Clinical Trials of Cancer-related Pain: Translational research linking genetic variation to pain experience and response to oral opioids

Cancer-related pain is a major clinical problem. The World Health Organisation recommends morphine first-line for moderate to severe cancer-related pain, however several other strong opioids are available. There is wide inter-individual variation in morphine response, in terms of analgesic efficacy and side effects. Switching to an alternative opioid such as oxycodone has become common clinical practice to improve outcomes. There has been growing interest in potential genetic factors behind such differences in clinical response. This thesis aimed to compare the overall response rates of morphine and oxycodone, explore the effects of opioid switching in non-responders, and to redefine opioid response phenotypes to allow predictive modelling. Data from two opioid response studies is presented: the first a prospective observational study of morphine in cancer-related pain (n=298), the second a large open-label randomised controlled trial of oral morphine versus oral oxycodone in cancer-related pain (n=200). Single nucleotide polymorphisms from 15 candidate genes were tested using sequence specific primer polymerase chain reaction. Principal Component Analysis (PCA) was used to mathematically define opioid response phenotypes. Multivariate regression analysis of Component scores was used to build predictive models from genetic and clinical variables. There was no difference between the response rates of oral morphine and oral oxycodone when used first-line in cancer-related pain. Analgesia and adverse reaction profiles were similar. Switching from morphine to oxycodone and vice versa improved outcomes in the majority of non-responders. Opioid response appears to have three main domains identified by PCA in the two studies: analgesic response, upper gastrointestinal adverse reactions and central adverse reactions. Morphine and oxycodone although had similar response phenotypes had different clinical and genetic factors contributing to each, suggesting different mechanisms. Future work includes collaboration to enable larger studies to be conducted and to investigate the potential role of metabolites in oxycodone response

Dependence of the 12^{12}C(γ⃗\vec{\gamma},pd) reaction on photon linear polarisation

The sensitivity of the $^{12}$C$(\vec{\gamma},pd)$ reaction to photon linear polarisation has been determined at MAMI, giving the first measurement of the reaction for a nucleus heavier than $^{3}$He. Photon asymmetries and cross sections were measured for $E_{\gamma}$=170 to 350 MeV. For $E_{\gamma}$ below the $\Delta$ resonance, reactions leaving the residual $^{9}$Be near its ground state show a positive asymmetry of up to 0.3, similar to that observed for $^{3}$He suggesting a similar reaction mechanism for the two nuclei.Comment: 4 pages, 2 figure

States Of Discontent

Latin America’s recent inclusionary turn centers on changing relationships between the popular sectors and the state. Yet the new inclusion unfolds in a region in which most states are weak and prone to severe pathologies, such as corruption, inefficiency, and particularism. The first part of the chapter outlines an argument, developed at more length elsewhere, regarding how “state crises” helped drive the consolidation of three distinct party system trajectories among the eight South American countries where the Left would eventually win power. The second part of the chapter argues that these trajectories differed in three ways that likely conditioned how the concomitant inclusionary Left turn unfolded in each case: the institutionalization of left-wing parties, the occurrence of state transformation via constitutional reform, and the level of state capacity. The discussion helps highlight the central role of the state and its pathologies in both driving alternative paths of political development and in conditioning the politics of inclusion. By putting the emphasis on the state and its pathologies, we can better consider not just the sources of sociopolitical exclusion but also the limits of sociopolitical inclusion

Clinical trials of cancer-related pain : translational research linking genetic variation to pain experience and response to oral opioids

Cancer-related pain is a major clinical problem. The World Health Organisation recommends morphine first-line for moderate to severe cancer-related pain, however several other strong opioids are available. There is wide inter-individual variation in morphine response, in terms of analgesic efficacy and side effects. Switching to an alternative opioid such as oxycodone has become common clinical practice to improve outcomes. There has been growing interest in potential genetic factors behind such differences in clinical response. This thesis aimed to compare the overall response rates of morphine and oxycodone, explore the effects of opioid switching in non-responders, and to redefine opioid response phenotypes to allow predictive modelling. Data from two opioid response studies is presented: the first a prospective observational study of morphine in cancer-related pain (n=298), the second a large open-label randomised controlled trial of oral morphine versus oral oxycodone in cancer-related pain (n=200). Single nucleotide polymorphisms from 15 candidate genes were tested using sequence specific primer polymerase chain reaction. Principal Component Analysis (PCA) was used to mathematically define opioid response phenotypes. Multivariate regression analysis of Component scores was used to build predictive models from genetic and clinical variables. There was no difference between the response rates of oral morphine and oral oxycodone when used first-line in cancer-related pain. Analgesia and adverse reaction profiles were similar. Switching from morphine to oxycodone and vice versa improved outcomes in the majority of non-responders. Opioid response appears to have three main domains identified by PCA in the two studies: analgesic response, upper gastrointestinal adverse reactions and central adverse reactions. Morphine and oxycodone although had similar response phenotypes had different clinical and genetic factors contributing to each, suggesting different mechanisms. Future work includes collaboration to enable larger studies to be conducted and to investigate the potential role of metabolites in oxycodone response.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Association Between Human Pain-Related Genotypes and Variability in Opioid Analgesia:An Updated Review

On an individual level, there is a difference in the analgesic response to a given opioid. Various factors such as gender, age, and genetic variation can affect the analgesic response. The genetic variation can influence pharmacokinetics (eg drug transporters and drug-metabolizing enzymes) and/or pharmacodynamics (eg opioid receptor and catechol-O-methyltransferase enzymes). We present recent experimentally induced pain, postoperative pain, and cancer pain and chronic non-malignant pain conditions studies in humans, focusing on the association between genetic variation and analgesic response assessed as opioid consumption or changes in pain scores. Studies have shown promising results regarding pharmacogenetics as a diagnostic tool for predicting the individual response to a given opioid in the experimental settings; however, in the clinic, it is a more complicated task to accomplish

The Characteristics and Quality of Randomized Controlled Trials in Neuropathic Pain A Descriptive Study Based on a Systematic Review

Sauzet O, Williams JE, Ross J, et al. The Characteristics and Quality of Randomized Controlled Trials in Neuropathic Pain A Descriptive Study Based on a Systematic Review. Clinical Journal of Pain. 2013;29(7):591-599.Background: Evidence from randomized controlled trials is regarded as the gold standard in clinical research and yet the quality of the conduct and reporting of trials is variable, even post-Consolidated Standards of Reporting Trials. This study arose from a systematic review and cost-effectiveness analysis of treatment for neuropathic pain. The aim was to provide a description of the included trials and investigate trends in study characteristics and measures of quality over time. Methods: The review provided data regarding study characteristics (patients, place, time, drugs, outcomes), methodological factors (sample size calculations, randomization, reporting baseline patient data, withdrawals, intention-to-treat (ITT), and statistical analysis (completeness and correctness of reporting of results, methods of analysis). Results: A total of 131 trials from 1969 to 2007 were included. Of these, 63% were parallel-group designs, the remainder were cross-over; 73% were placebo-controlled. Several trial features increased or improved over time: trial size, quality (using Jadad score), presentation of baseline data by group, reporting of power calculations, use of visual analogue score or numerical rating scale scales to assess pain, completeness of reporting of statistical results, use of modeling to allow for baseline pain scores. The proportion of withdrawals was constant over time with a mean of 14.3%. The proportion of studies stating the analysis as ITT, increased over time, but inspection of papers indicated that the proportion confirmed as ITT was unchanged. Conclusions: There have been a number of improvements regarding the quality and reporting of randomized controlled trials in neuropathic pain, but some failings remain that at best make some results difficult to interpret and at worst lead to bias