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Nitrous oxide (N2O) is an odorless and colorless gas routinely used as an adjuvant of anesthesia and for short duration analgesia in various clinical settings mostly in the form of a N2O/O2 50%-50% equimolar mixture (EMONO). Experimental studies have suggested that EMONO could also induce long lasting analgesic effects related to the blockade of NMDA receptors. We designed the first international multicenter proof of concept randomized, placebo-controlled study to assess the efficacy and safety of a one hour administration of EMONO or placebo (medical air) on three consecutive days up to one month after the last administration in patients with chronic peripheral neuropathic pain. A total of 240 patients were recruited in 22 centers in France and Germany and randomly assigned to one study group (120 per group). Average pain intensity (primary outcome), neuropathic pain characteristics (NPSI), patient global impression of change (PGIC), anxiety, depression and quality of life were systematically assessed before and after treatment. The changes in average pain intensity between baseline and seven days after the last administration were not significantly different between the two groups. However, evoked pain intensity (predefined secondary endpoint) and PGIC (exploratory endpoint), were significantly improved in the EMONO group and these effects were maintained up to four weeks after the last treatment administration. Mostly transient side effects were reported during the treatment administration. These encouraging results provide a basis for further investigation of the long term analgesic effects of EMONO in neuropathic pain patients.
Learn More >It currently remains unclear, why some patients with entrapment neuropathies develop neuropathic pain (neuP) whereas others have non-neuP, presumably of nociceptive character. Studying patients with carpal tunnel syndrome (CTS), this cross-sectional cohort study investigated changes in somatosensory structure and function as well as emotional wellbeing specific to the presence and severity of neuP.Patients with CTS (n=108) were subgrouped by the DN4 questionnaire into those without and with neuP. The latter group was further subdivided into mild and moderate/severe neuP using a pain visual analogue scale. N=32 participants served as healthy controls. All participants underwent a clinical examination, quantitative sensory testing (QST), electrodiagnostic testing (EDT) and skin biopsy to determine structural integrity of dermal and intraepidermal nerve fibres. Patients also completed questionnaires evaluating symptom severity and functional deficits, pain distribution, sleep quality and emotional wellbeing. The overall prevalence of neuP in patients with CTS was 80%, of which 63% had mild neuP. Symptom severity and functional deficits as well as somatosensory dysfunction were more pronounced with the presence and increasing severity of neuP. No difference was identified among patient groups for EDT and nerve fibre integrity on biopsies. The severity of neuP was accompanied by more pronounced deficits in emotional wellbeing and sleep quality. Intriguingly, extraterritorial spread of symptoms was more prevalent in patients with moderate/severe neuP, indicating the presence of central mechanisms. NeuP is common in patients with CTS and its severity is related to the extent of somatosensory dysfunction and a compromise of emotional wellbeing.
Learn More >This journal recently published a paper by Vowles et al., entitled "Initial Evaluation of the Chronic Pain Acceptance Questionnaire – 2. The authors discuss the development of a two-item measure to assess chronic pain acceptance. Items for this tool were derived from the Chronic Pain Acceptance Questionnaire (CPAQ) 20, and aim to map two key features of acceptance: (1) Activity Engagement, which entails participating in important or meaningful activities with continued pain and (2) Pain Willingness, which entails a willingness to experience pain without the need to reduce, avoid, or otherwise change it.
Learn More >Transient receptor potential melastatin member 8 (TRPM8), a Ca -permeable nonselective cation channel activated by cold and cooling agents, mediates allodynia. Dysfunction or abnormal expression of TRPM8 has been found in several human cancers. The role of ubiquitination in the regulation of TRPM8 function remains poorly understood. Here, we identified the ubiquitin (Ub)-ligase E3, tripartite motif-containing 4 (TRIM4), as a novel interaction partner of TRPM8 and confirmed that the TRIM4-TRPM8 interaction was mediated through the SPRY domain of TRIM4. Patch-clamp assays showed that TRIM4 negatively regulates TRPM8-mediated currents in HEK293 cells. Moreover, TRIM4 reduced the expression of TRPM8 on the cell surface by promoting the K63-linked ubiquitination of TRPM8. Further analyses revealed that the TRPM8 N-terminal lysine residue at 423 was the major ubiquitination site that mediates its functional regulation by TRIM4. A Ub-activating enzyme E1, Ub-like modifier-activating enzyme 1 (UBA1), was also found to interact with TRPM8, thereby regulating its channel function and ubiquitination. In addition, knockdown of UBA1 impaired the regulation of TRPM8 ubiquitination and function by TRIM4. Thus, this study demonstrates that TRIM4 downregulates TRPM8 via K423-mediated TRPM8 ubiquitination and requires UBA1 to regulate TRPM8.
Learn More >Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is known to reduce motor symptoms of Parkinson's disease (PD). The effects of DBS on various nonmotor symptoms often differ from patient to patient. The factors that determine whether or not a patient will respond to treatment have not been elucidated. Here, the authors evaluated sex differences in pain relief after DBS for PD.
Learn More >Chronic pain following musculoskeletal trauma is common, which may partially be attributed to the early presence of central sensitisation (CS). Multiple measures are suggested to assess clinical features of CS, yet no systematic review has evaluated the measurement properties of these measures in a musculoskeletal trauma population.
Learn More >Neuropathic pain is associated with poor health-related quality of life (HRQL) in pain conditions other than sickle cell disease (SCD); this relationship in SCD is unknown. We investigated this relationship and hypothesized neuropathic pain is associated with poor HRQL in adolescents with SCD.
Learn More >Chronic pain is a global health problem, affecting around 1 in 5 individuals in the general population. The understanding of the key role of functional brain alterations in the generation of chronic pain has led researchers to focus on pain treatments that target brain activity. Electroencephalographic neurofeedback attempts to modulate the power of maladaptive electroencephalography frequency powers to decrease chronic pain. Although several studies have provided promising evidence, the effect of electroencephalographic neurofeedback on chronic pain is uncertain.
Learn More >Interdisciplinary cognitive behavioral therapy (CBT) for chronic pain is effective at improving function, mood, and pain interference among individuals with disabling chronic pain. Traditionally, CBT assumes cognitive change is an active therapeutic ingredient in the determination of treatment outcome. Pain catastrophizing, a cognitive response style that views the experience of pain as uncontrollable, permanent, and destructive, has been identified as an important maladaptive cognition which contributes to difficulties with the management of chronic pain. Consequently, pain catastrophizing is commonly targeted in CBT for chronic pain.
Learn More >Oral cancer patients often have severe, chronic, and mechanically induced pain at the site of the primary cancer. Oral cancer pain is initiated and maintained in the cancer microenvironment and attributed to release of mediators that sensitize primary sensory nerves. This study was designed to investigate the histopathology associated with painful oral cancers in a preclinical model. The relationship of pain scores with pathologic variables was also investigated in a cohort of 72 oral cancer patients. Wild-type mice were exposed to the carcinogen, 4-nitroquinoline 1-oxide (4NQO). Nociceptive (pain) behavior was measured with the dolognawmeter, an operant device and assay for measuring functional and mechanical allodynia. Lesions developed on the tongues and esophagi of the 4NQO-treated animals and included hyperkeratoses, papillomas, dysplasias, and cancers. Papillomas included lesions with benign and dysplastic pathological features. Two histologic subtypes of squamous cell carcinomas (SCCs) were identified-SCCs with exophytic and invasive components associated with papillary lesions (pSCCs) and invasive SCCs without exophytic histology (iSCCs). Only the pSCC subtype of tongue cancer was associated with nociceptive behavior. Increased tumor size was associated with greater nociceptive behavior in the mouse model and more pain experienced by oral cancer patients. In addition, depth of invasion was associated with patient-reported pain. The pSCC histology identifies 4NQO-induced tongue cancers that are expected to be enriched for expression and release of nociceptive mediators.
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