Spinal Cord Injury Pain: Mechanisms and Management

Patients with spinal cord injury (SCI) may experience several types of chronic pain, including peripheral and central neuropathic pain, pain secondary to overuse, painful muscle spasms, and visceral pain. An accurate classification of the patient's pain is important for choosing the optimal treatment strategy. In particular, neuropathic pain appears to be persistent despite various treatment attempts. In recent years, we have gained increasing knowledge of SCI pain mechanisms from experimental models and clinical studies. Nevertheless, treatment remains difficult and inadequate. In line with the recommendations for peripheral neuropathic pain, evidence from randomized controlled treatment trials suggests that tricyclic antidepressants and pregabalin are first-line treatments. This review highlights the diagnosis and classification of SCI pain and recent improvements in the understanding of underlying mechanisms, and provides an update on treatment of SCI pain.     

Longstanding neuropathic pain after spinal cord injury is refractory to transcranial direct current stimulation: A randomized controlled trial

Neuropathic pain remains one of the most difficult consequences of spinal cord injury (SCI) to manage. It is a major cause of suffering and adds to the physical, emotional, and societal impact of the injury. Despite the use of the best available treatments, two thirds of people experiencing neuropathic pain after SCI do not achieve satisfactory pain relief. This study was undertaken in response to a recent clinical trial reporting short-term, clinically significant reductions in neuropathic SCI pain with primary motor cortex transcranial direct current stimulation (tDCS). In this investigation, we aimed to build on this previous clinical trial by extending the assessment period to determine the short-, medium-, and long-term efficacy of tDCS for the treatment of neuropathic pain after SCI. We found that, contrary to previous reports, after 5 tDCS treatment periods, mean pain intensity and unpleasantness rating were not significantly different from initial assessment. That is, in this trial tDCS did not provide any pain relief in subjects with neuropathic SCI pain (n = 10). A similar lack of effect was also seen after sham treatment. Because the injury duration in this study was significantly greater than that of previous investigations, it is possible that tDCS is an effective analgesic only in individuals with relatively recent injuries and pain. Future investigations comparing a range of injury durations are required if we are to determine whether this is indeed the case.     

Above-level mechanical hyperalgesia in rats develops after incomplete spinal cord injury but not after cord transection, and is reversed by amitriptyline, morphine and gabapentin

Spinal cord injury (SCI) is a major cause of persistent neuropathic pain of central origin. Recent evidence suggests neuropathic pain in clinically complete SCI patients correlates with limited sensory function below the lesion (sensory discomplete). On this basis we examined if the onset of mechanical hyperalgesia was different in rodents after a severe incomplete clip-compression SCI versus a complete spinal cord transection at thoracic segment T13. Above-level withdrawal behaviors evoked by forepaw stimulation provided evidence of mechanical hyperalgesia after incomplete but not complete SCI, whereas below-level responses evoked by hindpaw stimulation revealed hypersensitivity after both injuries. The latency of the above-level response was 4-5 wks but was longer after a moderate clip-compression injury. Mechanical hyperalgesia was fully reversed by three analgesic drugs used in treating neuropathic SCI pain, but their duration of action differed significantly, showing a rank order of amitriptyline (24-48 h) ? morphine (6 h) > gabapentin (2 h). Evidence of central sensitization in cervical spinal cord segments that receive sensory projections from the forelimbs was provided by immunohistochemistry for Zif268, a functional marker of neuroplasticity. Zif268-immunoreactive neurons in laminae I/II increased in response to repetitive noxious forepaw stimulation in the incomplete SCI group, and this response was reduced in the complete transection and sham-operated groups. These data are consistent with the hypothesis that neuropathic pain of cord origin is more likely to develop after SCI when there is an incomplete loss of axons traversing the lesion.     

Pulsed Radiofrequency Ablation for Residual and Phantom Limb Pain: A Case Series

Residual limb pain (RLP) and phantom limb pain (PLP) can be debilitating and can prevent functional gains following amputation. High correlations have been reported between RLP and the stump neuromas following amputation. Many treatment methods including physical therapy, medications, and interventions, have been used with limited success. Pulsed radiofrequency ablation (PRFA) has shown promise in treating neuropathic pain because of the inhibition of evoked synaptic activity. We present 4 amputees who were treated with PRFA after failing conservative management for their RLP and PLP. All 4 patients underwent PRFA and demonstrated at least 80% relief of RLP for over 6 months. One patient reported a complete resolution of phantom sensation while another patient had significantly decreased frequency of spontaneous PLP and resolution of evoked PLP. In addition, all patients reported improved overall function including increased prosthetic tolerance and decreased oral pain medications. This case series suggests that PRFA is a viable treatment option which might be used for long‐term relief of intractable RLP and/or PLP.     

Metabolite concentrations in the anterior cingulate cortex predict high neuropathic pain impact after spinal cord injury

Persistent pain is a common reason for reduced quality of life after a spinal cord injury (SCI). Biomarkers of neuropathic pain may facilitate translational research and the understanding of underlying mechanisms. Research suggests that pain and affective distress are anatomically and functionally integrated in the anterior cingulate cortex and can modulate sensory and affective aspects of pain. We hypothesized that severe neuropathic pain with a significant psychosocial impact would be associated with metabolite concentrations (obtained by magnetic resonance spectroscopy) in the anterior cingulate cortex, indicating neuronal and/or glial dysfunction. Participants with SCI and severe, high-impact neuropathic pain (SCI-HPI; n = 16), SCI and moderate, low-impact neuropathic pain (SCI-LPI; n = 24), SCI without neuropathic pain (SCI-noNP; n = 14), and able-bodied, pain-free control subjects (A-B; n = 22) underwent a 3-T magnetic resonance imaging brain scan. Analyses revealed that the SCI-HPI group had significantly higher levels of myoinositol (Ins) (P < .000), creatine (P = .007), and choline (P = .014), and significantly lower levels of N-acetyl aspartate/Ins (P = .024) and glutamate-glutamine (Glx)/Ins (P = .003) ratios than the SCI-LPI group. The lower Glx/Ins ratio significantly discriminated between SCI-HPI and the A-B (P = .006) and SCI-noNP (P = .026) groups, displayed excellent test-retest reliability, and was significantly related to greater pain severity, interference, and affective distress. This suggests that the combination of lower glutamatergic metabolism and proliferation of glia and glial activation are underlying mechanisms contributing to the maintenance of severe neuropathic pain with significant psychosocial impact in chronic SCI. These findings indicate that the Glx/Ins ratio may be a useful biomarker for severe SCI-related neuropathic pain with significant psychosocial impact.     

Topical analgesics for neuropathic pain: Preclinical exploration,clinical validation,future development

Topical analgesics applied locally to skin or to specialized compartments modify pain by actions on sensory nerve endings and/or adjacent cellular elements. With this approach, there are low systemic drug levels, good tolerability and few drug interactions, and combination with oral formulations is feasible. The goal of this review is to provide an overview of the potential for topical analgesics to contribute to improved management of neuropathic pain. Mechanistic and preclinical studies indicate much potential for development of novel topical analgesics for neuropathic pain. In humans, two topical analgesics are approved for use in post‐herpetic neuralgia (lidocaine 5% medicated plaster, capsaicin 8% patch), and there is evidence for efficacy in other neuropathic pain conditions. Comparative trials indicate similar efficacy between topical and oral analgesics. Not all individuals respond to topical analgesics, and there is interest in determining factors (patient factors, sensory characteristics) which might predict responsiveness to topical analgesics. There is a growing number of controlled trials and case reports of investigational agents (vasodilators, glutamate receptor antagonists, α2‐adrenoreceptor agonists, antidepressants, centrally acting drugs), including combinations of several agents, indicating these produce pain relief in neuropathic pain. There is interest in compounding topical analgesics for neuropathic pain, but several challenges remain for this approach. Topical analgesics have the potential to be a valuable additional approach for the management of neuropathic pain.     

On the relation between sensory deafferentation, pain and thalamic activity in Wallenberg’s syndrome: A PET-scan study before and after motor cortex stimulation

Decrease of thalamic blood flow contralateral to neuropathic pain has been described by several groups, but its relation with sensory deafferentation remains unclear. Here we report one instance where the thalamic effects of sensory deafferentation could be dissociated from those of neuropathic pain. A 50-year-old patient underwent a left medullary infarct leading to right-sided thermal and pain hypaesthesia up to the third right trigeminal division, as well as in the left face. During the following months the patient developed neuropathic pain limited to the left side of the face. Although the territory with sensory loss was much wider in the right (non painful) than in the left (painful) side of the body, PET-scan demonstrated significant reduction of blood flow in the right thalamus (contralateral to the small painful area) relative to its homologous region. After 3 months of right motor cortex stimulation the patient reported 60% relief of his left facial pain, and a new PET-scan showed correction of the thalamic asymmetry. We conclude that thalamic PET-scan hypoactivity contralateral to neuropathic pain does not merely reflect deafferentation, but appears related to the pain pathophysiology, and may be normalized in parallel with pain relief. The possible mechanisms linking thalamic hypoactivity and pain are discussed in relation with findings in epileptic patients, possible compensation phenomena and bursting thalamic discharges described in animals and humans. Restoration of thalamic activity in neuropathic pain might represent one important condition to obtain successful relief by analgesic procedures, including cortical neurostimulation.     

Subarachnoid transplant of a human neuronal cell line attenuates chronic allodynia and hyperalgesia after excitotoxic spinal cord injury in the rat.

The relief of neuropathic pain after spinal cord injury (SCI) remains daunting, because pharmacologic intervention works incompletely and is accompanied by multiple side effects. Transplantation of human cells that make specific biologic agents that can potentially modulate the sensory responses that are painful would be very useful to treat problems such as pain. To address this need for clinically useful human cells, the human neuronal NT2 cell line was used as a source to isolate a unique human neuronal cell line that synthesizes and secretes/releases the inhibitory neurotransmitters gamma-aminobutyric acid (GABA) and glycine. This new cell line, hNT2.17, expresses an exclusively neuronal phenotype, does not incorporate bromodeoxyuridine during differentiation, and does not express the tumor-related proteins fibroblast growth factor 4 and transforming growth factor-alpha during differentiation after 2 weeks of treatment with retinoic acid and mitotic inhibitors. The transplant of predifferentiated hNT2.17 cells was used in the excitotoxic SCI pain model, after intraspinal injection of the mixed AMPA/metabotropic receptor agonist quisqualic acid (QUIS). When hNT2.17 cells were transplanted into the lumbar subarachnoid space, tactile allodynia and thermal hyperalgesia induced by the injury were quickly and potently reversed. Control cell transplants of nonviable hNT2.17 cells had no effect on the hypersensitivity induced by QUIS. The effects of hNT2.17 cell grafts appeared 1 week after transplants and did not diminish during the 8-week course of the experiment when grafts were placed 2 weeks after SCI. Immunohistochemistry and quantification of the human grafts were used to ensure that many grafted cells were still present and synthesizing GABA at the end of the study. These data suggest that the human neuronal hNT2.17 cells can be used as a "biologic minipump" for antinociception in models of SCI and neuropathic pain. PERSPECTIVE: This study describes the initial characterization and use of a human-derived cell line to treat neuropathic pain that would be suitable for clinical application, once further tested for safety and approved by the Food and Drug Administration. A dose of these human cells could be delivered with a spinal tap and affect the intrathecal spinal environment for sensory system modulation.     

Calcium channel alpha-2-delta-1 protein upregulation in dorsal spinal cord mediates spinal cord injury-induced neuropathic pain states

Spinal cord injury (SCI) commonly results in the development of neuropathic pain, which can dramatically impair the quality of life for SCI patients. SCI-induced neuropathic pain can be manifested as both tactile allodynia (a painful sensation to a non-noxious stimulus) and hyperalgesia (an enhanced sensation to a painful stimulus). The mechanisms underlying these pain states are poorly understood. Clinical studies have shown that gabapentin, a drug that binds to the voltage-gated calcium channel alpha-2-delta-1 subunit (Ca_vα2δ-1) proteins is effective in the management of SCI-induced neuropathic pain. Accordingly, we hypothesized that tactile allodynia post SCI is mediated by an upregulation of Ca_vα2δ-1 in dorsal spinal cord. To test this hypothesis, we examined whether SCI-induced dysregulation of spinal Ca_vα2δ-1 plays a contributory role in below-level allodynia development in a rat spinal T9 contusion injury model. We found that Ca_vα2δ-1 expression levels were significantly increased in L4-6 dorsal, but not ventral, spinal cord of SCI rats that correlated with tactile allodynia development in the hind paw plantar surface. Furthermore, both intrathecal gabapentin treatment and blocking SCI-induced Ca_vα2δ-1 protein upregulation by intrathecal Ca_vα2δ-1 antisense oligodeoxynucleotides could reverse tactile allodynia in SCI rats. These findings support that SCI-induced Ca_vα2δ-1 upregulation in spinal dorsal horn is a key component in mediating below-level neuropathic pain states, and selectively targeting this pathway may provide effective pain relief for SCI patients.     

Pain report and the relationship of pain to physical factors in the first 6 months following spinal cord injury.

A prospective, longitudinal study of 100 people with traumatic spinal cord injury (SCI) was performed to determine the time of onset. prevalence and severity of different types of pain (musculoskeletal, visceral, neuropathic at level, neuropathic below level) at 2, 4, 8, 13 and 26 weeks following SCI. In addition, we sought to determine the relationship between physical factors such as level of lesion, completeness and clinical SCI syndrome and the presence of pain. At 6 months following SCI, 40% of people had musculoskeletal pain, none had visceral pain, 36% had neuropathic at level pain and 19% had neuropathic below level pain. When all types of pain were included, at 6 months following injury, 64% of people in the study had pain, and 21% of people had pain that was rated as severe. Those with neuropathic below level pain were most likely to report their pain as severe or excruciating. There was no relationship between the presence of pain overall and level or completeness of lesion, or type of injury. Significant differences were found, however, when specific types of pain were examined. Musculoskeletal pain was more common in people with thoracic level injuries. Neuropathic pain associated with allodynia was more common in people who had incomplete spinal cord lesions, cervical rather than thoracic spinal cord lesions, and central cord syndrome. Therefore, this study suggests that most people continue to experience pain 6 months following spinal cord injury and 21% of people continue to experience severe pain. While the presence or absence of pain overall does not appear to be related to physical factors following SCI, there does appear to be a relationship between physical factors and pain when the pain is classified into specific types.     

Movement imagery increases pain in people with neuropathic pain following complete thoracic spinal cord injury

Spinal cord injury (SCI) results in deafferentation and the onset of neuropathic pain in a substantial proportion of people. Based on evidence suggesting motor cortex activation results in attenuation of neuropathic pain, we sought to determine whether neuropathic SCI pain could be modified by imagined movements of the foot. Fifteen subjects with a complete thoracic SCI (7 with below-level neuropathic pain and 8 without pain) were instructed in the use of movement imagery. Movement imagery was practiced three times daily for 7days. On the eighth day, subjects performed the movement imagery in the laboratory and recorded pain ratings during the period of imagined movement. Six out of 7 subjects with neuropathic pain reported an increase in pain during imagined movements from 2.9+/-0.7 during baseline to 5.0+/-1.0 during movement imagery (p<0.01). In SCI subjects without neuropathic pain, movement imagery evoked an increase in non-painful sensation intensity from a baseline of 1.9+/-0.7 to 4.8+/-1.3 during the movement imagery (p<0.01). Two subjects without a history of pain or non-painful phantom sensations had onset of dysesthesia while performing imagined movements. This study reports exacerbation of pain in response to imagined movements and it contrasts with reports of pain reduction in people with peripheral neuropathic pain. The potential mechanisms underlying this sensory enhancement with movement imagery are discussed.     

Experimental Spinal Cord Stimulation and Neuropathic Pain: Mechanism of Action,Technical Aspects,and Effectiveness

Abstract: Spinal cord stimulation (SCS) is a valuable treatment for chronic intractable neuropathic pain. Although SCS has gone through a technological revolution over the last four decades, the neurophysiologic and biochemical mechanisms of action have only been partly elucidated. Animal experimental work has provided some evidence for spinal as well as supraspinal mechanisms of neuropathic pain relief of SCS. A SCS computer model of the electrical properties of the human spinal cord revealed many basic neurophysiologic principles that were clinically validated later on. The main question in clinical SCS is how to further improve the effectiveness of SCS as there is still a significant failure rate of 30%. In this context, experimental studies are needed to elucidate which target pain neuron(s) are involved, as well as with what exact electrical stimulation this target neuron can be influenced to produce an optimal supapression of neuropathic pain. This article reviews the basic clinical and experimental technical aspects in relation to the effectiveness of SCS in view of recent understanding of the dorsal horn pain circuit involved. These data may then result in experiments needed for an improved understanding of the mechanisms underlying SCS and consequently lead to improvement and increased effectiveness of SCS in neuropathic pain as a clinical therapy.     

Update on Neuropathic Pain Treatment: Ion Channel Blockers and Gabapentinoids

Neuropathic pain is a debilitating chronic pain condition, which remains difficult to treat. The current mainstays of treatment include physical therapy, interventional procedures and medications. Among medications, ion channel blockers and gabapentinoids are the 2 classes of drugs commonly used to treat neuropathic pain. It has been suggested that these medications may be useful to treat a variety of neuropathic pain conditions. This article provides several updates on the utility of both ion channel blockers and gabapentinoids for the treatment of neuropathic pain.     

Defining the role for gabapentin in the treatment of trigeminal neuralgia: a retrospective study.

The preferred treatment for trigeminal neuralgia consists of antiepileptic drugs. Among them, gabapentin has shown promise in relieving some forms of neuropathic pain. This retrospective review examined 194 consecutive cases of trigeminal neuralgia, many of whom had paroxysmal facial pain resistant to previous surgical interventions or treatment with multiple medications. Of the 92 who had received a trial of gabapentin, 43 reported reduction in facial pain. This benefit was complete in 16, nearly complete in 9, moderate in 12, and partial in 6. Onset of pain relief occurred generally within 1 to 3 weeks, depending on the rate and end point of dose titration. The effective range of stable daily dosing varied from 100 to 2400 mg divided 3 times a day, with a mean of 930 mg. Pain relief was sustained in two thirds during a mean follow-up time of 8 months. The fact that gabapentin was well-tolerated and without serious side effects is an important advantage when prescribing for elderly patients. The present study suggests that gabapentin can be effective as first or second line treatment of trigeminal neuralgia, even in cases resistant to traditional treatment modalities.     

NeuPSIG guidelines on neuropathic pain assessment

This is a revision of guidelines, originally published in 2004, for the assessment of patients with neuropathic pain. Neuropathic pain is defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system either at peripheral or central level.Screening questionnaires are suitable for identifying potential patients with neuropathic pain, but further validation of them is needed for epidemiological purposes. Clinical examination, including accurate sensory examination, is the basis of neuropathic pain diagnosis. For more accurate sensory profiling, quantitative sensory testing is recommended for selected cases in clinic, including the diagnosis of small fiber neuropathies and for research purposes.Measurement of trigeminal reflexes mediated by A-beta fibers can be used to differentiate symptomatic trigeminal neuralgia from classical trigeminal neuralgia. Measurement of laser-evoked potentials is useful for assessing function of the A-delta fiber pathways in patients with neuropathic pain. Functional brain imaging is not currently useful for individual patients in clinical practice, but is an interesting research tool. Skin biopsy to measure the intraepidermal nerve fiber density should be performed in patients with clinical signs of small fiber dysfunction.The intensity of pain and treatment effect (both in clinic and trials) should be assessed with numerical rating scale or visual analog scale. For future neuropathic pain trials, pain relief scales, patient and clinician global impression of change, the proportion of responders (50% and 30% pain relief), validated neuropathic pain quality measures and assessment of sleep, mood, functional capacity and quality of life are recommended.     

Update on pharmacotherapy guidelines for treatment of neuropathic pain

Neuropathic pain encompasses a myriad of painful disease states that are often hard to treat, especially with one single medication. In the comprehensive treatment of neuropathic pain, the concept of complex polypharmacy is a rational approach, accompanied by physical and mental health therapies. Medications primarily used for neuropathic pain generally fall into the categories of anticonvulsants, antidepressants, opioids, and topical agents. Generally, most first-line medications used today show a response rate of approximately 30% to 50% reduction in pain in up to 50% of patients treated. There is no “gold standard” in regard to one medication for neuropathic pain. Some new medications have emerged during the past few years that help to augment the armamentarium of medications used in neuropathic pain. This paper reviews the definition of neuropathic pain and introduces the reader to the evidence-based literature on these new medications available for the treatment of neuropathic     

Functional Characterization of At-Level Hypersensitivity in Patients With Spinal Cord Injury

At-level and above-level hypersensitivity was assessed in patients with chronic complete thoracic spinal cord injury (SCI). Patients were classified using somatosensory mapping (brush, cold, pinprick) and assigned into 2 groups (ie, patients with at-level hypersensitivity [SCIHs, n = 8] and without at-level hypersensitivity [SCINHs, n = 7]). Gender and age-matched healthy subjects served as controls. Quantitative sensory testing (QST), electrically- and histamine-induced pain and itch, laser Doppler imaging, and laser-evoked potentials (LEP) were recorded at-level and above-level in SCI-patients. Six of 8 SCIHs, but 0 of 7 SCINHs patients suffered from neuropathic below-level pain. Clinical sensory mapping revealed spreading of hypersensitivity to more cranial areas (above-level) in 3 SCIHs. Cold pain threshold measures confirmed clinical hypersensitivity at-level in SCIHs. At-level and above-level hypersensitivity to electrical stimulation did not differ significantly between SCIHs and SCINHs. Mechanical allodynia, cold, and pin-prick hypersensitivity did not relate to impaired sensory function (QST), axon reflex flare, or LEPs. Clinically assessed at-level hypersensitivity was linked to below-level neuropathic pain, suggesting neuronal hyperexcitability contributes to the development of neuropathic pain. However, electrically evoked pain was not significantly different between SCI patients. Thus, SCI-induced enhanced excitability of nociceptive processing does not necessarily lead to neuropathic pain. QST and LEP revealed no crucial role of deafferentation for hypersensitivity development after SCI.

Opioids for neuropathic pain

Whether opioids are effective for neuropathic pain has been a matter of controversy for decades. Within limits, it is clear that opioids in general are effective for neuropathic pain. Furthermore, there is no evidence that opioids are any less effective for neuropathic pain than for non-neuropathic pain, no evidence that opioids are less effective for neuropathic pain than are other medications, and no evidence that one opioid is any more effective than another for neuropathic pain. It remains uncertain whether opioids are effective for central pain, although they may have a role. Although some patients appear to enjoy long-term benefits, most studies have been short-term. Opioids have an important role in the treatment of neuropathic pain; however, skillful opioid use balances the benefits with management of side effects and prevention and treatment of abuse and addiction.