Rufinamide Attenuates Mechanical Allodynia in a Model of Neuropathic Pain in the Mouse and Stabilizes Voltage-gated Sodium Channel Inactivated State.

BACKGROUND:: Voltage-gated sodium channels dysregulation is important for hyperexcitability leading to pain persistence. Sodium channel blockers currently used to treat neuropathic pain are poorly tolerated. Getting new molecules to clinical use is laborious. We here propose a drug already marketed as anticonvulsant, rufinamide. METHODS:: We compared the behavioral effect of rufinamide to amitriptyline using the Spared Nerve Injury neuropathic pain model in mice. We compared the effect of rufinamide on sodium currents using in vitro patch clamp in cells expressing the voltage-gated sodium channel Nav1.7 isoform and on dissociated dorsal root ganglion neurons to amitriptyline and mexiletine. RESULTS:: In naive mice, amitriptyline (20 mg/kg) increased withdrawal threshold to mechanical stimulation from 1.3 (0.6-1.9) (median [95% CI]) to 2.3 g (2.2-2.5) and latency of withdrawal to heat stimulation from 13.1 (10.4-15.5) to 30.0 s (21.8-31.9), whereas rufinamide had no effect. Rufinamide and amitriptyline alleviated injury-induced mechanical allodynia for 4 h (maximal effect: 0.10 ± 0.03 g (mean ± SD) to 1.99 ± 0.26 g for rufinamide and 0.25 ± 0.22 g to 1.92 ± 0.85 g for amitriptyline). All drugs reduced peak current and stabilized the inactivated state of voltage-gated sodium channel Nav1.7, with similar effects in dorsal root ganglion neurons. CONCLUSIONS:: At doses alleviating neuropathic pain, amitriptyline showed alteration of behavioral response possibly related to either alteration of basal pain sensitivity or sedative effect or both. Side-effects and drug tolerance/compliance are major problems with drugs such as amitriptyline. Rufinamide seems to have a better tolerability profile and could be a new alternative to explore for the treatment of neuropathic pain.

Chronic pain and antidepressants: A systematic review of efficacy

Background and aims: chronic pain is a major public health care problem with a prevalence in Europe as high as 19% in the general population (Breivik et al. 2006). Beside classical analgesics, Antidepressants (AD) remain an essential part of the therapeutic armamentarium. The present study was aimed at reviewing current evidence for efficacy of AD in main chronic pain conditions. Methods: We performed a systematic literature search through Ovid Medline, Psychinfo and Cochrane database to retrieve controlled studies and reviews on the use of AD in specific chronic pain conditions: neuropathic pain, migraine and tension-type headache, muskuloskeletal pain, and fibromyalgia. Results: There is sufficient data to support the use of tricyclic antidepressants (TCAs) in neuropathic pain, migraine and tension-type headache. There is also good evidence for a beneficial effect of TCAs in chronic low back pain and fibromyalgia. The SNRI venlafaxine and duloxetine are drugs with less established efficacy in neuropathic pain, tension type headache and fibromyalgia, but may be recommended as second line treatment. Available data do not support the use of SSRIs in any of these conditions. Given the limitations of available studies, there is still room to better characterize putative benefits of SNRIs and SSRIs in some of these conditions. Conclusions: Efficacy of AD in chronic pain appear to vary greatly between type of AD. Beneficial effects when present seem independent of the effect on mood. There is a lack of long term controlled trials in most type of chronic pain conditions.

Role of JNK isoforms in the development of neuropathic pain following sciatic nerve transection in the mouse.

ABSTRACT: BACKGROUND: Current tools for analgesia are often only partially successful, thus investigations of new targets for pain therapy stimulate great interest. Consequent to peripheral nerve injury, c-Jun N-terminal kinase (JNK) activity in cells of the dorsal root ganglia (DRGs) and spinal cord is involved in triggering neuropathic pain. However, the relative contribution of distinct JNK isoforms is unclear. Using knockout mice for single isoforms, and blockade of JNK activity by a peptide inhibitor, we have used behavioral tests to analyze the contribution of JNK in the development of neuropathic pain after unilateral sciatic nerve transection. In addition, immunohistochemical labelling for the growth associated protein (GAP)-43 and Calcitonin Gene Related Peptide (CGRP) in DRGs was used to relate injury related compensatory growth to altered sensory function. RESULTS: Peripheral nerve injury produced pain-related behavior on the ipsilateral hindpaw, accompanied by an increase in the percentage of GAP43-immunoreactive (IR) neurons and a decrease in the percentage of CGRP-IR neurons in the lumbar DRGs. The JNK inhibitor, D-JNKI-1, successfully modulated the effects of the sciatic nerve transection. The onset of neuropathic pain was not prevented by the deletion of a single JNK isoform, leading us to conclude that all JNK isoforms collectively contribute to maintain neuropathy. Autotomy behavior, typically induced by sciatic nerve axotomy, was absent in both the JNK1 and JNK3 knockout mice. CONCLUSIONS: JNK signaling plays an important role in regulating pain threshold: the inhibition of all of the JNK isoforms prevents the onset of neuropathic pain, while the deletion of a single splice JNK isoform mitigates established sensory abnormalities. JNK inactivation also has an effect on axonal sprouting following peripheral nerve injury.

Surgical results in patients with chronic low back pain who failed multidisciplinary rehabilitation with cognitive intervention

Introduction¦Surgery for chronic low back pain (CLBP) is a controversial topic. One randomized controlled¦trial (RCT) showed superiority of surgery to physiotherapy only, whereas two more RCTs¦failed to show that surgery was better than multidisciplinary rehabilitation including cognitive¦intervention. The latter is therefore regarded as the golden standard of conservative¦treatment and in our unit it is whenever possible offered to patients prior to lumbar surgery¦for CLBP.¦The objective of this study was to compare results of lumbar surgery between one group of¦patients who failed to improve despite such rehabilitation and a second group of patients who¦underwent surgery following usual conservative therapies. Our hypothesis is that patients¦who failed such a comprehensive treatment would respond poorly to surgery.¦Patients and Methods¦43 patients (age 41.2±8.1 years, number of men 20) were operated between 2003 and 2009¦by a single surgeon for CLBP due to degenerative disc disease (36) or isthmic¦spondylolisthesis (7). Patients with sciatica or neurological abnormalities were excluded.¦Seventeen (40%) patients were operated having failed to improve following the¦aforementioned rehabilitation programme (Surgery following rehabilitation group) whereas¦the remaining 26 (60%) were operated having failed to improve with physiotherapy of varying¦intensity (Surgery following physiotherapy group). Oswestry disability index (ODI) pre¦operatively and at 2 years following surgery was prospectively evaluated. Fisher's exact test¦was used to compare groups.¦Results¦At two years following surgery, with an average follow up of 22 month, a 15 points ODI¦improvement was achieved for 9 (53%) patients of the surgery following rehabilitation group¦and in 15 (58%) patients of the surgery following physiotherapy group (p=1.0). A 50% ODI¦improvement was observed for 6 (35%) and 12 (46%) patients respectively (p=0.54).¦Discussion¦The main finding of this study was that surgery following failed multidisciplinary rehabilitation¦yields similar results to those of patients who only received usual physiotherapy treatment for¦CLBP prior to surgery. But surprisingly we found that it is possible with surgery to improve¦the quality of life of those CLBP sufferers who failed to respond to a comprehensive¦rehabilitation program and with a similar success rate to those reported in other series.¦But rehabilitation should still be offered as a treatment option in all CLBP patients prior to¦surgery, given that it is devoid of complications and that it will spare the need of surgery to a¦significant proportion of CLBP patients while not compromising surgical results in the¦remaining subjects who failed to improve.

Collaborative quality improvement to manage pain in acute care hospitals.

Objective. Collaborative quality improvement programs have been successfully used to manage chronic diseases in adults and acute lung complications in premature infants. Their effectiveness to improve pain management in acute care hospitals is currently unknown. The purpose of this study was to determine whether a collaborative quality improvement program implemented at hospital level could improve pain management and overall pain relief. Design.To assess the effectiveness of the program, we performed a before-after trial comparing patient's self-reported pain management and experience before and after program implementation. We included all adult patients hospitalized for more than 24 hours and discharged either to their home or to a nursing facility, between March 1, 2001 and March 31, 2001 (before program implementation) and between September 15, 2005 and October 15, 2005 (after program implementation). Setting.A teaching hospital of 2,096 beds in Geneva, Switzerland. Patients.All adult patients hospitalized for more than 24 hours and discharged between 1 to 31 March 2001 (before program) and 15 September to 15 October 2005 (after program implementation). Interventions.Implementation of a collaborative quality improvement program using multifaceted interventions (staff education, opinion leaders, patient education, audit, and feedback) to improve pain management at hospital level. Outcome Measures.Patient-reported pain experience, pain management, and overall hospital experience based on the Picker Patient Experience questionnaire, perceived health (SF-36 Health survey). Results.After implementation of the program only 2.3% of the patients reported having no pain relief during their hospital stay (vs 4.5% in 2001, P = 0.05). Among nonsurgical patients, improvements were observed for pain assessment (42.3% vs 27.9% of the patients had pain intensity measured with a visual analog scale, P = 0.012), pain management (staff did everything they could to help in 78.9% vs 67.9% of cases P = 0.003), and pain relief (70.4% vs 57.3% of patients reported full pain relief P = 0.008). In surgical patients, pain assessment also improved (53.7.3% vs 37.6%) as well as pain treatment. More patients received treatments to relieve pain regularly or intermittently after program implementation (95.1% vs 91.9% P = 0.046). Conclusion.Implementation of a collaborative quality improvement program at hospital level improved both pain management and pain relief in patients. Further studies are needed to determine the overall cost-effectiveness of such programs.

La douleur prolongée chez le nouveau-né: étude de cas [Prolonged pain in neonates: retrospective analysis].

INTRODUCTION: infants hospitalised in neonatology are inevitably exposed to pain repeatedly. Premature infants are particularly vulnerable, because they are hypersensitive to pain and demonstrate diminished behavioural responses to pain. They are therefore at risk of developing short and long-term complications if pain remains untreated. CONTEXT: compared to acute pain, there is limited evidence in the literature on prolonged pain in infants. However, the prevalence is reported between 20 and 40 %. OBJECTIVE : this single case study aimed to identify the bio-contextual characteristics of neonates who experienced prolonged pain. METHODS : this study was carried out in the neonatal unit of a tertiary referral centre in Western Switzerland. A retrospective data analysis of seven infants' profile, who experienced prolonged pain ,was performed using five different data sources. RESULTS : the mean gestational age of the seven infants was 32weeks. The main diagnosis included prematurity and respiratory distress syndrome. The total observations (N=55) showed that the participants had in average 21.8 (SD 6.9) painful procedures that were estimated to be of moderate to severe intensity each day. Out of the 164 recorded pain scores (2.9 pain assessment/day/infant), 14.6 % confirmed acute pain. Out of those experiencing acute pain, analgesia was given in 16.6 % of them and 79.1 % received no analgesia. CONCLUSION: this study highlighted the difficulty in managing pain in neonates who are exposed to numerous painful procedures. Pain in this population remains underevaluated and as a result undertreated.Results of this study showed that nursing documentation related to pain assessment is not systematic.Regular assessment and documentation of acute and prolonged pain are recommended. This could be achieved with clear guidelines on the Assessment Intervention Reassessment (AIR) cyclewith validated measures adapted to neonates. The adequacy of pain assessment is a pre-requisite for appropriate pain relief in neonates.

Interprofessional practices of physiotherapists working with adults with low back pain in Québec's private sector: results of a qualitative study.

BACKGROUND: Collaboration and interprofessional practices are highly valued in health systems, because they are thought to improve outcomes of care for persons with complex health problems, such as low back pain. Physiotherapists, like all health providers, are encouraged to take part in interprofessional practices. However, little is known about these practices, especially for private sector physiotherapists. This study aimed to: 1) explore how physiotherapists working in the private sector with adults with low back pain describe their interprofessional practices, 2) identify factors that influence their interprofessional practices, and 3) identify their perceived effects. METHODS: Participants were 13 physiotherapists, 10 women/3 men, having between 3 and 21 years of professional experience. For this descriptive qualitative study, we used face-to-face semi-structured interviews and conducted content analysis encompassing data coding and thematic regrouping. RESULTS: Physiotherapists described interprofessional practices heterogeneously, including numerous processes such as sharing information and referring. Factors that influenced physiotherapists' interprofessional practices were related to patients, providers, organizations, and wider systems (e.g. professional system). Physiotherapists mostly viewed positive effects of interprofessional practices, including elements such as gaining new knowledge as a provider and being valued in one's own role, as well as improvements in overall treatment and outcome. CONCLUSIONS: This qualitative study offers new insights into the interprofessional practices of physiotherapists working with adults with low back pain, as perceived by the physiotherapists' themselves. Based on the results, the development of strategies aiming to increase interprofessionalism in the management of low back pain would most likely require taking into consideration factors associated with patients, providers, the organizations within which they work, and the wider systems.

La lombalgie aiguë en médecine de premier recours [Acute low back pain in general practice medicine].

The practioner's first concern is knowing how to single out from the immense majority of situations susceptible to a favourable spontaneous evolution those patients with a bad prognostic necessitating reference to a specialist. We present in this paper the clinical steps designed to meet this challenge and a reminder of certain principles of patient diagnosis and care.

A comparison of pain scales in Thai children.

Three commonly used pain scales, the visual analogue scale, the Wong-Baker Faces Pain Scale, and the Faces Pain Scale Revised were administered to 122 Thai children, of whom half were HIV infected, in order to assess their validity. These scales presented moderate to good correlation and moderate agreement, sufficient for valid use in Thai children.

Intraoperative photodynamic therapy of the chest cavity in malignant pleural mesothelioma bearing rats.

BACKGROUND AND OBJECTIVE: Experimental assessment of anticancer effect, normal tissue damage, and toxicity of intrathoracic mTHPC-mediated photodynamic therapy (PDT) combined to surgery in malignant pleural mesothelioma (MPM) bearing rats. STUDY DESIGN/MATERIALS AND METHODS: Six days after implantation of syngenic malignant mesothelioma cells in the left chest cavity of Fischer rats (n = 21) and 4 days after sensitization (0.1 mg/kg mTHPC), a left-sided pneumonectomy was performed, followed by intraoperative light delivery (652 nm, fluence 20 J/cm(2)), either by spherical illumination of the chest cavity (fluence rate 15 mW/cm(2)) or by focal illumination of a tumor area (fluence rate 150 mW/cm(2)). Controls comprised tumor-bearing untreated animals, tumor-bearing animals undergoing pneumonectomy, and tumor-bearing animals undergoing pneumonectomy and light delivery without sensitization or sensitization without light delivery. No thoracocentesis was performed during follow-up. RESULTS: An invasively growing sarcomatous type of mesothelioma was found in all animals at day 10, without tumor necrosis in control animals. PDT resulted in 0.5-1 mm deep inhomogeneous tumor necrosis after spherical, and in a 1-2 mm deep tumor necrosis after focal illumination. No injury to mediastinal organs was observed, neither after PDT with spherical nor with focal light delivery except focal interstitial lung fibrosis at the mediastinal area of the opposite lung. All animals with pneumonectomy followed by spherical PDT of the entire tumor-bearing chest cavity died within 72 hours whereas all other animals survived. All animals that died presented massive pleural effusion. CONCLUSIONS: PDT following pneumonectomy in mesothelioma bearing rats was technically feasible and allowed to study its effect on tumor and normal tissues. PDT-related tumor necrosis was observed after spherical and focal light delivery, however, pneumonectomy followed by PDT with spherical light delivery to the tumor-bearing chest cavity resulted in fatal complications.

Selective inhibition of JNK with a peptide inhibitor attenuates pain hypersensitivity and tumor growth in a mouse skin cancer pain model.

Cancer pain significantly affects the quality of cancer patients, and current treatments for this pain are limited. C-Jun N-terminal kinase (JNK) has been implicated in tumor growth and neuropathic pain sensitization. We investigated the role of JNK in cancer pain and tumor growth in a skin cancer pain model. Injection of luciferase-transfected B16-Fluc melanoma cells into a hindpaw of mouse induced robust tumor growth, as indicated by increase in paw volume and fluorescence intensity. Pain hypersensitivity in this model developed rapidly (<5 days) and reached a peak in 2 weeks, and was characterized by mechanical allodynia and heat hyperalgesia. Tumor growth was associated with JNK activation in tumor mass, dorsal root ganglion (DRG), and spinal cord and a peripheral neuropathy, such as loss of nerve fibers in the hindpaw skin and induction of ATF-3 expression in DRG neurons. Repeated systemic injections of D-JNKI-1 (6 mg/kg, i.p.), a selective and cell-permeable peptide inhibitor of JNK, produced an accumulative inhibition of mechanical allodynia and heat hyperalgesia. A bolus spinal injection of D-JNKI-1 also inhibited mechanical allodynia. Further, JNK inhibition suppressed tumor growth in vivo and melanoma cell proliferation in vitro. In contrast, repeated injections of morphine (5 mg/kg), a commonly used analgesic for terminal cancer, produced analgesic tolerance after 1 day and did not inhibit tumor growth. Our data reveal a marked peripheral neuropathy in this skin cancer model and important roles of the JNK pathway in cancer pain development and tumor growth. JNK inhibitors such as D-JNKI-1 may be used to treat cancer pain.

Les rachialgies inflammatoires [Inflammatory back pain]

Inflammatory back pain is more than just inflammatory pain, but a set of symptoms which presence must evoke a diagnosis of ankylosing spondylitis. However, it is insufficient by itself for a diagnosis which can only be reach as part of a diagnostic strategy searching for other clinical, biological or radiological abnormalities in order to obtain adequate diagnostic probability, while acknowledging the limitations of all these examinations.

Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain.

Peripheral neuropathic pain is a disabling condition resulting from nerve injury. It is characterized by the dysregulation of voltage-gated sodium channels (Navs) expressed in dorsal root ganglion (DRG) sensory neurons. The mechanisms underlying the altered expression of Navs remain unknown. This study investigated the role of the E3 ubiquitin ligase NEDD4-2, which is known to ubiquitylate Navs, in the pathogenesis of neuropathic pain in mice. The spared nerve injury (SNI) model of traumatic nerve injury-induced neuropathic pain was used, and an Nav1.7-specific inhibitor, ProTxII, allowed the isolation of Nav1.7-mediated currents. SNI decreased NEDD4-2 expression in DRG cells and increased the amplitude of Nav1.7 and Nav1.8 currents. The redistribution of Nav1.7 channels toward peripheral axons was also observed. Similar changes were observed in the nociceptive DRG neurons of Nedd4L knockout mice (SNS-Nedd4L-/-). SNS-Nedd4L-/- mice exhibited thermal hypersensitivity and an enhanced second pain phase after formalin injection. Restoration of NEDD4-2 expression in DRG neurons using recombinant adenoassociated virus (rAAV2/6) not only reduced Nav1.7 and Nav1.8 current amplitudes, but also alleviated SNI-induced mechanical allodynia. These findings demonstrate that NEDD4-2 is a potent posttranslational regulator of Navs and that downregulation of NEDD4-2 leads to the hyperexcitability of DRG neurons and contributes to the genesis of pathological pain.