Many factors can contribute to chronic pain, such as nerve damage, increased nerve impulses, molecular changes in spinal cord receptors, functional changes in supraspinal and cortical structures, and spinal inflammation.
The pain may be nociceptive, neuropathic, or both. Neuropathic pain is caused by damage to the nervous system, while nociceptive pain is caused by damage to non-neural tissue. Neuropathic pain is the most common type of pain in patients with SCI and can be persistent. Musculoskeletal pain, which is the most common source of nociceptive pain, especially in patients with incomplete SCI, can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs).
Treatment of patients with SCI can be challenging as it can be accompanied by several severe impairments, such as paralysis, sensory loss, neurogenic bowel, bladder dysfunction, and chronic pain. Regardless of the type, chronic pain can significantly impact functioning, mood, and life satisfaction.
Many studies and systematic reviews revealed that antidepressants and anticonvulsants are the first-line therapies for neuropathic pain. Other invasive and noninvasive methods have been proposed, although most have not been adequately investigated.
This systematic review aims to examine all available management methods used to treat SCI-related pain and assess their effectiveness.
| Results |
Only 57 studies investigating the treatment of chronic pain after SCI were eligible for this systematic review. Most interventions were pharmacological and minimally invasive, and the quality of the studies ranged from “moderate” to “high.” Physiotherapy and alternative treatments were used, as well as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tECD) and cranial electrotherapy stimulation (CTE). These methods were considered to be of “moderate” methodological quality.
Gabapentin, mirogabalin, pregabalin, carbamazepine, lamotrigine and valproate were the anticonvulsants found in the included studies. One study investigated low-dose ketamine infusion as an adjuvant to oral gabapentin. The antidepressants studied were amitriptyline, venlafaxine, duloxetine and mexiletine. Additionally, individual studies investigated the role of bumetanide (diuretic), dronabinol (cannabinoid), and tramadol (opioid).
Minimally invasive methods included intravenous injections of ketamine and lidocaine, injection of botulinum toxin A, intrathecal injection/infusion of baclofen, infusion of lidocaine, and intrathecal infusion of clonidine and morphine. EMT and tECD were studied in 12 articles. A total of 16 studies evaluated physical therapy and other alternative methods of pain management. Clinical meditation and imagery intervention, 3D virtual reality, mental imagery, exercise, cognitive behavioral therapy (CBT), massage, anti-inflammatory diet, ultra-micronized palmitoylethanolamide, acupuncture, transcutaneous electrical nerve stimulation (CNTD), orthopedic manipulative therapy (OMT), and Self-hypnosis were found among the included studies.
| Discussion |
Anticonvulsants. Anticonvulsants have been used for decades as a first-line treatment for neuropathic pain. Gabapentin appears to be more effective than other anticonvulsants, and in studies it was the first-line medication for the treatment of neuropathic pain in patients with SCI, especially when the duration of injury was less than six months. It may cause dizziness and drowsiness, so it should be administered carefully.
Pregabalin was the second most common medication used in studies to treat neuropathic pain after SCI, with good tolerance. In addition to reducing pain, it was also observed to improve anxiety and sleep in patients.
On the other hand, in most studies, lamotrigine, valproate and carbamazepine were ineffective in the management of neuropathic pain in patients with complete and incomplete SCI.
Mirogabalin is a novel drug that was investigated by Ushida et al. in a randomized, double-blind, controlled trial to determine its safety and efficacy in the treatment of chronic neuropathic pain in patients with traumatic SCI. Its administration led to a statistically significant change in pain score and is therefore considered a promising drug for the treatment of these cases.
Antidepressants. Antidepressants are used to control chronic neuropathic pain and in many patients can be combined with anticonvulsants. Serotonin and norepinephrine reuptake inhibitors such as duloxetine and venlafaxine did not show a significant effect in reducing neuropathic pain after SCI. The efficacy of tricyclic antidepressants such as amitriptyline appears to be controversial. Agarwal and Joshi conducted a randomized longitudinal study to compare the efficacy of lamotrigine and amitriptyline in patients with SCI and neuropathic pain, and found a significant difference between the initial pain score and the value at follow-up in both treatment groups, concluding that both Medications can be used to treat this type of pain.
Tramadol. It is a weak opioid that can be used with caution for the short term for the management of chronic neuropathic pain. Norrbrink et al. conducted a study on the safety and effectiveness of tramadol to relieve neuropathic pain in patients with SCI and concluded that its use was associated with a reduction in pain intensity after four weeks of therapy, although with significant side effects. Therefore, tramadol should be considered after using tricyclic antidepressants and pregabalin or gabapentin.
Bumetanide. Zarepour et al. investigated the analgesic properties of bumetanide as an adjuvant in the treatment of neuropathic pain due to SCI, confirming its analgesic effect by disinhibiting the GABAergic pathway through positive regulation of the KCC2 protein.
Mexiletine. Chiou-Tan et al. examined the effect of mexiletine in the treatment of spinal cord dysesthetic pain, and concluded that it does not help in pain reduction.
Dronabinol. Only one study investigated the role of this cannabinoid in the treatment of neuropathic pain due to SCI, concluding that it does not surpass diphenhydramine in pain relief.
Transcranial direct current stimulation (ECDt). This appears to be a very promising and safe method to control chronic neuropathic pain due to SCI. In this method, an anode electrode and a cathode electrode are applied to the scalp and a sub-threshold low electrical current is applied to neuromodulate the targeted brain area. According to four of the five included studies, tECD, either alone or in combination with visual illusion, leads to a significant improvement in neuropathic pain after SCI.
Transcranial magnetic stimulation (TMS). TMS aims to interfere with brain circuits that generate electricity through the applied magnetic field. rTMS is a type of TMS that uses repetitive pulses to generate repetitive electrical currents in the targeted brain region. In some studies, rTMS appeared to significantly reduce neuropathic pain in patients with SCI.
Minimally invasive methods (botulinum toxin type A, lidocaine, ketamine, baclofen, morphine, and clonidine). Three studies examined the role of botulinum toxin type A in chronic SCI pain; two showed a statistically significant reduction in pain vs. placebo at 4 and 8 weeks after injection, demonstrating that it could be a viable treatment in these patients.
Intravenous lidocaine was used in three studies, with statistically significant results, but in small patient samples. The effects of ketamine, alone and as an adjunct therapy to oral gabapentin, were also studied, with a significant reduction in neuropathic pain in patients with SCI pain, but only for a few weeks.
The analgesic effects of intrathecal baclofen were examined in three studies. Only one showed a significant reduction in all subtypes of neuropathic pain, but the sample size was small and the effects were only studied over 24 hours.
The effects of the combination of morphine, an opioid, and clonidine, an antihypertensive, were studied to treat neuropathic pain, and the results showed better pain relief than both drugs alone compared to placebo. Although the results were significant, the sample size was small and further studies are needed on the effects of these medications in patients with SCI pain.
Physiotherapy and alternative methods. Of 16 studies examining the effect of physical therapy and other alternative methods on neuropathic pain, 4 used low-frequency transcutaneous electrical nerve stimulation (TENS), with significant reduction in pain compared to visual illusion and placebo.
Arienti et al. compared osteopathic manipulative treatment (OMT), pregabalin and OMT in combination with pregabalin and all interventions reduced pain, and in the group in which OMT was used in addition to medication, the relief was greater. Auricular acupuncture was also investigated, and its results showed a significant reduction in pain.
Hicks et al. suggested an aerobic load exercise and training protocol aimed at reducing pain and depression and found a statistically significant difference between the exercise group vs. no exercise. Mulroy et al. compared home strengthening, movement optimization, stretching, and education on wheelchair transfer, elevation, and propulsion with an educational video in patients with SCI and painful shoulder, with the intervention being effective in reducing pain and improving the general quality of life.
Conflicting results were found regarding the effect of mental imagery techniques on neuropathic pain; Since the direct effects of mental imagery are expected to be on the modification of the pain experience rather than on pain interference itself, the effects on pain interference are likely to be indirect and influenced by other extraneous factors. to the intervention. On the other hand, it was observed that massage therapy is as effective as image-guided relaxation in relieving pain, and that hypnosis is as effective as biofeedback relaxation in reducing neuropathic pain in the short term.
An anti-inflammatory diet could affect the inflammation related to neuropathic pain. Allison et al. demonstrated 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 due to SCI were studied by Andresen et al., without significant differences on pain intensity vs. placebo.
| Limitations |
A significant limitation is the small number of studies and participants. This reduces statistical power, increases the risk of bias, and limits the ability to detect subtle effects and potential variations in treatment responses.
Heterogeneity in some designs and outcome metrics of different trials makes direct comparison and synthesis difficult. This variability prevents drawing definitive conclusions and developing standardized treatment protocols. Also some studies relied on self-report measures, which may be subject to bias and subjective interpretations.
Objective measures and longer-term follow-up are necessary to strengthen the validity of the findings.
| Conclusions |
Several treatment options can reduce pain in patients after SCI. There is strong evidence that anticonvulsants and more specifically gabapentin have a beneficial role in the treatment of chronic neuropathic pain.
Pregabalin appears to be an effective alternative as it also reduces patients’ anxiety. Some studies have shown that rTMS and tECD reduce pain intensity, although studies with a larger sample size and methodological quality must be conducted.
All minimally invasive methods significantly reduced pain intensity. Physical therapy, alternative methods, and exercise therapy appear to be beneficial in managing chronic neuropathic pain from SCI.
Finally, virtual reality is a very promising treatment for pain management and more studies should be conducted with this method.
