Academic literature on the topic 'Breakthrough pain'

Breakthrough cancer pain (BTCP) is a type of pain characterised by transient pain exacerbations on the background of stable and well-controlled pain. It is a significant problem in cancer patients, however, there are no fully validated diagnostic or measurement instruments to identify and assess this type of pain. The aim of this study was to develop and validate a clinical tool to diagnose and quantify BTCP. This study consisted of two stages. Stage one involved the development of a BTCP diagnostic algorithm, which was tested for diagnostic accuracy in 135 cancer patients. The ‘gold-standard’ BTCP diagnostic test for comparison was a comprehensive clinical assessment with a cancer pain expert. The sensitivity of the diagnostic algorithm to detect ‘true cases’ of BTCP was 0.54 (i.e. 54% of expert diagnosed BTCP cases screened positively), specificity 0.78 (78% of non-BTCP patients screened negatively), positive predictive value 0.84 (84% of cases that screened positively had the condition of BTCP), and negative predictive value 0.60 (60% of those that screened negatively did not have the condition). Stage two involved the development of a BTCP measurement instrument from first principles according to international standards. This instrument was then tested on 100 BTCP patients to assess for measurement properties of validity, reliability, responsiveness and acceptability. Reliability testing confirmed that there was an acceptable degree of measurement error. Validity testing confirmed two underlying BTCP dimensions in the instrument. All items and summary scores correlated appropriately with external measures of BTCP. The instrument demonstrated responsiveness by correlating with the patient impression of change and clinical measures of change. In summary, this is the first measurement instrument with robust validity and reliability data for the clinical diagnosis and quantification of BTCP. The measurement instrument met all required standards to recommend its general use however, the diagnostic tool had a lower than expected ability to detect ‘true’ cases of BTCP. The clinical implications of this study mean that once BTCP has been identified the measurement tool could be used to quantify the severity of BTCP, and monitor BTCP experience over time.

Cancer-induced bone pain is characterized by moderate to severe ongoing pain that commonly requires the use of opiates. Even when ongoing pain is well controlled, patients can suffer breakthrough pain (BTP), episodic severe pain that "breaks through" the medication. We developed a novel model of cancer-induced BTP using female rats with mammary adenocarcinoma cells sealed within the tibia. We demonstrated previously that rats with bone cancer learn to prefer a context paired with saphenous nerve block to elicit pain relief (i.e., conditioned place preference, CPP), revealing the presence of ongoing pain. Treatment with systemic morphine abolished CPP to saphenous nerve block, demonstrating control of ongoing pain. Here, we show that pairing BTP induced by experimenter-induced movement of the tumor-bearing hindlimb with a context produces conditioned place avoidance (CPA) in rats treated with morphine to control ongoing pain, consistent with clinical observation of BTP. Preventing movement-induced afferent input by saphenous nerve block before, but not after, hindlimb movement blocked movement-induced BTP. Ablation of isolectin B4 (IB4)-binding, but not TRPV1(+), sensory afferents eliminated movement-induced BTP, suggesting that input from IB4-binding fibers mediates BTP. Identification of potential molecular targets specific to this population of fibers may allow for the development of peripherally restricted analgesics that control BTP and improve quality of life in patients with skeletal metastases.

Aim: To investigate the relationship between effective fentanyl sublingual spray (FSS) doses for breakthrough cancer pain (BTCP) and around-the-clock (ATC) transdermal fentanyl patch (TFP). Methods: Adults tolerating ATC opioids received open-label FSS for 26 days, followed by a 26-day double-blind phase for patients achieving an effective dose (100-1600 mu g). Results: Out of 50 patients on ATC TFP at baseline, 32 (64%) achieved an effective dose. FSS effective dose moderately correlated with mean TFP dose (r = 0.4; p = 0.03). Patient satisfaction increased during the study. Common adverse events included nausea (9%) and peripheral edema (9%). Conclusion: FSS can be safely titrated to an effective dose for BTCP in patients receiving ATC TFP as chronic cancer pain medication. ClinicalTrials.gov identifier: NCT00538850

Pain from bone metastases is multifaceted with clinical descriptors including ongoing pain, hypersensitivity to external stimuli and intermittent episodes of breakthrough pain characterized as a sudden and abrupt onset of severe pain on a background of well-controlled pain. Moreover, cancer-induced bone pain remains inadequately managed due to a myriad of side effects associated with the current pain relieving regimens, which primarily rely on administration of opiates. Despite advances made in cancer therapeutics, these patients experience an inferior quality of life with incapacitating pain with limited daily activities. Development of long-term novel, non-opiate mechanism-based therapeutics with limited side effects is considered beneficial in elevating the patients' quality of life. First part of this dissertation encompasses the role of p38 MAPK in a mouse model of cancer-induced bone pain in which breast cancer cells were injected and sealed into the femur. Our data demonstrated that both acute and prolonged inhibition of p38 MAPK blocked cancer-induced spontaneous pain but had no effect on the evoked pain indicating important differences in mechanisms mediating ongoing pain as opposed to evoked pain. Undermanaged control of breakthrough pain is attributed to poor understanding of underlying mechanisms and how they may differ from ongoing pain due, in part, to lack of a pre-clinical model in which these mechanisms can be studied. We have established a rat model of cancer-induced bone pain to examine ongoing pain and pain relief using conditioned place preference paradigm as well as breakthrough pain using palpation-induced conditioned place aversion. We have shown that while peripheral afferent input from the tumor-bearing tibia mediates cancer-induced ongoing pain and initiation of breakthrough pain, it does not contribute to the maintenance of breakthrough pain. These data suggest that molecular targets mediating these two mechanisms may be different. This hypothesis was confirmed by our findings in this model that acute blockade of interleukin-6 blocked movement-evoked breakthrough pain in tumor-bearing rats, but failed to block tumor-induced ongoing pain. Hence, we provide a platform to manipulate treatments that can be given alone or in combination with opiates in such a way that patients receive adequate control of breakthrough pain.

Breakthrough cancer pain due to its characteristics, fast onset, short duration and high severity implies a significant reduction in the quality of 2/2 life perceived by affected persons. For this reason, breakthrough pain deserves recognition, diagnosis, evaluation with specific scales, suitable early treatment and continuous follow-up. A descriptive and cross-sectional study was carried out, through an individual interview of 150 people with cancer and breakthrough pain, hospitalized at the Catalan Institute of Oncology of Girona (Catalonia, Spain) for the cross-cultural adaptation and validation of the Catalan and Spanish version of the Breakthrough Pain Assessment Tool scale. Breakthrough pain was studied with the adapted scale, therapeutic adherence with the Morisky-Green questionnaire and quality of life with the QLQ-C30 V. 3.0 scale. The scale studied has proven to be valid and with good psychometric properties to assess breakthrough cancer pain in a group of people with different types of cancer in Spain
El dolor irruptivo oncológico por sus características, inicio rápido, corta duración y alta severidad implica una reducción significativa de la calidad de vida percibida por las persones afectadas. Por este motivo merece reconocimiento, diagnóstico, valoración con escalas específicas, tratamiento precoz adecuado y seguimiento continuo. Se realizó un estudio descriptivo y transversal, mediante entrevista individual de 150 personas con cáncer y dolor irruptivo hospitalizadas en el Instituto Catalán de Oncología de Girona (Cataluña, España) para la adaptación transcultural y validación de la versión catalana y castellana de la escala Breakthrough Pain Assessment Tool. También se estudió el dolor irruptivo con la escala adaptada, la adherencia terapéutica con el cuestionario de Morisky-Green y la calidad de vida con la escala QLQ-C30 versión 3.0. La escala estudiada ha demostrado ser válida y con buenas propiedades psicométricas para valorar el dolor irruptivo oncológico en un grupo de personas con diferentes tipos de cáncer en España

Background: The buprenorphine transdermal system (BTDS) is approved in the US for the management of chronic pain. Due to its high affinity for mu-opioid receptors with a slow dissociation profile, buprenorphine may potentially displace or prevent the binding of competing mu-opioid-receptor agonists, including immediate-release (IR) opioids, in a dose-dependent manner. Health care professionals may assume that the use of IR opioids for supplemental analgesia during BTDS therapy is not acceptable. Materials and methods: This post hoc analysis evaluated the use of IR opioids as supplemental analgesia during the management of moderate-severe chronic pain with BTDS at 52 US sites (BUP3015S, NCT01125917). Patients were categorized into IR-opioid and no-IR-opioid groups. At each visit of the extension phase, adverse events, concomitant medications, and information from the Brief Pain Inventory (BPI) were recorded. Results: The most common supplemental IR opioids prescribed during BTDS treatment (n=354) were hydrocodone-acetaminophen and oxycodone-acetaminophen. The mean daily dose of IR opioids (morphine equivalents) for supplemental analgesia was 22 mg. At baseline, BPI pain intensity and BPI - interference scores were higher for patients in the IR-opioid group. In both treatment groups, scores improved by week 4, and then were maintained throughout 6 months of the open-label extension trial. The incidence of treatment-emergent adverse events was similar in both groups. Conclusion: Patients who were prescribed IR opioids reported lower scores for BPI pain intensity and pain interference to levels similar to patients receiving BTDS without IR opioids, without increasing the rate or severity of treatment-emergent adverse events. Patients prescribed concomitant use of IR opioids with BTDS had greater treatment persistence. The results of this post hoc analysis provide support for the concomitant use of IR opioids for supplemental analgesia during the management of moderate-severe chronic pain with BTDS.

Pain is the most feared symptom of cancer and can impact patients' lives more than the cancer itself. Despite improvements in cancer prevention and detection, pain is often the first sign of cancer, with an estimated 70-75% of advanced stage cancer patients presenting with skeletal metastases. Cancer metastasis to the bone is associated with persistent pain that increases in intensity over time. Current treatments follow the World Health Organization (WHO) analgesic ladder for cancer pain management suggesting non-steroidal anti-inflammatory drugs (NSAIDs) for mild to moderate pain and opioids for moderate to severe pain. However, estimates indicate as many as 50-80% of cancer patients worldwide receive inadequate pain management. Moreover, opioid doses required for these patients are associated with adverse side effects further diminishing quality of life. Development of improved non-opioid therapies is dependent on increased understanding of mechanisms driving cancer pain and its relief. The objective of this dissertation was to characterize a rat model of cancer-induced bone pain, to develop approaches to measure both ongoing and breakthrough pain and to investigate the contribution of underlying inflammatory mechanisms to pain, bone destruction and bone remodeling. Using female Fischer F344/NhSD rats, histocompatible MAT B III mammary adenocarcinoma cells were sealed into the intramedullary space of the right rear tibia for a time course of 13 days. Ongoing pain was characterized based on the WHO 3-step ladder for pain management utilizing novel behavioral and neurochemical assays. Morphine and peripheral nerve block were sufficient to control ongoing pain, whereas NSAID treatment failed to provide pain relief. Cancer-bearing rats selectively displayed movement-induced breakthrough pain to a background of morphine-controlled ongoing pain. Furthermore, we determined that breakthrough pain is initiated, but not maintained, by peripheral afferent input from the tumor-bearing tibia using lidocaine administration prior to or following movement. For the final part of this study, we investigated the role of transient receptor potential vanilloid 1 (TRPV1) and interleukin-6 (IL-6) blockade, as these have been shown to be important mediators in animal models CIBP. Acute blockade of TRPV1 channels by AMG9810 selectively reversed inflammatory-induced pain, but failed to control evoked or ongoing CIBP. Acute blockade of interleukin-6 signaling by TB-2-081, an IL-6 receptor antagonist, successfully reversed evoke pain responses, but like AMG9810, failed to control ongoing pain. Sustained administration of TB-2-081 reversed cancer-induced tactile hypersensitivity and tumor-induced bone remodeling of the tibia. Further in vitro analysis revealed TB-2-081 functions by inhibiting the Jak/STAT cascade on both tumor cells and osteoblasts, suggesting that blockade of IL-6 signaling can effectively modulate the bone microenvironment to reduce tumor burden and pain. Combined, our data introduce a rat model of breast cancer bone metastasis, in which the underlying mechanisms of ongoing and breakthrough CIBP can be effectively studied. From this, novel therapeutic agents can be developed and investigated to help improve quality of life in patients suffering from this disease.

iNTRODUÇÃO A dor associada ao cancro (DAC) afecta indubitavelmente a qualidade de vida dos doentes. Dada a natureza multidimensional da DAC, o seu tratamento inadequado é muitas vezes atribuído a uma avaliação deficiente e a uma classificação arbitrária. Em doentes com DAC, a identificação de uma dor com componente neuropática (DCN) influencia a selecção das intervenções analgésicas. De igual modo, o reconhecimento de eventos transitórios de exacerbação da dor, amplamente referidos como “dor episódica”, representa um ingrediente importante da atenção multidimensional. Estes surtos de agravamento da DAC, distintos da dor basal (i.e., a dor que dura >12horas por dia), nem sempre são categorizados de forma consensual. O fraco entendimento sobre a DAC e a prescrição inadequada de analgesia, sem considerar todos os alvos terapêuticos, podem condicionar uma adulteração do tempo necessário para controlar e estabilizar a dor (TCED). A intensidade da dor e o seu subtratamento; a DCN; a dor episódica; a angústia psicológica; a adição de álcool ou drogas ilícitas; o uso de opioides (e doses) e de fármacos adjuvantes; e o TCED constituem alguns dos resultados em saúde que podem explicar a complexidade da gestão da dor em doentes oncológicos. OBJECTIVOS Na perspectiva de involucrar o doente na gestão da sua DAC é fundamental que ele tenha a opção de relatar, descrever e avaliar a sua percepção de dor. No fundo, almeja-se uma aproximação à tríade da neuromatriz particular de dor (sensação, emoção, cognição) por via da subjectividade de uma descrição individual. Pode esta subjectividade da dor (quanto lhe dói?), avaliada numa primeira consulta, representar parte da complexidade da gestão da DAC? Pode uma valorização subjectiva da DAC ter uma correspondência clínica, objectivável, num seguimento longitudinal e prospectivo? Numa amostra de doentes com DAC, referenciados consecutivamente para uma Clínica de Dor Oncológica (CDO), pretendeu-se com o estudo PROSPIC (Prospective Study of Pain Intensity in Cancer): • Objectivo 1- determinar as características e os factores associados à intensidade da DAC no momento de admissão dos doentes numa CDO. • Objectivo 2- determinar a adequação do tratamento da DAC e dos seus factores preditivos no momento de admissão dos doentes numa CDO. • Objectivo 3- determinar a prevalência, as características e os preditores de DCN no momento de admissão dos doentes numa CDO. • Objectivo 4- determinar as associações e os preditores de dor episódica, concretamente de dor irruptiva (IRRU) e de dor incidental (INCID), no momento de admissão dos doentes numa CDO. • Objectivo 5- determinar o TCED e identificar os seus preditores no momento de admissão dos doentes numa CDO. MATERIAIS E MÉTODOS O estudo PROSPIC (Prospective Study of Pain Intensity in Cancer) foi realizado de modo longitudinal, prospectivo (70 dias) e observacional, com a participação de doentes com DAC consecutivamente referenciados para uma CDO. Cada doente teve três consultas externas (inicial; na 5.ª e na 10.ª semanas) e recebeu oito telefonemas pré-agendados, semanalmente. Cada doente preenchia o seu “diário de dor”. Para cada participante foram registados os dados relativos a: tumor primário; metástases; tratamentos para a dor e modificadores do cancro (último mês); duração da dor; mecanismo da dor; Eastern Cooperative Oncology Group (ECOG); Escala Hospitalar de Ansiedade e Depressão (HADS); Termómetro de Emoções (TERM); Inventário Breve da Dor (IBD); Índice de Gestão da Dor (IGD) cujo status negativo significava subtratamento da dor; Dor Neuropática em 4 Questões (DN4) cujo status positivo significava DN4>4; IRRU e INCID; dose diária equivalente de morfina (DDEM); Foram definidos como “resultados em saúde” as seguintes variáveis dependentes: • Objectivo 1- intensidade da dor inicial (IDI); • Objectivo 2- IGD; • Objectivo 3- DCN; • Objectivo 4- IRRU (dor episódica espontânea) e INCID (dor episódica com gatilho identificável); • Objectivo 5- TCED. A presença de IRRU ou INCID, segundo a definição do PROSPIC, deveria estar consubstanciada em intensidades de dor ≥4, auto-avaliadas pelos doentes usando uma escala numérica graduada de zero a dez. O TCED foi definido como o tempo decorrido (dias) desde a avaliação inicial até se alcançar uma situação em que, cumulativamente, o doente: durante 3 dias consecutivos; avaliasse a sua dor como sendo ≤3 (escala numérica de zero a dez); necessitasse de <3 doses de resgates de opioides. Para concretizar os Objectivos 1 a 4 foram implementados quatro estudos de desenho transversal com análises relativas ao momento de admissão dos doentes na primeira consulta da CDO. Para concretizar o Objectivo 5, a investigação foi longitudinal, prospectiva, com análise de sobrevivência do “tempo até ao evento” durante os 70 dias de seguimento dos doentes. RESULTADOS Nos quatro estudos transversais do PROSPIC foram escrutinados 459 doentes, sendo excluídos 88 por terem dor não oncológica (n=69), não terem cancros activos (n=16) e recusarem o consentimento (n=3). A amostra final incluiu 371 doentes: mulheres (n=199, 53.6%); idade 62.1±14.3 anos; alta proporção de tumores da cabeça/pescoço (n=92, 24.8%) e baixa de tumores do pulmão (n=10, 2.7%); doença metastática (n=263, 71%), sobretudo óssea (n=129, 34.8%); ECOG 0-2 (n=309, 83.3%); depressão (n=280, 75.5%) e ansiedade (n=262, 70.6%); história de adição de substâncias (n=86, 23.2%); com dor moderada a severa (n=285, 77%); duração da dor >3 meses (n=179, 48.2%). Tratamentos à admissão, feitos há <30 dias: quimioterapia (n=167, 45.0%); radioterapia (n=176, 47.4%); cirurgia (n=112, 30.2%); nenhum opioide (n=42, 11.3%); adjuvantes (n=210, 56.6%); objectivo paliativo (n=176, 47.4%). A DDEM mediana era baixa, de 30 mg (20-60). No seguimento longitudinal e prospectivo, para além dos 88 excluídos, outros 52 doentes foram eliminados da análise por já terem alcançado o TCED no início do estudo. Da amostra final (n=319), morreram 72 (22.6%) e 14 (4.4%) foram “perdidos” no seguimento. A idade média era 62.4±14.4 anos e 163 (51.1%) eram mulheres. A doença metastática estava presente em 240 (71%) participantes, sobretudo a óssea (37%). O cancro da cabeça/pescoço foi o mais comum, afectando 86 (27%) doentes. O objectivo paliativo do tratamento foi documentado em 52.7% da amostra e a maioria (81.5%) tinha ECOG de 0-2. Antes da admissão no estudo, os participantes tinham realizado cirurgia (32%), quimioterapia (46.7%) e radioterapia (50.8%). CONCLUSÕES São factores explicativos de IDI: maior rendimento mensal; status funcional baixo; tumores da cabeça/pescoço, genito-urinários e gastro-intestinais; uso de fármacos 14 Paulo Reis Pina – Tese de Doutoramento – FMUL – 2020 adjuvantes; e DDEM inicial. A diversidade de factores associados à IDI e a explicação limitada da sua variância enfatizam a complexidade biopsicossocial da DAC. Um em cada quatro doentes oncológicos apresenta subtratamento da sua DAC, o qual está associado independentemente ao género feminino; pontuações elevadas da "interferência da dor com a actividade geral"; radioterapia recente; prescrição de adjuvantes; DCN; necessidade de ajuda emocional; e maior alívio sentido com a medicação prescrita antes da primeira consulta. Um em cada três doentes oncológicos tem DCN, que está associada independentemente a quimioterapia e cirurgia recentes; uso de analgésicos adjuvantes; IRRU e INCID; maior duração da dor; maior IDI; e localização pélvica ou perineal da dor. A DCN deve ser diagnosticada precocemente e tratada de forma adequada para melhorar a qualidade de vida dos doentes com cancro. Entre os doentes referenciados para uma CDO, a IRRU e a INCID ocorrem frequentemente, com prevalências de 37.7% e 48.8%, respectivamente. A IRRU e a INCID estão ambas associadas a: DCN, maiores IDI e DDEM. Ademais, foram encontradas associações independentes positivas entre a IRRU e a dor localizada na cabeça/pescoço; a INCID e a radioterapia recente; a INCID e a dor afectando os tecidos moles. As associações independentes foram negativas, quer entre a IRRU e a dor abdominal, quer entre a IRRU e a INCID. A maioria dos doentes oncológicos consegue controlar e estabilizar a sua dor, embora possa demorar algumas semanas. A mediana do TCED foi de 22 (19-25) dias. O género feminino, a DCN, a utilização de adjuvantes e uma história de abuso de álcool/drogas predizem um TCED mais longo, enquanto a dor associada a tecidos moles e a idade mais avançada predizem um TCED mais curto. A avaliação global da DAC, a sua classificação apropriada e a adequação do seu tratamento deveriam ser mais investigadas. Urgem medidas apropriadas, quer de âmbito educacional, quer a nível das políticas de saúde, que pudessem combater o subtratamento da DAC e, consequentemente, o sofrimento evitável. A melhoria do conhecimento científico sobre a DAC conduzirá, inevitavelmente, ao exercício pleno de um direito fundamental: toda a pessoa humana deve ter acesso a um plano eficiente para controlar e estabilizar a sua dor.
Introduction Uncontrolled cancer pain (CP) may impair quality of life. Given the multidimensional nature of CP, its poor control is often attributed to poor assessment and classification. In patients with CP, identifying a neuropathic pain component (NPC) may inform the selection of subsequent therapeutic interventions. Moreover, better understanding of the episodic CP spectrum, including patient-reported pain flares, may inform CP assessment and management. These outbreaks of worsening of CP, distinct from the patient's background CP (i.e., pain that lasts >12 hours a day), are not always categorized consensually. Poor recognition and inappropriate therapeutic targeting of CP domains may result in poor pain control, affecting the time to achieve stable pain control (TSPC). Pain intensity and its undertreatment; NPC; episodic pain; emotional distress; history of alcohol and drug abuse; opioid use; adjuvant drugs use; and TSPC are some of the health outcomes that may explain the complexity of pain management in cancer patients Objectives From the point of view of involving the patient in the management of his/her pain, it is essential that the patient has the option to report, describe and evaluate his/her perception of CP. It is intended an approximation to the neuromatrix of pain (sensation, emotion, cognition) through the subjectivity of an individual description. Can this subjectivity of pain (how much does it hurt?), evaluated in a first consultation, represent part of the complexity of pain management? Can a subjective appreciation of pain have a clinical, objective correspondence at a longitudinal and prospective follow-up? In a sample of consecutive patients with CP who were referred to a specialist Cancer Pain Clinic (CPC), the “Prospective Study of Pain Intensity in Cancer” (PROSPIC) aimed: • Objective 1 - to determine the characteristics and associations of CP intensity at admission. • Objective 2 - to determine the adequacy of CP management and its patient-related predictors at admission. • Objective 3 - to determine the prevalence and predictors of CP with an NPC at admission. • Objective 4 - to determine the prevalence of episodic patient-reported CP, specifically episodic incident (INCID) and breakthrough CP (BTCP), at admission. • Objective 5 - to determine the median TSPC and identify its predictors at admission Methods The “Prospective Study of Pain Intensity in Cancer” (PROSPIC) is a longitudinal, prospective (70 day-period), observational study of patients attending a CPC. Three scheduled clinic attendances (initial, at week 5, and final) and eight weekly investigator-led phone calls enabled monitoring of patients’ daily pain diary, opioid use, and other analgesic interventions. Consecutive patients referred to a CPC had standardized initial assessments and status documentation of the following: cancer diagnosis; metastases; pain and cancer modifying treatments (<30 days); pain mechanism and duration; Eastern Cooperative Oncology Group (ECOG) rating; Hospital Anxiety Depression Scale and Emotional Thermometer scores; Brief Pain Inventory (BPI); Pain Management Index (PMI), with a negative status indicating undertreatment of CP; Douleur Neuropathique 4 tool; INCID and BTCP; morphine equivalent daily dose (MEDD). The following dependent variables were defined as "health outcomes": • Objective 1- initial pain intensity (IPI); • Objective 2- PMI; • Objective 3- NPC; • Objective 4- BTCP (spontaneous pain) and INCID (trigger identified); • Objective 5- TSPC. Study-defined BTCP and INCID were based on a preceding 7-day history of episodic or transitory pain flares and BPI-worst pain or BPI-now pain intensities ≥4 (self-assessment using a numerical scale, from 0 to 10). TSPC was achieved when: pain intensity <3 and <3 breakthrough opioid doses over three consecutive days. To achieve Objectives 1 to 4, four cross-sectional studies were implemented with analyses at the point of admission of patients in CPC. To achieve Objective 5, a longitudinal and prospective study, with survival analysis of the "time to the event" during the 70 days of follow-up of patients. Results In four cross-sectional studies of PROSPIC, 459 patients were screened and 88 excluded because of non-CP (n=69), non-active cancer (n=16) and failure to consent (n=3). Of 371 participants, 199 (53.6%) were women; mean age= 62.1+14.3 years; high proportion of head and neck cancers (n=92, 24.8%) and low of lung cancers (n=10, 2.7%); 263 (71%) had metastatic disease, mainly bone (n=179, 48.2%); ECOG 0-2 (n=309, 83.3%); depression (n=280, 75.5%) and anxiety (n=262, 70.6%); history of alcohol/drug abuse (n=86, 23.2%); 285 (77%) had moderate to severe pain; for >3 months (n=179, 48.2%). Treatments done <30 days before the CPC attendance: chemotherapy (n=167, 45.0%); radiotherapy (n=176, 47.4%); surgery (n=112, 30.2%); no opioids prescribed (n=42, 11.3%); adjuvant analgesics (n=210, 56.6%); goal documented as palliative (n=176, 47.4%). The initial median MEDD was relatively low 30 mg (20-60). In the longitudinal and prospective study, a part from patients who were initially excluded (n=88), more patients had to be excluded due to pre-study presence of stable pain control (n=52). Of the final study sample (n=319), 72 (22.6%) died and 14 (4.4%) were lost to follow-up. The mean age was 62.4+14.4 years and 163 (51.1%) were female. Metastatic disease was present in 240 (71%) participants; bone (37%) was the most common site. The most common cancer was head and neck, which occurred in 86 (27%) participants. A palliative treatment goal was documented for 52.7% of the participants and most (81.5%) had an ECOG score in the 0-2 range. Before the CPC attendance participants had undergone surgery (32%), chemotherapy (46.7%) and radiotherapy (50.8%). Conclusions IPI is significatively associated with higher income; ECOG 3 -4; head and neck, genitourinary and gastrointestinal cancers; use of adjuvant analgesics; and initial MEDD. One in four cancer patients presents CP undertreatment, which is independently associated with: female gender; high scores of "pain interference with general activity"; recent radiotherapy; prescription of adjuvant analgesics; NPC; more need for emotional help; feeling greater relief with the prescribed medication before the first consultation. One in three cancer patients have a NPC, which is independently associated with recent chemotherapy and surgery; adjuvant analgesic use; INCID and BTCP; longer pain duration; higher IPI; and pelvic or perineal pain location. NPC should be diagnosed early and treated appropriately to improve the quality of life of cancer patients. Among patients referred to a CPC, BTCP and INCID often occur, with a prevalence of 37.7% and 48.8%, respectively. The variety of definitions used for BTCP and INCID makes it difficult to compare prevalence rates. Patients usually report transient exacerbations of pain that do not fit in conventional criteria published for BTCP and INCID, but should be included in a more aggregating term, episodic pain. Both BTCP and INCID are associated with NPC, higher IPI and higher MEDD. Moreover, positive independent associations were found between BTCP and pain localized in the head/neck; INCID and recent radiotherapy; INCID and soft tissues pain. Independent associations were negative, between BTCP and abdominal pain, and between BTCP and INCID. Most cancer patients may achieve stable pain control. The median TSPC was 22 (19- 25) days. Female gender, NPC, use of adjuvants and history of alcohol/drug abuse predict longer TSPC; while soft tissue related pain and older age predict shorter TSPC. The comprehensive assessment of CP, its appropriate classification and adequacy of its treatment should be further investigated. Appropriate educational and health policies are needed, which would eliminate the undertreatment of CP and, consequently, avoidable suffering. Improving scientific knowledge about CP will, inevitably, lead to the full exercise of a fundamental right: every human being must have access to an efficient plan to achieve stable pain control.

The meaning of loss is love. I know this through attention to experience. Whether loss or love is experienced in abundance or in absence, the meaning is mystical with an opening of body, mind, heart and soul to spirit. And so, in the style of a memoir, in the way of contemplative prayer, I contemplate and share my soul as a promise kept in the mystical reach through loss. With the first, initiating loss, the loss of my nine-year-old nephew, Caleb, I experience an epiphany that gives me spiritual instructions that will not be ignored. I experience loss as an abundance of meaning that comes to me as gnosis, as “knowledge of the heart” according to Elaine Pagels or divine revelation in what Evelyn Underhill calls mystical illumination in the experience of “losing-to-find” in union with the divine. Then, with gnostic import, in leaving the ordinary for the extraordinary, I enter the empty room in the painful yet liberating experience of the loss of my self. In the embrace of emptiness, I proceed to the first wall, the second wall, the third wall, the dark corner of denial, the return to centre, and, finally, to breaking the fourth wall in the empty room so as to keep my promise to you. Who are “you”? You are God. You are Caleb. You are spirit. You are my higher soul or self. And, you are the reader. You are my dear companion in silence. And then, through a series of broken promises and more loss, within what John of the Cross calls, “the dark night of the soul,” I am stopped by the ineffability of the dark corner of denial, the horror of separation and the absence of meaning, which is depicted as the grueling gap between the spiritual abyss and the breakthrough. What does it mean to keep going through a solemn succession of losses? I don’t know. In going into the empty room, I simply put pain to work in order to reach you. Through loss, though there are infinite manifestations, there is only one way: keep going. And so, in a triumph of the spirit, I keep going so as to be: a promise kept in the mystical reach through loss. As for you, through my illumined and dark experiences of loss, what is my promise to you? I keep going to reach the unreachable you. In the loss of self, with embodied emptiness, in going into the dark corner of denial, with a return to the divine centre of my emptied self, in an invitation to you, I give my soul to you in union with you.
Graduate
2020-06-25

Radioactive waste treatment is planned in LWTF (Low-level radioactive Waste Treatment Facility, JAEA) for LLW generated from the Tokai-reprocessing facility. The target LLW consists of highly concentrated sodium nitrate (5 M NaNO3) containing low-level 90Sr. In this study, selective adsorption properties of Sr2+ for highly functional A type zeolites (A51-JHP, A51-J (Union Showa) and A-4, X type zeolite (F-9) and Titanic acid-PAN (polyacrylamide) were clarified by batch and column adsorption methods. The irradiation stabilities of these adsorbents were also evaluated. The distribution properties of Sr2+ on different adsorbents were compared in simulated waste solution (5 M NaNO3, 0.1 ppm Sr2+, 85Sr as tracer). The order of distribution coefficients (Kd,Sr) was Titanic acid-PAN > A51-JHP > A51-J > A-4 > F-9. The largest value of Kd,Sr for titanic acid-PAN was estimated to be 218 cm3/g, while the saturated capacity (Qmax) was very small. Titanic acid-PAN had also the largest uptake rate of Sr2+ ions and the uptake attained equilibrium within 8 h. On the other hand, A51-JHP had a relatively large Kd,Sr value above 100 cm3/g and a Qmax value of 0.65 mmol/g. The breakthrough properties of Sr2+ were examined by varying cations present (single and mixed solutions) and flow rate (0.08 and 0.17 cm3/min). The components for the single solution were 400 g/L NaNO3, 100 ppm Sr2+, 85Sr as tracer, and the mixed solution contains 200 ppm Cs+, 100 ppm Ca2+, 50 ppm Mg2+, 50 ppm RuNO3+ in addition to the single solution components. The breakthrough curve for Titanic acid-PAN column using single solution had an S-shaped profile, while the “concentration phenomenon” exceeding C/C0 (breakthrough ratio) = 1 was observed in the case of mixed solution. As for the A51-JHP column, the breakthrough curve for single solution was similar to that for mixed solution and the 5% breakpoint was enhanced by decreasing the flow rate. The A51-JHP was stable under 60Co-irradiation up to 2.54 MGy; Kd,Sr and Qmax values were almost constant. In contrast, Titanic acid-PAN was affected above 0.28 MGy, due to the radiolysis of PAN matrix, and this surface alteration led to the release of active component of titanic acid. The novel A type zeolite (A51-JHP) is thus expected for the selective removal of Sr2+ in LWTF. The optimization of particle size and flow rate should be examined before practical use.

Summary Late in the life of the Steam Assisted Gravity Drainage (SAGD) process, it has become common practice to drill a single, horizontal infill well (called a “Wedge Well™” by some) in the oil bank located between two mature SAGD well pairs to produce the bitumen that has been heated and mobilized but is unable to be effectively drained by gravity given the largely lateral location relative to that of the SAGD producers. Since this oil bank is surrounded by the large, depleted steam chamber created by the existing well pairs, it requires little heat to mobilize bitumen. One of the challenges, however, in producing infill wells is that non-uniform drainage and local hot spots can be readily created in the first year of their operation, that in many cases require completion retrofits, such as with Flow Control Devices (FCDs), to improve the drainage profile. Installation of FCDs in these wells is quite challenging since the dynamics of the infill wells is changing with time and there is limited time to achieve conformance. To maintain pressure in SAGD chambers the common practice is to inject non-condensable gas (NCG). NCGs, such as methane, which is most common, do not condense in the steam chamber. Some of these NCG can short-cut into the infill through the existing hot-spot. The main reason is that the hot sections of infills are locations that are closer to the SAGD steam chamber, and due to steam condensate encroachment and higher mobility create a pathway for NCG breakthrough. FCDs are designed to promote a more uniform flux distribution along the producer, and exposure to NCG can change the impact of the FCDs. The true hot-spot temperature after NCG injection is decreasing and this can be mistaken as FCD efficiency and steam blocking. In reality, this temperature reduction is due to partial pressure effects associated with NCG encroachment. In this study, a new thermodynamic model is created to explain the NCG encroachment into infill wells, and a new temperature profile along the producer as a function of NCG breakthrough is calculated. The purpose of this work is to create a productivity index (PI) relationship that is fit for purpose for infill wells adjacent to SAGD well-pairs with NCG breakthrough that can primarily be used for analysis and optimization of SAGD FCD completions. This model can also be used to evaluate FCD performance in infill wells pre- and post- NCG breakthrough.

<p>In order to overcome stringent seismic requirement in the new Greater Jakarta Light Rail Transit Project, a breakthrough seismic system shall be chosen to obtain expected structural performance. This seismic system shall be designed to provide operational performance level after strong earthquake events. To achieve the criteria, seismic isolation system using Lead Rubber Bearings is chosen. With this isolation system, Greater Jakarta LRT has become the first seismically isolated infrastructure and apparently an infrastructure with the largest numbers of LRBs in one single project in Indonesia. More than 10.400 Pcs LRBs are used for the first phase of the construction and the numbers will be certainly increased in the next phase of the construction. To evaluate the structural performance, non-linear time history analysis is used. A total of 3 pair matched ground motions will be used as the input for the response history analysis. The ability of the lead rubber bearing to isolate and dissipate earthquake actions will determine its structural performance level. This will be represented by the nonlinear hysteretic curves obtained throughout the earthquake actions.</p>

The marine environment is hostile to most engineering materials, a combination of in-service wear and exposure to marine environment leads to an accelerated material degradation. Insufficient or poor protection of the substrates further assists the accelerated material degradation in marine environment. There is a direct relationship between the material-state of a ship and its operational capability, readiness, and service life. The current state-of-the-art practice is to use paint-based coatings to maintain the material-state of ships. However, the protection offered by paint coatings is usually brief due to inherent permeability and low damage tolerance of these coatings. For this reason, the paint coatings require renewal at regular intervals, typically less than 5-years, to maintain a minimum level of protection from the marine environment. The need for regular painting of ships results in a significant negative impact on the through-life availability, operational capability/readiness, and the cost of maintenance/operation of naval ships. Therefore, the fleet owners and operators should look beyond the conventional paint-based coatings to achieve significant breakthrough improvements in maintaining and enhancing the material-state of naval ships. Metallic coatings, if selected and applied appropriately, will outperform the paint coatings in the marine environment. Historically, the cost and performance of metallic coatings, mainly thermal metal spray (TMS) coatings, prevented their widespread use in the marine industry. The TMS coatings also have their own inherent application and performance related limitations that are widely reported in the literature. However, the cold metal spray (CMS) coating process can overcome the application and performance related limitations that are typically associated with the TMS coatings, therefore creating an opportunity for widespread use of metallic coatings in shipbuilding and fleet upkeep/maintenance. In this paper, the ability of low-pressure (LP-CMS) coatings to repair and reclaim damaged marine components, and application of functional coatings to improve in-service damage tolerance of the damaged/new components is investigated. The results of the investigation show that two LP-CMS coatings, Al-alloy and CuZn-alloy, can be used to repair and preserve both new and damaged components. The accelerated salt-spray and natural immersion corrosion testing of the LP-CMS coatings showed that each coating will be better suited to a particular operational environment, i.e. CuZn-alloy coating performed well in both immersion and atmospheric corrosion environments, whereas Al-alloy coating performed well only in atmospheric corrosion environment.