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The antihyperalgesic and sedative effects of the α2-subunit preferring GABA positive allosteric modulator (GAM), N-Desmethyl-Clobazam (NDMC), 20 and 60 mg, were assessed in a randomized, placebo and active-controlled (clonazepam 1,5 mg), 4-way crossover study, in healthy volunteers, using the UVB-induced experimental pain model. Single (20, 40, 60 mg) and repeated doses (20mg over 15 days) NDMC pharmacokinetic were evaluated. Thirty-two subjects participated to the study. Primary outcome parameter was maximal change in the area of cutaneous UVB irradiation-induced secondary hyperalgesia (ASH). ASH decreased under all treatments. Mean (SD) relative change was 79 (22) %, 83 (24) %, 77 (30) % and 92 (16) % for placebo, NDMC20, NDMC60 and clonazepam, respectively. Neither absolute change nor relative change in ASH was significantly different between NDMC60 and placebo (mean difference= 2.3 cm [95%CI 4.0 to 8.5], p=0.462 and 0.4% [-11.9 to 12.6], p=0.952, respectively). An overall treatment effect was found on level of sedation. Compared to placebo, sedation was higher under clonazepam (mean difference= 39 mm [30 to 49] on a visual analog scale, p<0.001) while NDMC was free of sedative effect. NDMC pharmacokinetic after single doses showed poor absorption, but was linear. Steady-state plasma concentrations of NDMC20 were attained within 14 days, with low between-subjects variability. Mean steady-state concentration (C , SD) reached 209 (22) ng/mL. NDMC absence of sedative effect and its overall well characterized safety coming from years of utilization as a metabolite from clobazam, raise the prospect of dose escalating trials in patients to quantify its clinical utility.
Learn More >Hyperalgesia is a heightened pain response to a noxious stimulus and is a hallmark of many common neuropathic and chronic pain conditions. In a double-blind placebo-controlled drug-crossover trial the effects of concomitant and delayed minocycline treatment on the initiation and resolution of muscle hyperalgesia were tested.
Learn More >Anodal transcranial direct current stimulation over the primary cortex has been shown to activate regions of the brain involved in the descending modulation of pain sensitivity. However, more research is required in order to dissect the spinal cord analgesic mechanisms associated with the development of central sensitisation.
Learn More >We aimed to evaluate the efficacy of an enhanced mindfulness based stress reduction (MBSR+) versus stress management for headache (SMH). We performed a randomized, assessor-blind, clinical trial of 98 adults with episodic migraine recruited at a single academic center comparing MBSR+ (n=50) to SMH (n=48). MBSR+ and SMH were delivered weekly by group for 8 weeks, then bi-weekly for another 8 weeks. The primary clinical outcome was reduction in headache days from baseline to 20 weeks. MRI outcomes included activity of left dorsolateral prefrontal cortex (DLPFC) and cognitive task network during cognitive challenge, resting state connectivity of right dorsal anterior insula (daINS) to DLPFC and cognitive task network, and gray matter volume of DLPFC, daINS, and anterior midcingulate. Secondary outcomes were headache-related disability, pain severity, response to treatment, migraine days, and MRI whole-brain analyses. Reduction in headache days from baseline to 20 weeks was greater for MBSR+ (7.8 [95%CI, 6.9-8.8] to 4.6 [95%CI, 3.7-5.6]) than for SMH (7.7 [95%CI 6.7-8.7] to 6.0 [95%CI, 4.9-7.0]) (P=0.04). 52% of the MBSR+ group showed a response to treatment (50% reduction in headache days) compared with 23% in the SMH group (P=0.004). Reduction in headache-related disability was greater for MBSR+ (59.6 [95%CI, 57.9-61.3] to 54.6 [95%CI, 52.9-56.4]) than SMH (59.6 [95%CI, 57.7-61.5] to 57.5 [95%CI, 55.5-59.4]) (P=0.02). There were no differences in clinical outcomes at 52 weeks or MRI outcomes at 20 weeks, although changes related to cognitive networks with MBSR+ were observed. MBSR+ is an effective treatment option for episodic migraine.
Learn More >We previously identified alpha frequency slowing and beta attenuation in the dynamic pain connectome related to pain severity and interference in patients with multiple sclerosis-related neuropathic pain (NP). Here, we determined whether these abnormalities, are markers of aberrant temporal dynamics in non-neuropathic inflammatory pain (non-NP) or when NP is also suspected. We measured resting-state magnetoencephalography (MEG) spectral density in 45 people (17 females, 28 males) with chronic back pain due to ankylosing spondylitis (AS) and 38 age/sex matched healthy controls. We used painDETECT scores to divide the chronic pain group into those with only non-NP (NNP) and those who likely also had a component of NP in addition to their inflammatory pain. We also assessed pain severity, pain interference, and disease activity with the Brief Pain Inventory and Bath AS Disease Activity Index (BASDAI). We examined spectral power in the dynamic pain connectome, including nodes of the ascending nociceptive pathway (ANP), default mode (DMN), and salience networks (SN). Compared to the healthy controls, the AS patients exhibited increased theta power in the DMN and decreased low-gamma power in the DMN and ANP, but did not exhibit beta-band attenuation or peak-alpha slowing. The NNP patients were not different from HCs. Compared to both healthy controls and NNP, NP patients had increased alpha power in the ANP. Increased alpha power within the ANP was associated with reduced BASDAI in the NNP group, and increased pain in the mixed-NP group within the DMN, SN, and ANP. Thus, high theta and low gamma activity may be markers of chronic pain but high alpha-band activity may relate to particular features of neuropathic chronic pain.
Learn More >Dupilumab is an anti-interleukin-4 receptor monoclonal antibody that was recently approved for the treatment of atopic dermatitis (AD). In this single-center retrospective study, clinical baseline data of 117 severe AD patients treated with dupilumab were collected. At baseline and at weeks 4 and 16, disease severity was assessed through the Eczema Area and Severity Index (EASI) and quality of life through the Dermatology Life Quality Index (DLQI) questionnaire, Patient-Oriented Eczema Measure (POEM), Hospital Anxiety and Depression Scale (HADS), Peak Pruritus Numerical Rating Scale (NRS-itch), and VAS-sleep. Response to dupilumab was defined as an improvement of ≥75% in EASI from baseline (EASI75). At multivariate analysis, AD onset before 18 years [OR, 2.9; 95% CI, 1.2-7.2; = 0.0207] and absence of hypereosinophilia [OR, 2.24; 95% CI, 1.03-4.86; = 0.0412] were identified as significant predictive parameters for response to dupilumab in terms of EASI75 at week 4 but not at week 16. Significant reductions in EASI, DLQI, POEM, HADS, NRS-itch, and VAS-sleep were found between week 4 versus baseline ( < 0.0001 for all) and week 16 versus baseline ( < 0.0001 for all). Early AD onset and absence of hypereosinophilia may be suggested as predictive markers of early response to dupilumab. We confirmed the efficacy and safety of this agent along with the improvement of life quality in severe AD patients.
Learn More >The aim of this study was to investigate the changes of calcitonin gene-related peptide (CGRP) plasma levels in patients with classical trigeminal neuralgia (TN) and if plasma CGRP concentrations could be used to predict the response to botulinum toxin type A (BTX-A).
Learn More >In this prospective, multicenter, double-blinded, randomized, crossover study, we compared the therapeutic efficacy of burst SCS delivered using a lead implanted with the paresthesia mapping approach to a lead implanted with an anatomic placement approach.
Learn More >To determine whether a pre-existing smartphone app to teach mindfulness meditation is acceptable to women with chronic pelvic pain (CPP) and can be integrated into clinical practice within the National Health Service (NHS) CPP pathways, and to inform the design of a potential randomised clinical trial.
Learn More >To evaluate the feasibility of a randomised trial of a modified, pre-existing, mindfulness meditation smartphone app for women with chronic pelvic pain.
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