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.

A role for peripheral afferents in the pathophysiology and treatment of at-level neuropathic pain in spinal cord injury? A case report

At-level neuropathic pain is a frequent symptom following spinal cord injury, but the underlying pathophysiology is not completely understood. We report a patient suffering from treatment-resistant at-level pain characterized by ongoing pain and mechanical allodynia for three years after an incomplete spinal lesion. Quantitative sensory testing revealed severe thermosensory deficits in the neuropathic pain area. However, topical application of capsaicin in the neuropathic pain area induced a burning pain sensation, a marked decrease in heat pain threshold and an increase in mechanical allodynia. Treatment with topical lidocaine patches (5%) led to considerable pain relief. These results indicate a functional connection between peripheral, spinal and supraspinal nociceptive pathways and that peripheral afferents may contribute to at-level neuropathic pain after spinal cord injury in this patient. Lesioned peripheral afferents in combination with central neuronal hyperexcitability are discussed as a likely underlying pain mechanism.     

Reduced intraepidermal nerve fiber density in patients with chronic ischemic pain in peripheral arterial disease

Chronic ischemic pain in peripheral arterial disease (PAD) is a leading cause of pain in the lower extremities. A neuropathic component of chronic ischemic pain has been shown independent of coexisting diabetes. We aimed to identify a morphological correlate potentially associated with pain and sensory deficits in PAD. Forty patients with symptomatic PAD (Fontaine stages II-IV), 20 with intermittent claudication (CI), and 20 with critical limb ischemia (CLI) were enrolled; 12 volunteers served as healthy controls. All patients were examined using pain scales and questionnaires. All study participants underwent quantitative sensory testing (QST) at the distal calf and skin punch biopsy at the distal leg for determination of intraepidermal nerve fiber density (IENFD). Additionally, S100beta serum levels were measured as a potential marker for ischemic nerve damage. Neuropathic pain questionnaires revealed slightly higher scores and more pronounced pain-induced disability in CLI patients compared to CI patients. QST showed elevated thermal and mechanical detection pain thresholds as well as dynamic mechanical allodynia, particularly in patients with advanced disease. IENFD was reduced in PAD compared to controls (P < 0.05), more pronounced in the CLI subgroup (CLI: 1.3 ± 0.5 fibers/mm, CI: 2.9 ± 0.5 fibers/mm, controls: 5.3 ± 0.6 fibers/mm). In particular, increased mechanical and heat pain thresholds negatively correlated with lower IENFD. Mean S100beta levels were in the normal range but were higher in advanced disease. Patients with chronic ischemic pain had a reduced IENFD associated with impaired sensory functions. These findings support the concept of a neuropathic component in ischemic pain.     

A longitudinal study of the prevalence and characteristics of pain in the first 5 years following spinal cord injury

A longitudinal cohort study of 100 people with traumatic spinal cord injury (SCI) was performed to determine the prevalence and severity of different types of pain (musculoskeletal, visceral, neuropathic at-level, neuropathic below-level) at 5 years following SCI. Prospective data on the characteristics of pain up to 6 months following injury had been collected previously and allowed comparisons between the presence of pain at different time points. In addition, we sought to determine the relationship between the presence of pain and physical factors related to the injury such as level of lesion, completeness and clinical SCI syndrome. We also obtained information regarding mood, global self-rated health and the impact of pain on function. Of the 100 subjects in the original cohort, 73 were available for follow up. When all types of pain were included, 59 of the 73 subjects (81%) reported the presence of pain. Musculoskeletal pain was the most common type of pain experienced and was present in 43 subjects (59%), at-level neuropathic pain was present in 30 subjects (41%), below-level neuropathic pain was present in 25 subjects (34%) and visceral pain was present in four subjects (5%). Overall, 58% reported their pain as severe or excruciating and those with visceral pain were most likely to rate their pain in these categories. There was no relationship between the presence of pain overall and level or completeness of lesion, or type of injury. However, tetraplegics were more likely to report below-level neuropathic pain. This study prospectively demonstrates the differing time courses of different types of pain over the first 5 years following SCI. There was a strong correlation between the presence of both types of neuropathic pain at 5 years and earlier time points but both visceral pain and musculoskeletal pain demonstrated a poor correlation between time points. Chronic visceral pain occurs in a small percentage of patients and does not correlate with the presence of visceral pain early following injury. Those with neuropathic pain early following their injury are likely to continue to experience ongoing pain and the pain is likely to be severe. In contrast, chronic musculoskeletal pain is more common but less likely to be severe and cannot be predicted by the presence of pain in the first 6 months following injury.     

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.     

Classifying post‐stroke shoulder pain: Can the DN4 be helpful?

The etiology of post‐stroke shoulder pain (PSSP) is largely unclear and may involve both nociceptive and neuropathic mechanisms. No gold standard is present for PSSP diagnosis. The neuropathic pain diagnostic questionnaire (DN4), was originally developed to identify neuropathic pain in the clinical context. In this study we used the DN4 to categorize PSSP patients and compared symptoms and signs suggestive of either nociceptive or neuropathic pain. Pain complaints and sensory functions were compared between patients with chronic PSSP scoring at least four (DN4+, n=9) or less than four (DN4⁻, n=10) on the DN4. Pain was assessed using a numeric rating scale and the McGill pain questionnaire. Sensory functions were assessed using clinical examination and quantitative sensory testing combined with a cold pressor test. Patients classified as DN4+ reported constant pain, higher pain intensity, a higher impact of pain on daily living, more frequent loss of cold sensation, reduced QST thresholds at the unaffected side and increased QST thresholds at the affected side. Notably, several symptoms and signs suggestive of either neuropathic or nociceptive pain corresponded to the subgroups DN4+ and DN4⁻ respectively. However, since the pathophysiological mechanisms remain unclear and none of the sensory signs could be exclusively related to either DN4+ or DN4⁻, PSSP prognosis and treatment should not be solely based on the DN4. Nonetheless, a thorough assessment of neuropathic and nociceptive pain complaints and somatosensory functions should be included in the diagnostic work‐up of PSSP.     

Lidocaine 5% Medicated Plaster for Spinal Neuropathic Pain

Spinal cord injuries frequently determine central pain symptoms that are difficult to control. The authors present the case of a 67-year-old suffering from a pleural mesothelioma. During the disease course, he developed a paraplegia syndrome from mesothelioma compression of the spinal cord at T4–T5 level. Following spinal decompression surgery, the patient presented an intense at-level, superficial neuropathic pain syndrome with allodynia and hyperalgesia. After systemic pharmacological therapies had failed, treatment with lidocaine 5% plaster was initiated. The superficial neuropathic symptoms almost completely disappeared within a few days. The lidocaine topical treatment was continued for months with durable analgesic effect.     

Lamotrigine in spinal cord injury pain: a randomized controlled trial

The objective was to investigate the effectiveness of lamotrigine for the treatment of spinal cord injury pain and clinical signs of neuronal hyperexcitability. Thirty patients with spinal cord injury (SCI) and at or below level neuropathic pain participated in a randomized double blind, placebo-controlled, crossover trial. A 1-week baseline period was followed by two treatment periods of 9 weeks duration with lamotrigine slowly increased to a maximum of 400 mg or placebo separated by a 2-week washout period. The primary outcome measure was the change in median pain score from baseline week to the last week of treatment. Secondary outcome measures included thresholds to standardized sensory stimuli using quantitative sensory testing. Twenty-two patients completed the trial. We found no statistically significant effect of lamotrigine as evaluated in the total sample. However, in patients with incomplete SCI, lamotrigine significantly reduced pain at or below SCI level. Patients with brush evoked allodynia and wind-up-like pain in the area of maximal pain were more likely to have a positive effect to lamotrigine than patients without these evoked pains (7 of 7 vs. 1 of 14). Lamotrigine was generally well tolerated. While this trial showed no significant effect on spontaneous and evoked pain in complete and incomplete spinal cord injury, lamotrigine reduced spontaneous pain in patients with incomplete spinal cord injury and evoked pain in the area of spontaneous pain.     

Dermatomal Scratching After Intramedullary Quisqualate Injection: Correlation With Cutaneous Denervation

Central nervous system lesions cause peripheral dysfunctions currently attributed to central cell death that compromises function of intact peripheral nerves. Injecting quisqualate (QUIS) into the rat spinal cord models spinal cord injury (SCI) and causes at-level scratching and self-injury. Such overgrooming was interpreted to model pain until patients with self-injurious scratching after SCI reported itch motivated scratching that was painless because of sensory loss. Because self-injurious scratching is difficult to explain by central mechanisms alone, we hypothesized that QUIS injections damage peripheral axons of at-level afferents. QUIS was injected into thoracic spinal cords of 18 Long-Evans rats. Animals were killed 3 days after overgrooming began or 14 days after injection. Spinal cord lesions were localized and DRG-immunolabeled for ATF-3. At-level and control skin samples were PGP9.5-immunabeled to quantify axons. Eighty-four percent of QUIS rats overgroomed. Skin in these regions had lost two-thirds of epidermal innervation as compared with controls (P < .001). Rats that overgroomed had 47% less axon-length than nongrooming rats (P = .006). The presence of ATF-3 immunolabeled neurons within diagnosis-related groups of QUIS rats indicated death of afferent cell bodies. Overgrooming after QUIS injections may not be due entirely to central changes. As in humans, self-injurious neuropathic scratching appeared to require loss of protective pain sensations in addition to peripheral denervation.PerspectiveThis study suggests that intramedullary injection of quisqualic acid in rats causes death of at-level peripheral as well as central neurons. Self-injurious dermatomal scratching that develops in spinal-injured rats may reflect neuropathic itch and loss of protective pain sensations.     

Combined approaches for the relief of spinal cord injury-induced neuropathic pain

The adequate treatment of spinal cord injury (SCI)-induced neuropathic pain still remains an unresolved problem. The current medications predominantly used in the SCI-induced neuropathic pain therapy are morphine, anticonvulsants, antidepressants, and antiepileptics, which suggests that psychiatric aspects might be important factors in the treatment of neuropathic pain.It is well documented that the modulation of the sensory events is not a unique way for achieving pain relief. In addition, pain patients still express dissatisfaction and complain of unwanted effects of the medications, suggesting that alternative approaches for the treatment of neuropathic pain are essential. In psychiatry, pain relief represents relaxation and a feeling of comfort and satisfaction, which suggests that cognitive and emotional motivations are important factors in the treatment of neuropathic pain. The comorbidity of chronic pain and psychiatric disorders, which is well recognized, suggests that the effective therapeutic relief for neuropathic pain induced by SCI can be achieved in conjunction with the management of the sensory and psychiatric aspects of patient.In this review, we address the feasibility of a combined acupuncture and pharmacotherapy treatment for the relief of neuropathic pain behavior following SCI.     

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.     

The Lindblom roller.

Neuropathic pain is caused by injury of the peripheral or central nervous system. The neurological examination of the sensory system in neuropathic pain patients guides the anatomical localization of the injury. Among the sensory modalities to be tested, priority should be given to those subserved by small peripheral sensory fibers or by the spinothalamic tract that most commonly are abnormal in neuropathic pain patients. Testing of cold and warm perception was traditionally carried out in the clinic using tubes filled with water at different temperatures, a cumbersome method that has limited the routine examination of these sensory modalities. The Lindblom roller offers a practical and effective method of readily testing temperature perception and is among the best available clinical tools for delineating the anatomical boundaries of a sensory abnormality. Routinely use of the Lindblom roller shall be standard bedside clinical assessment of neuropathic pain patients. To exemplify this statement we describe two patients affected by complex and fluctuating painful sensory abnormalities caused by an extradural mass compressing the spinal cord. The level of the injury was readily localized with a roller kept at room temperature.     

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.     

HDAC inhibitors attenuate the development of hypersensitivity in models of neuropathic pain

Histone deacetylase inhibitors (HDACIs) interfere with the epigenetic process of histone acetylation and are known to have analgesic properties in models of chronic inflammatory pain. The aim of this study was to determine whether these compounds could also affect neuropathic pain. Different class I HDACIs were delivered intrathecally into rat spinal cord in models of traumatic nerve injury and antiretroviral drug–induced peripheral neuropathy (stavudine, d4T). Mechanical and thermal hypersensitivity was attenuated by 40% to 50% as a result of HDACI treatment, but only if started before any insult. The drugs globally increased histone acetylation in the spinal cord, but appeared to have no measurable effects in relevant dorsal root ganglia in this treatment paradigm, suggesting that any potential mechanism should be sought in the central nervous system. Microarray analysis of dorsal cord RNA revealed the signature of the specific compound used (MS-275) and suggested that its main effect was mediated through HDAC1. Taken together, these data support a role for histone acetylation in the emergence of neuropathic pain.     

Role of SIP30 in the development and maintenance of peripheral nerve injury-induced neuropathic pain

Using the chronic constriction injury (CCI) model of neuropathic pain, we profiled gene expression in the rat spinal cord, and identified SIP30 as a gene whose expression was elevated after CCI. SIP30 was previously shown to interact with SNAP25, but whose function was otherwise unknown. We now show that in the spinal cord, SIP30 was present in the dorsal horn laminae where the peripheral nociceptive inputs first synapse, co-localizing with nociception-related neuropeptides CGRP and substance P. With the onset of neuropathic pain after CCI surgery, SIP30 mRNA and protein levels increased in the ipsilateral side of the spinal cord, suggesting a potential association between SIP30 and neuropathic pain. When CCI-upregulated SIP30 was inhibited by intrathecal antisense oligonucleotide administration, neuropathic pain was attenuated. This neuropathic pain-reducing effect was observed both during neuropathic pain onset following CCI, and after neuropathic pain was fully established, implicating SIP30 involvement in the development and maintenance phases of neuropathic pain. Using a secretion assay in PC12 cells, anti-SIP30 siRNA decreased the total pool of synaptic vesicles available for exocytosis, pointing to a potential function for SIP30. These results suggest a role of SIP30 in the development and maintenance of peripheral nerve injury-induced neuropathic pain.     

Referred sensations and neuropathic pain following spinal cord injury

It has been proposed that painful and non-painful referred sensations (RSs) are associated with reorganization of sensory pathways in patients with complete spinal cord injury (SCI). In order to investigate the referred sensation (RS) phenomenon and its correlation with neuropathic pain (NP) 48 patients with complete SCI, 24 with chronic NP and 24 without pain or paraesthesias were studied using clinical examination and neurophysiological tests. Patients reporting RSs were re-examined at 2 and 10 weeks after the first examination. We defined the presence of RS as sensations perceived below the injury level in response to touch and pinprick stimuli in various body points above the injury level. The examination was carried out by one researcher applying the stimuli to the patient under two visual conditions (open and closed eyes), and then asking the patient to make tactile self-stimulation. Seven patients with SCI and NP (29%) reported RS below the injury level. RS were well located and consistently evoked at repeated examinations. Touch and pinprick stimulation elicited similar RS that were non-painful in six patients and painful in one. Visual feedback did not change RS perception and characteristics. None of the patients in the SCI group without NP presented RS. In conclusion, our results indicate that RS is relatively frequent in patients with complete SCI and NP. The common occurrence of RS in patients with NP and the location of the sensations in the same area as NP suggest that pain and RS share common pathophysiological mechanisms.     

Spinal cord stimulation of dorsal columns in a rat model of neuropathic pain: evidence for a segmental spinal mechanism of pain relief

Although spinal cord stimulation (SCS) of the dorsal columns is an established method for treating chronic neuropathic pain, patients still suffer from a substantial level of pain. From a clinical perspective it is known that the location of the SCS is of pivotal importance, thereby suggesting a segmental spinal mode of action. However, experimental studies suggest that SCS acts also through the modulation of supraspinal mechanisms, which might suggest that the location is unimportant. Here we investigated the effect of the rostrocaudal location of SCS stimulation and the effectiveness of pain relief in a rat model of chronic neuropathic pain. Adult male rats (n = 45) were submitted to a partial ligation of the sciatic nerve. The majority of animals developed tactile hypersensitivity in the nerve lesioned paw. All allodynic rats were submitted to SCS (n = 33) for 30 minutes (f = 50 Hz; pulse width 0.2 ms). In one group (n = 16) the electrodes were located at the level where the injured sciatic nerve afferents enter the spinal cord (T13), and in a second group (n = 17) the electrodes were positioned at more rostral levels (T11) as verified by X-ray. A repositioning experiment of electrodes from T12 to T13 was performed in 2 animals. Our data demonstrate that SCS of the dorsal columns at the level where the injured fibers enter the spinal cord dorsal horn result in a much better pain-relieving effect than SCS at more rostral levels. From this we conclude that SCS in treatment of neuropathic pain acts through a segmental spinal site of action.