Introduction

Pain is a common sequela of spinal cord injury (SCI), with an estimated pooled prevalence of 53% in SCI patients [1]. The disability and distress caused by pain profoundly affect patients’ functionality, quality of life, and psychological wellbeing [2, 3].

The SCI pain classification, proposed by Bryce et al., presents four types of pain, including nociceptive pain, neuropathic pain, other pain, and unknown pain. Nociceptive pain is defined as the pain arising from activation of a sensory receptor that responds to noxious stimuli, which subdivides into musculoskeletal pain (e.g., spinal fractures, muscle injury, muscle spasms), visceral pain (constipation, urinary tract infection, bowel impaction), or other nociceptive pain (e.g., pressure sores, autonomic dysreflexia headache) [4]. Neuropathic pain (NP) is defined as “pain caused by a lesion or disease of the somatosensory nervous system” which is usually described as burning, prickling, tingling, pins and needles, sharp, shooting, squeezing, painful cold, or electric shock-like pain. They are classified as at-level SCI pain, below-level SCI pain, and other neuropathic pain [4, 5].

The management of neuropathic pain has been an ongoing challenge for healthcare professionals. There are pharmacological and non-pharmacological intervention options, but there is conflicting evidence for their use in reducing neuropathic pain.

Non-pharmacological options for the management of SCI pain generally have no significant adverse effects (AEs), but they have been used as combination therapy with pharmacological treatments or when the patient is refractory to the pharmacological treatments.

The pharmacological treatments that have been used to manage SCI pain are numerous and could be classified into five categories [6]:

  1. 1.

    Analgesics, which include lidocaine, intravenous ketamine, intravenous alfentanil, intrathecal morphine or clonidine, tramadol, oxycodone, and capsaicin

  2. 2.

    Anticonvulsants, which include gabapentin, pregabalin, valproic acid, levetiracetam, lamotrigine

  3. 3.

    Antidepressants, which include trazodone, amitriptyline, duloxetine, venlafaxine

  4. 4.

    Antispastics, which include intrathecal baclofen, phenol blocks, botulinum toxin

  5. 5.

    Cannabinoids, which include dronabinol and tetrahydrocannabinol (THC)

Despite various medications being tested for treatment, only pregabalin has gained the US Food and Drug Administration (FDA) approval for SCI pain [7]. This systematic review aimed to appraise the evidence of randomized clinical trials (RCTs) conducted on assessing the efficacy and safety of pharmacologic therapies for the treatment of SCI pain.

Methods

Research approach

The PubMed/Medline, EMBASE, and Cochrane library online databases were searched from 1946 to May 2019 using specific search terms for (1) SCI, (2) pain, and (3) RCTs. The search terms were adjusted to meet the requirements of the databases. Appendix 1 in the supplemental material contains a detailed search strategy. Furthermore, the reference checking of the included papers was performed to identify the potentially missed items in the original search. Our systematic review was conducted according to the PRISMA 2020 Checklist [8].

Study criteria

Studies had to meet the following criteria in order to be included in our review: (1) ≥50% participants were SCI patients, or the results were stratified by population type (2) RCTs in adults aged ≥18 years (3) Any intervention that involved pharmacological treatment in alleviating pain. Studies that used drugs in combination with nonpharmacological modalities or food supplements were excluded. There were no exclusion criteria based on the type of post-SCI pain (i.e., nociceptive, neuropathic, mixed), specific etiology, or language. Two independent researchers (M.A.D.O and H.Y) reviewed the titles and abstracts of articles. Potentially eligible trials were selected through a consensus process, with conflicts concerning the inclusion or exclusion of studies being resolved by a third reviewer (S.B.J). Full texts of the eligible studies were retrieved. Figure 1 provides an outline of the retrieval and selection of studies.

Fig. 1
figure 1

Literature search flow diagram.

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Data extraction

Four researchers (M.H,A, M.A.D.O, H.Y, and T.I.P), two by two, extracted data independently. The data describing study characteristics, including characteristics of participants, interventions, comparisons, outcomes, analysis approach, results, and study sponsorship were extracted. The relevant statistical significance for each drug comparison is summarized in Table 2. The risk of bias was also evaluated by two researchers independently (H.Y and S.B.J). The third blinded reviewer (V.R.M) resolved the discrepancies.

Outcomes

The primary endpoint of this study was the efficacy of pain reduction in response to pharmacological options for SCI-related pain. This pain reduction is defined as the mean and standard deviation of the change of pain score of an outcome assessment tool for pain such as Numeric Pain Scale (NPS) or Visual Analog Scale (VAS), or other pain-related questionnaires. Furthermore, we assessed the percentage of patients who experienced more than 30% or 50% pain reduction during the study period. The adverse effects of each drug and the proportion of patients who discontinued a drug were our endpoints regarding drug safety. In studies that did not provide the percentage of pain reduction, we computed it using the difference between the pre-and post-intervention pain scores with the following formula:

$$\left( {\left( {{{{\mathrm{pre}}}} {\hbox{-}} {{{\mathrm{treatment}}}}\;{{{\mathrm{pain}}}}\;{{{\mathrm{score}}}} {\hbox{-}} {{{\mathrm{post}}}} {\hbox{-}} {{{\mathrm{treatment}}}}} \right)/{{{\mathrm{pre}}}} {\hbox{-}} {{{\mathrm{treatment}}}}\;{{{\mathrm{pain}}}}\;{{{\mathrm{score}}}}} \right)\,{{{\mathrm{multiply}}}}\;{{{\mathrm{by}}}}100$$

Assessment of methodological quality

We used the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2) (9) for risk of bias assessment. This tool categorizes five domains of bias into (1) bias arising from the random sequence generation and allocation concealment (selection bias); (2) bias due to deviations from intended interventions; (3) bias due to missing outcome data (attrition bias); (4) bias in the measurement of the outcome and (5) bias in the selection of the reported result.

We assessed attrition bias as follows: the study was qualified as low-risk if the number of participants who were randomly assigned but withdrew or dropped out did not exceed 20%. If the intention-to-treat analysis was used for studies with more than a 20% dropout rate, we qualified them as high-risk, with some concerns, or low-risk based on their descriptions.

Selective outcome reporting was assessed as follows: studies were qualified as low-risk if (1) they had a pre-trial registration on a clinical trial registry and (2) their published report was consistent with the registered form.

Ethical approval

This study was approved by the Ethics Committee of Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, with reference number 96-01-38-295.

Results

Results of the search

A total of 2746 records were identified through database searching, of which 703 duplicates were deleted. 1814 out of 2043 studies were excluded at the title and abstract screening phase. The full text of the remaining 230 articles was reviewed in detail, and 202 full-texts were excluded according to the following reasons: type of study (n = 78), not related (n = 81), unavailable full-texts (n = 4), other reasons (n = 39). Finally, 28 papers met the inclusion criteria and were selected for drafting (Fig. 1).

Effects of anticonvulsant on SCI associated pain

Among different anticonvulsants, only RCTs conducted on pregabalin [9,10,11,12,13], gabapentin [9, 13,14,15,16,17,18], lamotrigine [19, 20], valproic acid [21] and levetiracetam [22] met the inclusion criteria for our review (Tables 1 & 2). Pregabalin and gabapentin are the most studied drugs against neuropathic pain following SCI.

Table 1 Demographic and Baseline Features of Randomized Clinical Trials (RCTs) for Pain Following Spinal Cord Injury (SCI).
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Table 2 Study Characteristics and Primary and Secondary Outcomes of Randomized Clinical Trials (RCTs) for Pain Following Spinal Cord Injury (SCI).
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Seven studies have evaluated the efficacy of prescribed gabapentin with the dose, ranging between 300 and 3600 mg/day on SCI-associated pain [9, 13,14,15,16,17,18]. Five RCTs showed a 32–54% reduction in VAS in groups treated with gabapentin compared to the baseline [9, 13, 14, 16, 17], while two RCTs showed conflicting results [15, 18] (Tables 1 & 2).

Pregabalin has been studied in five RCTs with prescribed doses ranging between 150 and 600 mg/ day, which showed that pregabalin is more effective than placebo or significantly reduced SCI associated pain compared to baseline, with a 32–65% reduction in VAS [9,10,11,12, 23].

Lamotrigine was evaluated in two RCTs using 25–400 mg/day doses in patients with SCI-associated pain [19, 20]. Near one-third of patients reported moderate or good pain relief. Lamotrigine was shown to be effective on neuropathic pain in patients suffering from incomplete injury, unlike complete injury [19]. In the second study, although they reported a 0.2–0.4 difference in Short-Form McGill Pain Questionnaire (SFMPQ) scores through follow-ups (day 7, 14, 21), the authors did not divide the study population between complete and incomplete SCI [20]. Only one study evaluated Levetiracetam which showed no reduction in pain intensity measured by Numeric Rating Scale (NRS), and 75% of patients reported no pain relief at all [22]. In another study, 30% of patients taking sodium valproate reported improvement, yet there was no significant effect on SCI-associated NP compared to placebo [21].

No serious adverse event was reported among patients treated with anticonvulsants. Only a few mild to moderate side effects were reported, summarized in Table 2.

Effects of antidepressants on SCI associated pain

Among different antidepressants, only RCTs conducted on trazodone, amitriptyline, and duloxetine met the inclusion criteria for our review (Tables 1 & 2). Apart from amitriptyline, on which three RCTs have been conducted, only one RCT was included in our systematic review for each of the other antidepressants. They showed no significant difference in decreasing SCI-associated pain compared to placebo. On the other hand, amitriptyline, a tricyclic antidepressant that has been investigated in three RCTs [15, 20, 24], was found to be effective in two studies. Amitriptyline was associated with VAS average pain reduction by 40% and decrease in SFMPQ by 0.2–0.4 scores; furthermore, 50% of patients reported more than 30% pain relief with amitriptyline [15, 20], while one of the included studies found no significant difference and did not confirm this effect [24]. Although all three of them were RCTs, there were a few differences in the method of the aforementioned studies, including the prescribed doses (varying between 10 and 150 mg), study design (cross over or parallel), and pain measurement tools (NRS, Short-Form McGill Pain Questionnaire (SFMPQ), Brief Pain Inventory (BPI), VAS) which makes it impossible to compare them directly. Mild to moderate adverse effects such as xerostomia, drowsiness or tiredness, constipation, urinary retention, and increased spasticity were reported in all three studies but their frequency increased in the study administering higher doses [15].

Effects of analgesics on SCI associated pain

Analgesics are potent medications whose indications include the treatment of post-SCI intractable pain. Among different analgesics, only the RCTs conducted on ketamine [18, 25, 26], intravenous alfentanil [26], intrathecal morphine [27, 28], or clonidine [28], tramadol [29], and lidocaine (26) met the inclusion criteria for our review (Tables 1 & 2).

Three RCTs were found for ketamine [18, 25, 26], Ketamin was adminsterated intravenously in all three studies however the dosage protocol was different. Eide et al. used a single bolus dose of 0.18 mg/kg (60 µg/kg followed by 6 µg/kg/min continuous infusion for 17–21 min), however Kvarnström et al. used 0.4 mg/kg which is nearly 2 times higher than the dose used in the previous study. Amr et al. adminstrated a low dose ketamine infusion (80 mg with a rate of 16 mg/h) for 7 days. All three studies showed more than 40% reduction in VAS (Table 1) as well as significantly higher side effects in patients who received ketamine, but no severe side effects were reported (Table 2). Dizziness and short-lasting delusion were the most reported side effect among the three studies (Table 2).

Alfentanil was evaluated only in one RCT [26], which reported 20%, 80% and 70% pain reductuin in VAS from baseline for continuous pain, allodynia and wind-up-like pain respectively.

A randomized placebo-controlled study conducted on 35 patients with neuropathic pain due to SCI showed that tramadol administration results in greater than 25% pain reduction in general and worst pain intensity and about 16% reduction in MPI (pain severity), with more than 55% of patients reporting much (33%) or minimal improvement (25%) [29]. However, significant AEs were reported for tramadol (more than 90% of patients); therefore, caution should be taken when considering its use (Table 2).

In a crossover RCT in patients with neuropathic pain, intravenous morphine reduced spontaneous ongoing pain (~46%, from 61.6 to 33), however the difference between patients who were administered morphine and the placebo group was not statistically significant [28]. The proportion of patients who benefitted from total or partial (a reduction greater than or equal to 50% in VAS score) pain relief from the treatment was 46% with morphine vs. 13% with placebo [28]. Morphine significantly reduced the intensity of brush-evoked allodynia (but did not affect other evoked pains) [28]. There was a correlation between the magnitude of initial allodynia and the effects of morphine on this symptom [28]. The results of IV morphine were correlated with those of oral morphine at one month [28]. However, in another RCT involving 15 patients, when morphine was given intrathecally together with clonidine, a 37% reduction in the mean pain level was observed compared to the placebo group (p = 0.0084) [27], while only a 20% and 17% reduction in the mean pain level was observed, respectively, for morphine or clonidine when they were administered alone. This difference was not statistically significant compared to the placebo group [27]. Significant side effects were reported for morphine in both RCTs, the most frequent being sedation, somnolence, nausea, and headache.

Intravenous lidocaine (2.5 mg/kg), was studied only in one RCT [25], and 10% pain relief was reported for lidocaine, but this difference was not significant.

Effects of antispastics on SCI associated pain

Among the different antispastics reviewed, only baclofen [30] and botulinum toxin A (BTA) [31] were reported in RCTs. Only one RCT has been conducted on baclofen for evaluation of NP which reported >49% reduction in NRS, > 36% in continuous pain, >35% in BPI, and diminished interference of neuropathic pain with activities of daily living [30]. Moreover, one RCT published on BTA showed >20% significant pain relief in SCI patients [31].

Quality of studies

Table 3 shows the result of quality assessments. Figure 2 represents judgments about each item in assessing the risk of bias presented as percentages across studies.

Table 3 Risk of Bias Assessment of Included Studies.
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Fig. 2
figure 2

The overall risk of bias assessment of studies.

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Eighteen of the twenty-eight studies properly reported their randomization and concealment methods. However, nine studies did not mention their randomization or concealment procedure. One study was found to have a high risk of bias due to randomization or concealment. This study was an open-label study in which 21 of the 55 participants were not randomly assigned.

Only a single study was not blinded (open-label). All other studies claimed to be blinded, although five of them did not mention the blinding process. Even though the blinding process was reported in seven publications, the method of analysis for individuals who were excluded from the analysis was not addressed.

All studies used at least one valid outcome measure for pain intensity at comparable time points for patients and controls. However, because patients were the outcome assessors in our study and, in some studies, the patients were not blinded, we qualified such studies as high-risk.

Only five studies had pre-trial registration and therefore were considered low-risk regarding Selective Outcome Reporting. All studies reported at least a clinically relevant pain scale.

Discussion

Our systematic review identified twenty-eight RCTs, which is the highest number of included studies compared to other published reviews of RCTs on the pharmacologic management of pain due to SCI. Unlike other published reviews, only randomized clinical trials are included in this study. Moreover, we included studies that greater than 50% of their participants were suffering from SCI, and following utilizing the formula mentioned in the method section, we calculated pain reduction for each trial using the reported data, if available. Our results show that there is still an insufficient number of clinical studies and comparative data among the identified pharmacologic options. While the included studies have a good quality level according to our risk of bias assessment, the reported data are often missing uncertainty measures, such as confidence interval or standard error surrounding the mean outcomes, which resulted in the impossibility to perform a meta-analysis.

Pregabalin was the only drug evaluated by four different studies [9, 10, 12, 23] and had the strongest impact on pain reduction of all the evaluated medications, with an 11-point NRS treatment effect. Interestingly, one of the pregabalin studies [10] also included the largest sample of patients (n = 220) of all the studies, which might justify identifying statistically significant results.

A risk of all-cause discontinuations greater than placebo was not observed in any of the included studies. However, for several treatments, the risk of AEs was significantly higher compared to placebo. A possible reason for this finding could be related to patients deciding to remain on therapy as the beneficial effects outweigh the AEs.

It should be noted that two studies used diphenhydramine as a placebo [15, 32] to mirror some of the AEs experienced by patients when taking their active comparators. Hence, the severity of AEs and the level of discontinuations between diphenhydramine and the active comparators (amitriptyline, gabapentin, and trazodone) may be inferior to what was observed in other studies comparing actual placebo and active treatments.

A systematic review [33] published in 2013 reported that pregabalin, followed by amitriptyline, was the most effective of all medications used to reduce post-SCI NP, compared to placebo. Our review also showed that pregabalin and amitriptyline were evaluated in four [9, 10, 12, 23] and three [15, 20, 24] studies, respectively. Two studies, one on levetiracetam and one on pregabalin, reported the proportion of patients experiencing a decrease in pain by >30% and >50% compared to baseline [33]. Patients on pregabalin were more than twofold likely to experience >30% (risk ratio of 2.6 (95% CI 1.4–4.7)) and >50% (risk ratio of 2.9 (95% CI 1.1–7.6)) pain reduction compared to placebo [33]. On the other hand, the effect of levetiracetam could be considered similar to placebo, as the associated relative risks approximated 1 [33]. Our review also showed no significant difference in levetiracetam and placebo in terms of pain improvement [22].

According to another review study [34], amitriptyline, gabapentin, and pregabalin should be considered the first choice in managing neuropathic pain after SCI. The available clinical trials show that using higher doses leads to more and more severe AEs. Moreover, they suggested that a combination of various medications or measures, albeit scarcely investigated as an option, is likely to have a more pronounced effect than the administration of one single drug. Our review also found that combination therapies may be more effective than monotherapy in improving SCI-associated pain. For instance, combination therapy of ketamine and gabapentin decreased pain significantly compared to gabapentin alone [18]. Similarly, another study [27] showed that a mixture of clonidine and morphine was more effective than either drug administered alone. Studies examining the effect of combined treatment compared to monotherapy may lead to a better approach to pain management which takes a multidisciplinary perspective into account. In this regard, a non-randomized clinical trial involving ten patients reported a 70–100% reduction in chronic neuropathic pain by intrathecal administration of clonidine (average dose of 44 µg/day), combined with opioids [35].

Previous guidelines on pain management recommended the use of antidepressants and anticonvulsants as first-line treatment for this condition [36,37,38]. Our review found that amitriptyline was ineffective in reducing SCI-related pain in one study [24] and significantly improved pain in two studies [15, 20]; at the same time trazodone made no difference in pain improvement [32]. However, Mehta et al. reported that most antidepressants (i.e., amitriptyline, duloxetine, trazodone, and venlafaxine) were not effective in decreasing pain due to SCI [34] but were effective in reducing pain in people with SCI who are also experiencing a significant comorbid depressive disorder [34].

Most anticonvulsants reviewed in our study were effective in reducing post-SCI pain. No significant difference was observed in levetiracetam [22] and valproate [21], even though not enough RCTs were conducted on either. Gabapentin, the most studied anticonvulsant in improving post-SCI pain, was found to be effective in most studies. However, one study did not report data on whether gabapentin led to an improvement in pain symptoms compared to the baseline. This strengthens the current evidence that gabapentin could become the first choice to manage SCI-induced pain.

Limitations

There are certain limitations to this review that should be mentioned. Among the number of studies included in our review, sample sizes were generally limited. Moreover, only RCTs were included in order to minimize bias, however results may differ from what is usually observed in clinical practice; for instance, the duration of many of the RCTs did not exceed 12 weeks, while patients are usually treated for a longer period of time in the clinical setting. However, we did not consider the aforementioned example a limitation when interpreting the study results as most studies assessing pain have demonstrated pain improvement within one to three weeks [39]. As the study’s primary outcome, pain relief was evaluated in most studies by using McGill Pain Questionnaire (MPQ), NPS, VAS, or Verbal Numeric Scale (VNS), which are relatively subjective tools and may be affected by multiple unknown factors. Meta-analysis was not possible due to different methodologies, heterogeneity of the data reported, different routes of administration, and lack of sufficient studies for each drug.

In some studies, patients could not discontinue their standard medication regimens. In those cases, the observed result might have derived from the synergistic effect of the prescribed intervention medication and the patients’ self-consumed drugs instead of the prescribed intervention alone, despite the baseline being not significantly different between the studied groups.

Conclusion

Our systematic review collects the best available evidence on the treatment of SCI-related pain, demonstrating the need for more studies comparing different pharmacologic options for this condition. To this end, considering sample size, study design (parallel or crossover), statistical analysis methods, and efficacy outcomes for each study included in the review is paramount.

According to the most updated evidence, the use of anticonvulsants such as gabapentin and pregabalin in the management of pain due to SCI is supported. Their mechanism and optimal administration, including dose, duration, and onset time, need to be explored by future studies.

Local anesthetics are still recognized as an effective option for short-term pain management, and current evidence is still supporting the use of cannabinoids, intrathecal baclofen, and botulinum toxin for the treatment of nociceptive or spasticity-related pain. Future studies conducting sub-analyses based on pain subtypes may shed more light on treatment effectiveness, not to mention the need for more studies evaluating the consequences of multiple treatments combined.

Presently, we are unable to demonstrate a possible lack of efficacy for the other identified treatments as the data reported in the included studies were limited. Our systematic review suggests investigating new treatment options with fewer side effects that afford longer pain relief durations.