Validation, reproducibility and safety of trans dermal electrical stimulation in chronic pain patients and healthy volunteers.

BACKGROUND: Surrogate pain models have been extensively tested in Normal Human Volunteers (NHV). There are few studies that examined pain models in chronic pain patients. Patients are likely to have altered pain mechanisms. It is of interest to test patient pain responses to selective pain stimuli under controlled laboratory conditions. METHODS: The Institutional Ethic Committee approved the study. 16 patients with chronic neuropathic radiculopathy and 16 healthy volunteers were enrolled to the study after obtaining informed consent. During electrical stimulation (150 minutes for volunteers and 75 minutes for patients) the following parameters were measured every 10 minutes: Ongoing pain: Visual Analogue Scale (VAS) and Numeric Rate Scale (NRS)Allodynia (soft foam brush)Hyperalgesia (von Frey monofilament 20 g)Flare. For each endpoint, the area under the curve (AUC) was estimated from the start of stimulation to the end of stimulation by the trapezoidal rule. The individual AUC values for both periods were plotted to show the inter- and intra-subject variability. For each endpoint a mixed effect model was fitted with random effect subject and fixed effect visit. The estimate of intra-subject variance and the mean value were then used to estimate the sample size of a crossover study required to have a probability of 0.80 to detect a 25% change in the mean value. Analysis was done using GenStat 8th edition. RESULTS: Each endpoint achieved very good reproducibility for patients and NHV. Comparison between groups revealed trends towards: Faster habituation to painful stimuli in patients. Bigger areas of hyperalgesia in patients. Similar area of allodynia and flare (no statistical significance) CONCLUSION: The differences demonstrated between patients and NHVs suggest that the electrical stimulation device used here may stimulate pathways that are affected in the pathological state.

Contribution of protein kinase A and protein kinase C signalling pathways to the regulation of HSD11B2 expression and proliferation of MCF-7 cells.

Contribution of the protein kinase A (PKA) and protein kinase C (PKC) signalling pathways to the regulation of 11beta-hydroxysteroid dehydrogenase type II (HSD11B2) gene expression was investigated in human breast cancer cell line MCF-7. Treatment of the cells with an adenylyl cyclase activator, forskolin, known to stimulate the PKA pathway, resulted in an increase in HSD11B2 mRNA content. Semi-quantitative RT-PCR revealed attenuation of the effect of forskolin by phorbol ester, tetradecanoyl phorbol acetate (TPA), an activator of the PKC pathway. It was also demonstrated that specific inhibitors significantly reduced the effect of activators of the two pathways. Stimulation of the PKA pathway did not affect, whereas stimulation of the PKC pathway significantly reduced MCF-7 cell proliferation in a time-dependent manner. A cell growth inhibitor, dexamethasone, at high concentrations, caused a 40% decrease in proliferation of MCF-7 cells and this effect was abolished under conditions of increased HSD11B2 expression. It was concluded that in MCF-7 cells, stimulation of the PKA signal transduction pathway results in the induction of HSD11B2 expression and that this effect is markedly reduced by activation of the PKC pathway. Activation of the PKC pathway also resulted in inhibition of cell proliferation, while activation of the PKA pathway abolished the antiproliferative effect of dexamethasone. These effects might be due to oxidation of dexamethasone by the PKA-inducible HSD11B2.

Fentanyl buccal tablet: faster rescue analgesia for breakthrough pain?

Breakthrough pain (BTP) is an unmet clinical need that is still poorly diagnosed, evaluated and inadequately treated. The prevalence of BTP has been estimated to affect at least 64% of cancer patients. Two pain-relief strategies were proposed: preventive and active ('rescue'). Oral short-acting opioid seems to be the most popular approach for BTP treatment, however, it is likely to be inadequate for a substantial proportion of patients as a result of the slow-onset of most available opioid preparations. Fentanyl buccal tablet (FBT) is a novel delivery system for fentanyl citrate. FBT utilizes OraVescent technology to improve bioavailability and speed of drug delivery. Recent studies have demonstrated superior pharmacokinetic profiles when compared with other available transmucosal opioids (OTFC), however, pharmacodynamic data are still somewhat limited.