analgesic effect, but mirogabalin is a novel and promising drug. Antidepressants (selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors) did not reduce the pain of the patients, although some studies showed an efficacy of amitriptyline especially in depressed patients and tramadol should be considered short-term with caution. Also, tDCS and rTMS reduced pain. Moreover, botulinum toxin type A, lidocaine, ketamine, and intrathecal baclofen significantly reduced pain intensity, although the sample of the studies was small. Physiotherapy and alternative treatments seem to relieve pain, and transcutaneous electrical nerve stimulation had the greatest reduction of pain intensity. In conclusion, several pharmaceutical and non-pharmaceutical methods exist, which can reduce pain in patients after SCI. The type of intervention can be considered by the physician depending on the patients' preference, age, medical history, type of pain, and associated symptoms. However, more studies with greater samples and with better methodological quality should be conducted.


Introduction And Background
Pain is a very common problem for patients with spinal cord injuries (SCIs), with up to 80% of these patients experiencing chronic pain that negatively affects their quality of life.Many factors may contribute to chronic pain, such as damage to nerves, increased nerve impulses, molecular changes in spinal cord receptors, functional changes in supraspinal and cortex structures, and inflammation that occurs in the spinal cord [1,2].Patients with SCI often report different types of pain.The pain may be a nociceptive type or a neuropathic type or both.Neuropathic pain is a type of pain that is caused by damage to the nervous system, while nociceptive pain is a type of pain that is caused by damage to the non-neural tissue [1].Neuropathic pain seems to be the most common type of pain in SCI patients and seems persistent despite the existing treatment options.Also, musculoskeletal pain, which is the most common source of nociceptive pain,

Search Strategy
The literature search was conducted to allocate all studies through PubMed, Physiotherapy Evidence Database (PEDro), and Cochrane Library databases.Studies between 1969 and 2023 were screened.Only clinical trials and randomized controlled trials were included in the study according to PRISMA guidelines.The search strategy was based on the following MeSH (Medical Subject Headings) terms: ("Spinal Cord Injuries"[Mesh]) AND "Pain" [Mesh]).Firstly, we screened the title and the abstract of the studies and then assessed the full text of the potentially eligible articles.Studies were included in this systematic review if they were written in English or Greek, had more than four patients who had an SCI, and if any intervention was used (pharmaceutical, minimally invasive, surgical, physical therapy, etc.) for the management of pain.

Exclusion Criteria
The exclusion criteria were established from the beginning of this systematic review.Other articles except randomized controlled trials or clinical trials were not included in this study.Also, articles written in different languages except English and Greek, studies with less than four patients, and articles with no interventions were not included, as well as articles that did not have full text available.

Methodological Quality
The methodological quality of the included studies was assessed by all the authors independently using the PEDro scoring system [7].This tool assesses 11 criteria.The maximum total score is 10.To evaluate the quality of the studies, the total PEDro score was categorized as <<low>> for articles with scores less than 4, <<moderate>> for articles with scores between 4 and 6, and <<high>> with scores between 7 and 10.

Data Extraction
The data were extracted from the articles using an electronic sheet, which included the authors' name and date, experimental group, control group, study design, duration of intervention, number of participants, type of pain (neuropathic, nociceptive, mixed), type of injury, and the outcomes.

Literature Review Results
The study selection and systematic review processes are present in the flow diagram (Figure 1).From the initial database search, 3,608 articles were collected (PubMed: 3220, Cochrane: 353, Pedro : 35).Articles were reduced to 3,580 after removing duplications (28 total articles).Based on the inclusion and exclusion criteria mentioned previously and the design of this systematic review, a total of 587 records were screened.Only 57 studies (clinical trials and randomized controlled trials) were eligible to be included in this systematic review, with a total of 2,234 patients.Overall, 530 studies were excluded because they were written in different languages, the authors did not mention the type of the study, the type of the study was not eligible, full text was not available, and the topic of the articles was not relevant.The included articles are listed in Table 1.Gabapentin has some beneficial effects on certain types of NP.
There was a significant decrease in "unpleasant feeling" and a trend toward a reduction of both the "pain intensity" and "burning sensation" at the fourth week of gabapentin treatment compared with those on the placebo   A total of 57 studies investigated the management of chronic pain after SCI.Most interventions were pharmacological and minimally invasive (29 studies).Also, the quality of these studies is characterized as "moderate" to "high."Physiotherapy and alternative treatments were used, as well as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and cranial electrotherapy stimulation (CES).The authors characterized these methods as having "moderate" methodological quality.Table 2 to presents the methodological quality of included studies.

Anticonvulsants
Anticonvulsants have been used for decades as a first-line treatment for neuropathic pain as many studies have revealed their effectiveness in many patients.Gabapentin seems to be more effective than other anticonvulsants such as pregabalin, mirogabalin, lamotrigine, carbamazepine, and valproate.
patients that have SCIs.Also, Ahn et al. [13] affirmed the effectiveness of gabapentin in reducing neuropathic pain after SCI especially if the duration of the injury was less than six months.Moreover, Tai et al. [14] also investigated the efficacy of gabapentin in reducing neuropathic pain after SCI.They concluded that gabapentin can reduce some types of neuropathic pain in patients with SCI, although it can cause dizziness and drowsiness in some patients, especially in the elderly, and thus it should be administrated with caution.
Pregabalin was the second most common medication used in the studies for treating neuropathic pain after SCI.Cardenas et al. [10] conducted a randomized controlled trial with various doses of pregabalin for treating neuropathic pain after SCI.They found a statistically significant change when compared to a placebo in improving pain throughout the trial period.They, therefore, concluded that pregabalin was well tolerated, and the medication was also effective in treating neuropathic pain due to SCIs.Also, Siddall et al. [12] in their study found that pregabalin reduced neuropathic pain as well as seemed to improve anxiety and sleep in patients.
On the other hand, in most of the studies, lamotrigine, valproate, and carbamazepine were ineffective in managing neuropathic pain in SCI patients.Finnerup et al. [15] investigated the effectiveness of lamotrigine.They conducted a randomized, double-blind controlled trial and concluded that lamotrigine did not reduce both evoked and spontaneous pain in patients with both complete and incomplete SCI, as opposed to the usual belief that lamotrigine use is associated with reduced pain in both patients with incomplete and complete SCI.Also, Salinas et al. [11], who conducted a randomized, placebo-controlled, double-blind trial, concluded that carbamazepine only effectively reduced neuropathic pain at one month.However, longerterm pain control at three and six months was not demonstrated in patients with neuropathic pain [29].
Drewes et al. [16], who investigated the use of valproate in a double-blind, cross-over study in treating severe chronic central pain, found no analgesic effect of the medication and advised no further studies to explore this.
It is well mentioned that mirogabalin is a novel drug researched by Ushida et al. [9], who conducted a randomized, double-blind, controlled phase 3 trial to determine its safety and efficacy in treating chronic neuropathic pain in patients with traumatic SCI.They concluded that the administration of mirogabalin led to a statistically significant change in the pain score from baseline in patients with SCI and therefore concluded that mirogabalin is a promising drug for treating chronic neuropathic pain following SCI.

Antidepressants
Antidepressants are another category of drugs used daily for managing chronic neuropathic pain and they can be combined in many patients with anticonvulsants.More specifically, serotonin and norepinephrine reuptake inhibitors such as duloxetine and venlafaxine did not show a significant effect in reducing neuropathic pain after SCI, as shown in the studies by Richards et al. [20] and Vranken et al. [21].
The effectiveness of tricyclic antidepressants such as amitriptyline seems to be controversial.The study of Cardenas et al. [22], who investigated the efficacy of amitriptyline, showed that it did not improve pain in six weeks of treatment.On the other hand, Rintala et al. [17] in a randomized, controlled, double-blind, triple cross-over trial compared the effectiveness of gabapentin and amitriptyline and concluded that amitriptyline was as effective as gabapentin.However, in patients with depressive symptoms, amitriptyline seemed more effective than gabapentin in reducing neuropathic pain after eight weeks of therapy.Moreover, Agarwal and Joshi [19], who conducted a randomized longitudinal study to compare the efficacy of lamotrigine and amitriptyline in patients with neuropathic pain following SCI, found a significant difference between the baseline average pain score and the value at follow-up in both the lamotrigine and the amitriptyline groups.Therefore, they concluded that both medications can be used to treat neuropathic pain following SCI.

Tramadol
Tramadol, which is a weak opioid, can be used with caution for a short term for the management of chronic neuropathic pain.Norrbrink et al. [26] conducted a study on the safety and effectiveness of tramadol in relieving neuropathic pain in patients with SCI.They conducted a randomized, placebo-controlled, doubleblind trial and concluded that tramadol use was associated with a reduction in pain intensity after four weeks of therapy.However, patients had significant side effects.They, therefore, advised that tramadol can be considered after using tricyclic antidepressants and either pregabalin or gabapentin.

Bumetanide
Zarepour et al. [24] investigated the analgesic properties of bumetanide as an adjunct in managing neuropathic pain in patients with SCI.They conducted an open-label single-arm pilot trial of bumetanide, which was added to treat patients with SCI for 19 weeks.They concluded that the data reiterated the analgesic effect of bumetanide through disinhibiting the GABAergic pathway by upregulating the KCC2 protein.

Mexiletine
Chiou-Tan et al. [23] examined the effect of mexiletine in treating spinal cord dysesthetic pain.They performed a randomized, placebo-controlled, double-blind crossover trial.They found that there was no significant effect on pain in patients with SCI and concluded that mexiletine does not help in pain reduction in these patients.

Dronabinol
Last but not least, only one study investigated the role of dronabinol, which is a cannabinoid in the treatment of chronic neuropathic pain after SCI.Rintala et al. [25] concluded that dronabinol did not outperform diphenhydramine in relieving chronic pain.
tDCS tDCS seems to be a very promising and safe method for managing chronic neuropathic pain after SCI.In this method, one anode and one cathode electrode are applied to the scalp, and a low sub-threshold electric current is applied to neuromodulate the targeted brain area.According to four of the five included studies, tDCS either alone or in combined visual illusion leads to a significant improvement in neuropathic pain after SCI [38,[43][44][45][46]. Kumru et al. [45] assessed the pain perception threshold and found that there were significant changes in the evoked potentials after two weeks of tDCS and visual illusion.Soler et al. [46] after assessing different combinations of tDCS, sham tDCS, visual illusion, and control illusion concluded that tDCS combined with visual illusion resulted in the most significant reduction of neuropathic pain intensity.tDCS seems to induce metabolic changes, increasing metabolism in the medulla and subgenual anterior cingulate cortex as well as reducing metabolic activity in the left dorsolateral prefrontal cortex, as shown in a PET study by Yoon et al. [48].Nevertheless, a study by Yeh et al. [38] showed no superiority of tDCS combined with exercise regarding pain relief.

TMS
TMS aims to interfere with brain circuits generating electricity through the applied magnetic field.rTMS is a kind of TMS that uses repetitive pulses to generate repetitive electric currents in the targeted brain region.In some studies, rTMS seems to significantly reduce the neuropathic pain in SCI patients, as shown in the studies by Nardone et al. [42] and Jetté et al. [44].Jetté et al. [44] found that corticospinal excitability was increased after stimulation of the hand area, but neuropathic pain was reduced after stimulation over either leg or hand motor cortex.Defrin et al. [40] found that rTMS and sham TMS both significantly and similarly reduced pain intensity.However, only rTMS increased the heat-pain threshold and showed an effect on the follow-up period.Also, two studies included in this systematic review showed intermediate-term pain reduction and no difference between rTMS and placebo long-termly [39,41].Lastly, a study by Kang et al. [39] regarding rTMS over hand motor cortical area showed no difference in pain relief between rTMS and placebo group, but their measurements were held only one week after rTMS and intermediate and long-term results were not assessed.
Minimally Invasive Methods (Botulinum Toxin Type A, Intravenous Lidocaine, Ketamine, Baclofen, Morphine, and Clonidine) Moreover, in our systematic review, three studies examined the role of botulinum toxin type A in chronic pain after SCI.Two studies, one performed by Li et al. [30] and the other by Han et al. [22], showed a statistically significant reduction of pain in patients who received the toxin than placebo.In both studies, the patients in the intervention group received subcutaneous 200 units of botulinum toxin A in 4 mL saline solution at the painful area.Li et al. [30] in their study used a sample of 41 patients (21 intervention group, 20 placebo group), Han et al. [31] used a sample of 40 patients (20 intervention group, 20 placebo group) and both studies performed a follow-up at 4 and 8 weeks after the injection.Both studies yielded statistically significant results in neuropathic pain reduction at 4 and 8 weeks of follow-up, demonstrating that botulinum toxin might be a viable treatment for patients with SCI-related chronic pain.The third study was performed by Chun et al. [28] but due to the small sample size (n = 4), the results weren't statistically significant.
Intravenous lidocaine was used in three studies.Finnerup et al. [32] performed a randomized double-blind crossover trial comparing lidocaine with a placebo, and a total of 24 patients with SCI-related pain were examined.Each patient in the intervention group received 5 mg/kg of lidocaine over 30 min.The results were statistically significant, and lidocaine relieved both at-level and below-level neuropathic pain.Attal et al. [34] also studied the effects of lidocaine on patients with SCI pain and concluded that lidocaine is superior to placebo, although the study sample was only six patients therefore the study is considered as low statistical power.Kvarnström et al. [27] studied the effects of ketamine and lidocaine in a randomized, double-blind, cross-over study.Lidocaine did not show an analgesic effect in patients with neuropathic pain, although a small sample size was used (n = 4).
Kvarnström et al. [27] also studied the effects of ketamine on patients with SCI pain.Specifically, 4 mg/kg was given, and the results showed that ketamine reduced neuropathic pain.Amr [18] used ketamine infusion as a complementary therapy to oral gabapentin.Forty patients were examined and the results showed that complementary ketamine infusion significantly reduces neuropathic pain in patients with SCI pain compared to the placebo group but only for two weeks.
The analgesic effects of intrathecal baclofen were examined in three studies.Kumru et al. [29] conducted a randomized, double-blind study with a sample of 11 patients with SCI pain (n = 11).In the intervention group, 50 μg of intrathecal baclofen was used, and 1 mL of physiologic sodium chloride was used in the placebo group.The results showed that a single intrathecal baclofen bolus significantly improved all subtypes of neuropathic pain, but the sample size was small, and the effects were only studied for 24 hours.Loubser and Akman [35] and Herman et al. [36] also studied the effects of intrathecal baclofen on patients with SCI pain, but their results were not statistically significant.Herman et al. [36] used a sample of two patients in their study (n = 2), and Loubser and Akman [35] had a selection bias, lack of a placebo group, and poor pain measurement methods.
Morphine is a potent opioid and clonidine, which is an antihypertensive drug used to treat neuropathic pain.Siddall et al. [33] studied the effects of these two medications on patients with SCI.They performed a double-blinded, randomized controlled trial in 15 patients, and the results showed that the combination of morphine and clonidine demonstrated better pain relief than morphine or clonidine alone compared to placebo.Even though the results are statistically significant, the sample size remains small, and more studies need to be conducted on the effects of these medications on patients with SCI pain.
Figure 2 shows a synopsis of all the pharmaceutical methods used to manage chronic pain in patients after SCI.

FIGURE 2: Pharmaceutical methods for the management of chronic pain in patients after SCI
Abbreviations: SSRIs, selective serotonin reuptake inhibitors; SNRIs, serotonin and norepinephrine reuptake inhibitors; SCI, spinal cord injury

Physical Therapy and Alternative Methods
From the 16 studies found to examine the effect of physical therapy interventions and alternative methods on neuropathic pain, four used low-frequency TENS.Özkul et al. [63] in a randomized cross-over trial of 24 participants analyzed the results after the application of visual illusion and TENS for two weeks each in both groups and found a more significant decrease in pain intensity after TENS application than visual illusion.
The studies conducted by Celik et al. [64], Bi et al. [55], and Vitalii and Oleg [56] found that TENS had resulted in a significant reduction of neuropathic pain levels compared to placebo TENS with the difference that Vitalii and Oleg [56] used it in combination with gabapentin.
Arienti et al. [53] compared OMT, pregabalin, and OMT in combination with pregabalin in 47 patients, and the results showed that all the interventions reduced pain, and in the group in which OMT was used in addition to medication, the pain relief was greater.Auricular acupuncture was also researched by Estores et al. [62], and their results showed a significant pain reduction.
Hicks et al. [52] in a 34-participant trial suggested an exercise protocol including both aerobic and loads training aiming at the reduction of pain and depression and found a statistically significant difference between the exercise and non-exercise groups.On the same base, Mulroy et al. [51] compared home-based strengthening, optimal movements, stretching, and education on transfers, raises, and wheelchair propulsion to 1 hour of educational video in 80 SCI patients with painful shoulders.The results showed that the intervention was effective in reducing long-standing shoulder pain and that the patients had a better overall quality of life.
Contradictory results were found about the effect of mental imagery techniques on neuropathic pain.Kaur et al. [57] found noteworthy differences in pain intensity between mental imagery and especially laterality training and sham treatment.Also, Zanca et al. [49] used meditation in addition to mental imagery but showed that pain interference decreased more in the control group than the intervention group.A possible explanation could be that because the direct effects of mental imagery are expected to be on modification of the pain experience rather than pain interference itself, the effects on pain interference are likely to be indirect and influenced by other factors unrelated to the intervention.Additionally, Lovas et al. [59] found massage therapy as effective as guided imagery relaxation on pain relief.An interesting study by Jensen et al. [54] concluded that hypnosis was as effective as biofeedback relaxation in decreasing neuropathic pain, although the analgesia was maintained until the three-month follow-up only in the first group.
New techniques in rehabilitation have also emerged as Austin et al. [50] found that 3D head-mounted virtual reality was linked to greater levels of patients' awareness as well as pain relief compared to 2D screen application.Furthermore, Burke et al. [58] researched a self-reported internet-delivered six-module CBT pain management program and demonstrated a substantial short-term effect on pain intensity, with pain benefits lasting three months.
An anti-inflammatory diet might affect the inflammation related to neuropathic pain.Allison et al. [60] showed that reducing inflammation as a treatment method for neuropathic pain in SCI is effective, with a possible mechanism involving a decrease in pro-inflammatory cytokines and prostaglandin E2.The effects of ultra-micronized palmitoylethanolamide as an additional treatment for neuropathic pain in people with SCI were studied by Andresen et al. [61].However, they discovered no significant difference in pain intensity between ultra-micronized palmitoylethanolamide and placebo treatments, and ultra-micronized palmitoylethanolamide had no discernible effects on spasticity, sleep problems, anxiety, melancholy, or overall well-being.

Limitations
This systematic review included only studies written in English and Greek.One significant limitation is the limited number of studies and a small number of participants especially in minimally invasive methods and physical therapy and alternative treatments.That reduces the statistical power and increases the risk of bias.The small participant numbers also limit the ability to detect subtle effects and potential variations in treatment responses.
The heterogeneity in some study designs, especially in physical therapy and alternative interventions, and outcome metrics across the different trials make direct comparison and synthesis challenging.This variability makes it difficult to draw definitive conclusions and develop standardized treatment protocols.It is important to also note that some studies relied on self-report measures, which can be subject to biases and subjective interpretations by the participants.Objective measures and longer-term follow-up are necessary to strengthen the validity of the findings.Furthermore, incorporating diverse populations and utilizing more objective metrics would enhance the ability to generalize reliable data; therefore, physicians could use them in everyday practice.

Conclusions
Several treatment options can reduce pain in patients after SCI.Now there is strong evidence that anticonvulsants and more specifically gabapentin have a beneficial role in managing chronic neuropathic pain in these patients and that gabapentin is considered as first-line treatment.Pregabalin seems to be an effective alternative as it also reduces patients' anxiety.On the other hand, serotonin and noradrenaline reuptake inhibitors seem ineffective in treating neuropathic pain in patients with SCI, and the results of tricyclic antidepressants (amitriptyline) were controversial.

FIGURE 1 :
FIGURE 1: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram Abbreviations: CT: clinical trial, RCT: randomized controlled trial