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Thesis (Ph.D.) -- University of Western Sydney, Nepean, 2001. / A thesis submitted in total fulfilment of the rquirement for the degree of Doctor of Philosophy, University of Western Sydney, Nepean, 2001. Bibliography : leaves 242-269.

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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

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published_or_final_version / Anaesthesiology / Doctoral / Doctor of Philosophy

Many common cancers, including breast, prostate and lung, have a predilection to metastasize to the bone, bringing not only bone destruction but severe pain. Although novel chemotherapeutic agents have increased life expectancy, patients are experiencing higher incidences of fracture, pain and drug-induced side effects; furthermore, recent findings suggest that patients are severely under-treated for their cancer pain. Strong analgesics, namely opiates, are the first-line therapy in alleviating cancer-related pain despite severe side effects including enhanced bone destruction with sustained administration. Bone resorption is primarily treated with bisphosphonates, which can bring highly undesirable side-effects including nephrotoxicity and osteonecrosis of the jaw. Thus novel therapeutics are needed to treat the pain of metastatic cancer patients. Animal models of cancer-induced bone pain (CIBP) have revealed that the neurochemistry of cancer has distinctive features from other chronic pain states. These include factors released from the cancer cells, tumor activated macrophages and increased osteoclast degredation of bone within the bone microenvironment, all acting to sensitize free nerve endings.One possibility of inhibiting cancer-mediated pain inducing factors includes agonism of the Cannabinoid 2 receptor agonists. Cannabinoid CB2 receptor-specific agonists have been shown to reduce bone loss and stimulate bone formation in a model of osteoporosis. CB2 agonists produce analgesia in both inflammatory and neuropathic pain models. Notably, mixed CB1/CB2 agonists also demonstrate a reduction in ErbB2-driven breast cancer progression. Osteolytic sarcoma within the femur produced spontaneous and touch evoked behavioral signs of pain within the tumor-bearing limb. The systemic administration of AM1241 both acutely and for 7 days significantly attenuated spontaneous and evoked pain in the inoculated limb. Sustained AM1241 significantly reduced bone loss and decreased the incidence of cancer-induced bone fractures. In addition, CB2 agonists significantly reduce breast cancer-induced bone pain, bone loss and breast cancer proliferation in part via cytokine/chemokine suppression. Studies utilized the spontaneously-occurring syngenic murine mammary cell line (66.1) implanted and sealed into the femur intramedullary space. Measurements were made of spontaneous pain, bone loss and cancer proliferation. The central and systemic administration of the CB2 agonist JWH015 for seven days significantly attenuates pain. Pharmacological characterization with cannabinoid 1 and 2 antagonists demonstrates that the effects JWH015 on pain were mediated by the CB2 receptor. We and others have found that bone induced cancer pain increases the expression of GFAP and Iba1 in the lumbar spinal cord which are markers of astrocytes and microglia respectively, compared to control animals. After administration of JWH015 (i.t), the release of spinal pro-inflammatory cytokines, IL-6 and TNFá, are reduced suggesting that modulation of glial cytokines may be one mechanism by which CB2 agonists can attenuate pain centrally. On the other hand, systemic administration of JWH015 reduces cancer-induced elevation of cytokines in the tumor microenvironment, suggesting a mechanism by which CB2 agonist is attenuating pain peripherally. Additionally, systemic administration improves bone modification, as demonstrated via micro-computed tomography and bone serum markers while decreasing femoral tumor burden. In vitro, JWH015 reduced cancer cell proliferation and other inflammatory mediators shown to promote pain, bone loss and proliferation. These results suggest CB2 agonists as a novel treatment for breast cancer-induced bone pain, where disease modifications include a reduction in bone loss, suppression of cancer growth, attenuation of severe bone-pain and increased survival without the major side effects of current therapeutic options. Another future therapeutic option for metastatic bone cancer pain may include cathepsin inhibitors. Cysteine cathepsins (B, C, F, H, K, L, O, L2/V, W, X/Z) are highly expressed in many human cancers and have been associated with poor patient prognosis. In the RIP1-Tag2 transgenic model of pancreatic cancer, mice treated with VBY-825, a reversible inhibitor of cathepsins S, B, V, L, K showed a significant reduction in tumor incidence and growth. Here we demonstrate the cathepsin inhibitor VBY-825 reduces cancer-induced pain behaviors. Additionally, tumor bearing animals treated with VBY-825 demonstrate a reduction in bone resorption, possibly mediated through a reduction in osteoclast activity. These results indicate that a cathepsin inhibitor targeting multiple cathepsins, such as VBY-825, could be a novel therapeutic for bone metastases.Part of the failure to palliate cancer pain is due to a poor understanding of the etiology of cancer pain. Preclinical studies have just begun to scratch the surface on how such cancers may interact with the bone microenvironment to result in pain and bone loss. Further studies are desperately needed at both the preclinical and clinical level to determine the unique molecular profile of cancer pain that may lead to the development of superior therapeutics for CIBP. The studies presented herein provide preclinical evidence that warrant the investigation of these compounds in the clinic as treatment for cancer-induced bone pain.

Chronic non-cancer pain (CNCP) affects approximately 25% of Canadians. Opioids are medications frequently prescribed for management of patients with CNCP. Concern about addiction, misuse, and diversion for illicit use led the Canadian medical regulatory bodies to release a national guideline on the safe and effective use of opioids in CNCP. This thesis used an online survey to determine how closely the self-reported practices of Canadian family physicians matched the recommendations of the Canadian Guideline. We received 710 responses suitable for analysis. Thirteen percent of respondents did not prescribe strong opioids for CNCP. Practice gaps indentified were infrequently using a management agreement and monitoring pain with a scale; incorrect choice of second line opioid for mild to moderate pain; incorrect choice of first, second, and third line opioids for severe pain, and starting fentanyl incorrectly. Findings provide baseline information for future follow-up to compare physicians’ adherence to the guideline.

Made available in DSpace on 2014-06-11T19:23:07Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-03-03Bitstream added on 2014-06-13T20:10:38Z : No. of bitstreams: 1 takeda_n_me_botfm.pdf: 264551 bytes, checksum: b4235e7228efb9f456dda6be5d8a3221 (MD5) / Fundação Pio Xii - Barretos / Estudos têm relacionado o uso de atividades terapêuticas como uma técnica nãofarmacológica efetiva para o controle da dor oncológica e de outros sintomas decorrentes da doença, contribuindo de maneira significativa na melhora da qualidade de vida. O objetivo deste estudo foi avaliar os resultados de um programa de terapia ocupacional aplicado a pacientes oncológicos sob cuidados paliativos, no que se refere à modulação da dor, qualidade de vida e sintomas emocionais. Após a aprovação do comitê de ética e assinatura do termo de consentimento livre e esclarecido, foram incluídos 59 pacientes portadores de neoplasia avançada, em cuidados paliativos e que apresentavam dor E.V.A 5 cm (Escala Visual Analógica). Foram avaliados: dor (E.V.A, questionário de McGill e consumo de opióides), qualidade de vida (questionário SF-12) e sintomas de ansiedade e depressão (questionário HADS). Os pacientes foram aleatoriamente distribuídos, por sorteio de envelopes, em dois grupos e acompanhados diariamente por 10 dias consecutivos. O grupo intervenção realizou 30 minutos de atividades terapêuticas associado a orientações quanto ao desempenho das atividades de vida diária. O grupo controle recebeu somente orientações quanto atividades de vida diária. Os grupos foram demograficamente e clinicamente semelhantes em relação: sexo, cor, religião, escolaridade, estado civil, presença de cuidador, qualidade da dor, localização da dor e topografia do câncer. O grupo intervenção apresentou redução da dor (E.V.A e questionário de McGill) durante os dez dias de estudo. O grupo controle não apresentou diminuição satisfatória da dor. A média do consumo de morfina foi semelhante quando comparado os grupos (p>0,05). Entretanto, analisando cada grupo separadamente, no grupo controle observou-se maior consumo de morfina quando comparado ao grupo que realizou atividades... / Studies have connected the use of therapeutic activities as non-pharmacological practice effective for the control of cancer pain and other passing symptoms from the disease by helping to improve the quality of life in a significative way. The aim of this study was to create a program of occupational therapy as a helping technique in the modulation of the pain in cancer patients under palliative care. After the approval of the ethics committee and signature of the free and evident consent term, 59 patients who had advanced cancer in palliative care and had VAS 5 cm (Visual Analogue Scale) pain were included. Pain (VAS, McGill questionnaire and opioids consumption), quality of life (questionnaire SF-12) and anxiety and depression symptoms (questionnaire HADS) were evaluated. The patients were aleatorically distributed, by raffle envelopes, into two groups and accompanied daily for consecutive 10 days. The intervention group performed 30 minutes of therapeutic activities associated guidance on the performance of activities of daily life. The control group received only orientations of activities of daily life. The groups were similar demographically and clinically in relation to sex, race, religion, graduation, marital status, the presence of caregiver, quality of pain, localization of the pain and topography of cancer. The intervention group presented decreasing of the pain (VAS and McGill questionnaire) during ten days of the study. The control group did not present satisfactory reduction of pain. The average of morphine consumption was similar compared to the groups (p> 0.05). However, analyzing each group separately in the control group was observed a large consumption of morphine when compared to the group which accomplished therapeutic activities. The quality of life and anxiety and depression symptoms got better in relation to the first and the last day of the study... (Complete abstract click electronic access below)

Chronic pain induced by nerve damage due to trauma or invasion of cancer to the bone elicits severe ongoing pain as well as hyperalgesia and allodynia likely reflecting adaptive changes within central circuits that amplify nociceptive signals. The present study explored the possible contribution of the mesolimbic dopaminergic circuit in promoting allodynia related to neuropathic and cancer pain. Mice with ligation of the sciatic nerve or treated with intrafemoral osteosarcoma cells showed allodynia to a thermal stimulus applied to the paw on the injured side. Patch clamp electrophysiology revealed that the intrinsic neuronal excitability of ventral tegmental area (VTA) dopamine neurons projecting to the nucleus accumbens (N.Acc.) was significantly reduced in those mice. We used tyrosine hydroxylase (TH)-cre mice that were microinjected with adeno-associated virus (AAV) to express channelrhodopsin-2 (ChR2) to allow optogenetic stimulation of VTA dopaminergic neurons in the VTA or in their N.Acc. terminals. Optogenetic activation of these cells produced a significant but transient anti-allodynic effect in nerve injured or tumor-bearing mice without increasing response thresholds to thermal stimulation in sham-operated animals. Suppressed activity of mesolimbic dopaminergic neurons is likely to contribute to decreased inhibition of N.Acc. output neurons and to neuropathic or cancer pain-induced allodynia suggesting strategies for modulation of pathological pain states.