Determining Pain Detection and Tolerance Thresholds Using an Integrated, Multi-Modal Pain Task Battery

Human pain models are useful in the assessing the analgesic effect of drugs, providing information about a drug's pharmacology and identify potentially suitable therapeutic populations. The need to use a comprehensive battery of pain models is highlighted by studies whereby only a single pain model, thought to relate to the clinical situation, demonstrates lack of efficacy. No single experimental model can mimic the complex nature of clinical pain. The integrated, multi-modal pain task battery presented here encompasses the electrical stimulation task, pressure stimulation task, cold pressor task, the UVB inflammatory model which includes a thermal task and a paradigm for inhibitory conditioned pain modulation. These human pain models have been tested for predicative validity and reliability both in their own right and in combination, and can be used repeatedly, quickly, in short succession, with minimum burden for the subject and with a modest quantity of equipment. This allows a drug to be fully characterized and profiled for analgesic effect which is especially useful for drugs with a novel or untested mechanism of action. Perioperative Medicine: Efficacy, Safety and Outcom

Pharmacokinetics and pharmacodynamics of multiple doses of BG00010, a neurotrophic factor with anti-hyperalgesic effects, in patients with sciatica

AIMS: BG00010 is a protein in the glial cell line-derived neurotrophic factor (GDNF) family. It is a selective ligand for the GDNF family receptor alpha-3 (GFRα3) co-receptor that normalizes cellular changes resulting from damage or disease, and potentially alleviates neuropathic pain. The main objectives of this study were to evaluate the pharmacokinetic and safety profiles and to determine the effects on pain of ascending doses of intravenous injections of BG00010 in patients with sciatica.METHODS: This was a randomized, blinded, placebo-controlled multiple-dose study in subjects with sciatica. In Part I (16 patients), four IV dose levels were examined (50, 150, 400, 800 μg kg(-1) ) and in Part II (12 patients), three dose levels were examined (400, 600 and 1200 μg kg(-1) ). Safety and efficacy assessments were used as endpoints.RESULTS: The BG00010 concentration-time data indicated relatively low inter-patient variability and there was a dose-dependent (not dose-proportional) increase in serum exposure from 150 to 1200 μg kg(-1) . The effective half-life was between 40 and 60 h. The most frequently occurring adverse events (AEs) reported by patients receiving BG00010 were headache (67-83%), feeling hot (50-100%), and pruritus (42-67%). Most AEs were mild; no serious AEs or AEs leading to discontinuation occurred. Higher dose regimens of BG00010 resulted in greater pain reduction than placebo or lower dose regimens, although a clear dose-response relationship was not seen.CONCLUSIONS: The pharmacokinetic profile of BG00010 was characterized by low intra-patient variability. These data from a small sample suggest that BG00010 may have a benefit for patients with sciatica.TRIAL REGISTRATION: ClinicalTrials.gov NCT00961766 NCT01405833.Perioperative Medicine: Efficacy, Safety and Outcom

The use of a battery of evoked pain models in early phase drug development

Drug development scientists are on a search for suitable biomarkers that can assist in predicting the therapeutic potential of analgesic medication and, therefore, it’s efficacy in the target population. This is particularly appropriate for human pain where models can assist to bridge the preclinical and clinical findings. These models can provide valuable information about the mechanism of action of existing and new drugs. However, a single human pain model cannot be used exclusively to screen the pharmacological mechanism of a compound as it inherently only tests a single mechanism. In this thesis the performance of a battery of pain models (PainCart) was investigated. Three main topics were investigated. (1) The validation of the PainCart was described in which the effects of different classes of analgesics on this battery of pain models were explored. (2) The PainCart was used in different chronic pain populations. (3) The performance of the battery during the development of new analgesic compounds was studied. The battery of pain models can act as biomarker to assess the effect of analgesics on pain. It can be used to benchmark analgesic properties of new drugs against established analgesics in early phase clinical studies. </div

The use of a battery of evoked pain models in early phase drug development

Drug development scientists are on a search for suitable biomarkers that can assist in predicting the therapeutic potential of analgesic medication and, therefore, it’s efficacy in the target population. This is particularly appropriate for human pain where models can assist to bridge the preclinical and clinical findings. These models can provide valuable information about the mechanism of action of existing and new drugs. However, a single human pain model cannot be used exclusively to screen the pharmacological mechanism of a compound as it inherently only tests a single mechanism. In this thesis the performance of a battery of pain models (PainCart) was investigated. Three main topics were investigated. (1) The validation of the PainCart was described in which the effects of different classes of analgesics on this battery of pain models were explored. (2) The PainCart was used in different chronic pain populations. (3) The performance of the battery during the development of new analgesic compounds was studied. The battery of pain models can act as biomarker to assess the effect of analgesics on pain. It can be used to benchmark analgesic properties of new drugs against established analgesics in early phase clinical studies. </div

Blood pressure augmentation to supra normal levels to improve oxygenation in COVID-19

Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care