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.     

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.     

Characterization of Hyperacute Neuropathic Pain after Spinal Cord Injury: A Prospective Study

There is currently a lack of information regarding neuropathic pain in the very early stages of spinal cord injury (SCI). In the present study, neuropathic pain was assessed using the Douleur Neuropathique 4 Questions (DN4) for the patient's worst pain within the first 5 days of injury (i.e., hyperacute) and on follow-up at 3, 6, and 12 months. Within the hyperacute time frame (i.e., 5 days), at- and below-level neuropathic pain were reported as the worst pain in 23% (n = 18) and 5% (n = 4) of individuals with SCI, respectively. Compared to the neuropathic pain observed in this hyperacute setting, late presenting neuropathic pain was characterized by more intense painful electrical and cold sensations, but less itching sensations. Phenotypic differences between acute and late neuropathic pain support the incorporation of timing into a mechanism-based classification of neuropathic pain after SCI. The diagnosis of acute neuropathic pain after SCI is challenged by the presence of nociceptive and neuropathic pains, with the former potentially masking the latter. This may lead to an underestimation of the incidence of neuropathic pain during the very early, hyperacute time points post-injury.Trial registrationClinicalTrials.gov (Identifier: NCT01279811)PerspectiveThis article presents distinct pain phenotypes of hyperacute and late presenting neuropathic pain after spinal cord injury and highlights the challenges of pain assessments in the acute phase after injury. This information may be relevant to clinical trial design and broaden our understanding of neuropathic pain mechanisms after spinal cord injury.     

Chronic neuropathic pain management in spinal cord injury patients. What is the efficacy of pharmacological treatments with a general mode of administration? (oral,transdermal, intravenous)

IntroductionThe pharmacological treatment of patients with spinal cord injury (SCI) pain remains challenging despite new available drugs. Such treatment should always be viewed in the context of global pain management in these patients. To date few clinical trials have been specifically devoted to this topic, and the implementation of treatments is generally based on results obtained in peripheral neuropathic pain. The aim of this review is to present evidence for efficacy and tolerability of pharmacological treatments in SCI pain and propose therapeutic recommendations.Material and methodsThe methodology follows the guidelines of the French Society of Physical Medicine and Rehabilitation (SOFMER). It includes a systematic review of the litterature which is performed by two independent experts. The selected studies are analysed and classified into four levels of evidence (1 to 4) and three grades of recommendations are proposed (A, B, C). The review is further validated by a reading committee.ResultsThe efficacy of pregabalin has been confirmed in neuropathic pain associated with SCI (grade A). Gabapentin has a lower level of evidence in SCI pain (grade B) but a grade A level of evidence for efficacy in peripheral neuropathic pain. Both drugs can be proposed as first line therapy and are safe to use. Tricyclic antidepressants (TCAs) can also be proposed first line (grade B for SCI pain associated with depression, grade A for other neuropathic pain conditions), especially in patients with comorbid depressive symptoms. Tramadol can be proposed alone or in combination with antiepileptic drugs if the pain has a predominant non-neuropathic component. If these treatments fail, strong opioids can be proposed as second/third line (grade B in SCI, grade A in other types of neuropathic pain). Lamotrigine may also be proposed at this stage, particularly in patients with incomplete SCI associated with allodynia (grade B). In refractory central pain, cannabinoids may be proposed on the basis of positive results in other central pain conditions (e.g. multiple sclerosis). Intravenous ketamine and lidocaine can only be proposed in specialized centers. Drug combinations may be envisaged in case of partial response to first or second line therapy.ConclusionsVery few pharmacological studies have dealt specifically with neuropathic pain related to SCI. Large scale studies and trials comparing several active drugs are warranted in SCI pain.     

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.     

Spinal cord stimulation: A brief update on mechanisms of action

Spinal cord stimulation (SCS) originated from the gate control theory by Melzack and Wall some 40 years ago and is now widely practised as a therapy in neuropathic pain of peripheral origin. The physiological mechanisms behind the beneficial effects however are hitherto only fragmentarily known.In this short review the present knowledge is updated with recent data from animal experiments and from clinical observations. SCS used for neuropathic pain and for ischemic seems to utilize fundamentally different mechanisms and in the latter syndromes the primary effect seems to be reduction of tissue ischemia. In neuropathic pain, in contrast, the neuronal pain-generating mechanisms are directly targeted but the investigated networks are complex and much research on these matters is needed in order to further develop spinal neuromodulation for treatment-refractory pain syndromes.     

Symptom profiles differ in patients with neuropathic versus non-neuropathic pain.

The distinction between neuropathic and non-neuropathic pain reflects partially distinct mechanisms and patterns of treatment response. It was therefore hypothesized that patients with neuropathic and non-neuropathic pain have different profiles of symptoms and signs. To test this hypothesis, pain intensity, unpleasantness, quality, and spatial characteristics were examined in 618 patients with 1 of 3 peripheral neuropathic pain conditions (painful diabetic peripheral neuropathy, painful idiopathic sensory polyneuropathy, or postherpetic neuralgia), osteoarthritis pain, or low back pain. These assessments were conducted before treatment had begun in clinical trials of lidocaine patch 5% administered alone or with stable dosages of other analgesics. Patients with osteoarthritis pain and low back pain did not differ in their profile of pain quality and spatial characteristics and were combined to form a group of patients with non-neuropathic pain. In univariate analyses, patients with peripheral neuropathic pain reported significantly more intense hot, cold, sensitive, itchy, and surface pain and significantly less intense dull and deep pain than patients with non-neuropathic pain. In a multivariate analysis, the overall pattern of pain quality and spatial characteristics differed significantly between patients with neuropathic and non-neuropathic pain. In addition, specific pain quality and spatial characteristics improved the discrimination of patients with neuropathic and non-neuropathic pain in a logistic regression model that adjusted for demographic covariates and overall pain intensity and unpleasantness. PERSPECTIVE: The results indicate that the distinction between neuropathic and non-neuropathic pain is reflected in different profiles of pain quality and spatial characteristics and suggest that the assessment of patterns of pain symptoms might contribute to the identification of distinct pathophysiologic mechanisms and the development of mechanism-based treatment approaches.     

Neuropathic pain: clinical characteristics and diagnostic workup

Neuropathic pain is part of the neurological disease spectrum and may be an expression of severe medical pathology. Painful neuropathies have multiple disguises and may to a certain extent be mimicked by non-neurological pain conditions. Painful neuropathic conditions express themselves with spontaneous and/or abnormal stimulus-evoked pain. The diagnosis of peripheral or central neuropathic pain should be made only when the history and signs are indicative of neuropathy in conjunction with neuroanatomically correlated pain distribution and sensory abnormalities within the area of pain. A future mechanism-based classification of pain has recently been suggested to facilitate the development of mechanism-tailored treatment strategies. This is a sound approach and should be pursued. It is mandatory, however, to retain the traditional organ-based diagnostic workup, which should precede further in-depth characterization of specific pain mechanisms. Extensive preparatory work is needed on how to link certain symptoms and signs to specific mechanisms, as elucidated from animal studies, before we can introduce mechanism-coupled treatment strategies.     

Brain circuitry underlying pain in response to imagined movement in people with spinal cord injury

Pain following injury to the nervous system is characterized by changes in sensory processing including pain. Although there are many studies describing pain evoked by peripheral stimulation, we have recently reported that pain can be evoked in subjects with complete spinal cord injury (SCI) during a motor imagery task. In this study, we have used functional magnetic resonance imaging to explore brain sites underlying the expression of this phenomenon. In 9 out of 11 subjects with complete thoracic SCI and below-level neuropathic pain, imagined foot movements either evoked pain in a previously non-painful region or evoked a significant increase in pain within the region of on-going pain (3.2 ± 0.7–5.2 ± 0.8). In both controls (n = 19) and SCI subjects, movement imagery evoked signal increases in the supplementary motor area and cerebellar cortex. In SCI subjects, movement imagery also evoked increases in the left primary motor cortex (MI) and the right superior cerebellar cortex. In addition, in the SCI subjects, the magnitude of activation in the perigenual anterior cingulate cortex and right dorsolateral prefrontal cortex was significantly correlated with absolute increases in pain intensity. These regions expanded to include right and left anterior insula, supplementary motor area and right premotor cortex when percentage change in pain intensity was examined. This study demonstrates that in SCI subjects with neuropathic pain, a cognitive task is able to activate brain circuits involved in pain processing independently of peripheral inputs.     

Comparative actions of the opioid analgesics morphine, methadone and codeine in rat models of peripheral and central neuropathic pain

Controversy persists in relation to the analgesic efficacy of opioids in neuropathic pain. In the present study the effects of acute, subcutaneous administration of the mu-opioid receptor agonists morphine, methadone and codeine were examined in rat models of peripheral and central neuropathic pain. In the spared nerve injury (SNI) and chronic constriction injury (CCI) models of peripheral neuropathic pain, both morphine (6mg/kg) and methadone (3mg/kg) attenuated mechanical allodynia, mechanical hyperalgesia and cold allodynia for up to 1.5h post-injection (P<0.05); codeine (30mg/kg) minimally alleviated mechanical hypersensitivity in SNI, but not CCI rats. When administered to rats with photochemically-induced spinal cord injury (SCI), morphine (2 and 6mg/kg) and methadone (0.5-3mg/kg) robustly attenuated mechanical and cold allodynia for at least 2h post-injection (P<0.05). Codeine (10 and 30mg/kg) also attenuated mechanical and cold allodynia in this model for at least 3h after injection. The magnitude of opioid-mediated antinociception was similar between SNI, SCI and non-injured rats as measured in the tail flick test. At antinociceptive doses, no motor impairment as determined by the rotarod test was observed. The therapeutic window (based on antiallodynia versus ataxia) obtained for codeine, was vastly superior to that obtained with morphine or methadone in SNI and SCI rats. Furthermore, the therapeutic window for codeine in SCI rats was 4-fold greater than in SNI rats. Our results further support the efficacy of mu-opioid receptor agonists in alleviating signs of neuropathic pain in animal models of peripheral and especially central nerve injury.     

An overview of neuropathic pain: syndromes,symptoms, signs,and several mechanisms

OBJECTIVE: An overview is presented of neuropathic pain syndromes, their characteristic symptoms and signs, and recent approaches to identifying their pathophysiologic mechanisms. DESIGN: The results of recent clinical studies of neuropathic pain are reviewed. Chronic neuropathic pain syndromes are emphasized because these long-lasting and often disabling conditions present a much greater challenge for the clinician than acute pain. Peripheral neuropathic syndromes have received greater attention in the research literature than central pain, and studies of syndromes such as postherpetic neuralgia and painful diabetic neuropathy provide the basis for current knowledge of neuropathic pain. CONCLUSIONS: Precise estimates of the prevalence of neuropathic pain are not available, but chronic neuropathic pain may be much more common than has generally been appreciated and its prevalence can be expected to increase in the future. There is considerable agreement that both peripheral and central processes contribute to many chronic neuropathic pain syndromes, and that these different mechanisms may explain the qualitatively different symptoms and signs that patients experience. The limitations of existing treatments for neuropathic pain and the inability to provide relief for many patients has stimulated ongoing studies that examine different approaches to preventing neuropathic pain.     

Drug Combinations in the Treatment of Neuropathic Pain

Pharmacotherapy, the main treatment option for neuropathic pain, remains a major clinical challenge. The most commonly studied drug classes in the context of neuropathic pain—antidepressants, anticonvulsants, and opioids—have only limited efficacy and frequent dose-limiting adverse effects. Yet, most guidelines recommend monotherapy as the first line of neuropathic pain treatment. Recent understanding of neuropathic pain pathophysiology suggests that multiple mechanisms, both at the peripheral and the central nervous system levels, underlie neuropathic pain, pointing to the possibility that targeting multiple mechanisms simultaneously can improve treatment outcome. A few clinical trials using various drug combinations for neuropathic pain have already been published but yielded inconsistent results, partially due to methodological problems associated with the conduction of such trials. Nonetheless, combination therapy remains an intriguing treatment option for neuropathic pain, awaiting future high-quality validating trials.     

Assessing symptom distress in cancer patients. The M.D. Anderson symptom inventory. (The University of Texas M. D. Anderson Cancer Center, Houston, Texas) Cancer 2000;89:1634–1646.

This report presents a brief overview of the mechanisms of peripheral neuropathic pain, which are largely detailed elsewhere, and reviews the current pharmacologic approach to the treatment of neuropathic pain. Nonpharmacologic treatment of neuropathic pain is not addressed in this report.     

脊髓损伤后神经性疼痛患者大脑结构和功能变化的MRI研究进展

脊髓损伤（SCI）后,除感觉运动功能障碍外,神经性疼痛（NP）也是严重影响患者生活质量的主要因素,其发病机理尚不清楚,目前缺乏有效治疗手段。随着影像学技术的发展,SCI后大脑结构和功能改变对NP影响的逐渐被认识,不仅有利于从宏观上揭示NP的病理机制,且为治疗提供了新的思路。本文对SCI后NP患者大脑结构和功能变化及其可能机制进行综述。     

Peripheral opioid analgesia for the treatment of neuropathic pain: Gene mutation to virus mediated gene transfer

Neuropathic pain can result from a number of different diseases, medical interventions and injuries. In addition to varying aetiologies, neuropathic pain may also differ in the anatomical location of the lesion – from peripheral nociceptors to the highest centres in the brain. The management of neuropathic pain continues to be a challenge for clinicians and despite taking prescribed medication for pain, patients with neuropathic pain continue to have pain of moderate severity. The use of opioids for the treatment of chronic neuropathic pain remains controversial. Recent studies demonstrate opioid analgesics are effective in neuropathic pain states but their use is often limited by unacceptable side effects that are mediated by opioid actions in the central nervous system. While it was once dogma that opioids exert their analgesic effects by binding to receptors in the central nervous system, there is a growing recognition of a potent peripheral analgesia in experimental models of inflammatory and neuropathic pains, and in clinical settings. The working model is that peripheral opioids can be used to treat neuropathic pain while avoiding the often dose-limiting and unacceptable central nervous system mediated side effects. Our work has focused on characterizing this peripheral opioid analgesia such that it can be exploited to develop novel and potent peripheral analgesics for the treatment of neuropathic pain. This article will set the clinical stage for the need for novel treatments for neuropathic pain, the use of gene mutation strategies to make the case for the use of opioids in treating neuropathic pain, the demonstration of peripheral opioid analgesia in neuropathic pain, and our work with virus mediated gene transfer to enhance peripheral opioid analgesia in neuropathic pain.     

Importance of Hyperexcitability of DRG Neurons in Neuropathic Pain

Abstract: A number of good animal models have been developed in recent years that provide insights into the mechanisms of neuropathic pain. It now becomes evident that there are two separate peripheral components influencing neuropathic pain: one dependent on the hyperexcitability of axotomized dorsal root ganglion (DRG) neurons and the other independent of this hyperexcitability. The purpose of this review is to consider one of these components, the hyperexcitability of axotomized DRG neurons, as one of the important mechanisms underlying neuropathic pain. Several hours after nerve lesions, some axotomized DRG neurons become hyperexcitable and begin to show ongoing discharges that last many days or weeks. These ectopic discharges then enter the spinal cord and induce central sensitization, the underlying central mechanism for the generation of pain and allodynia. Although the exact causes of the development of hyperexcitability and ectopic discharges are not clear, various ion channels seem to play important roles, particularly sodium channels. In addition, important modulatory factors for ectopic discharges are purinergic and adrenergic components of the sympathetic nervous system. These findings suggest that manipulating sodium channels and/or adrenergic and purinergic receptors on axotomized DRG cells may give neuropathic pain sufferers some relief that is not available from present treatment regimens.     

Toxine botulinique et douleurs neuropathiques

Botulinum toxin type A is a potent neurotoxin which is widely used in the treatment of conditions involving muscular hyperactivity, such as dystonia and spasticity. Several recent clinical trials have indicated its beneficial impact, given subcutaneously or intradermally, on neuropathic pain and essential facial neuralgia. This review highlights the efficacy, safety of use and the potential mechanisms of action of botulinum toxin type A in peripheral or central neuropathic pain, and in essential facial neuralgia     

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.