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No description available.

Prostaglandin E2 (PGE2) is a chemical mediator of nociception that can evoke characteristic pain behaviour in animals after peripheral and spinal administration. The prostanoid is synthesised during tissue injury through activation of the arachidonic acid cascade, and its effects are mediated through binding to a family of specific G-protein coupled prostaglandin E (EP) receptors. The aim of the present study was to elucidate which EP receptors have an involvement in mediating the pronociceptive effects of PGE2 within the rat peripheral and central nervous system. Western blotting was used to characterise novel and commercially available EP receptor antibodies in EP receptor expressing cells to create a distribution of EP receptor subtypes present in the dorsal root ganglion (DRG) and spinal cord of the rat. A highly selective EP4 receptor antibody was identified, which immunocytochemically localised the EP4 receptor to small diameter (<1000microm2) DRG neurons of a nociceptor phenotype. In contrast, EP4 receptor expression within the spinal cord was wider was widespread and was not restricted to any of the laminae associated with nociceptive processing. Cultured rat DRG neurons were used to study the direct and sensitising effects of PGE2 on sensor neurons. PGE2 was seen to evoke reproducible increases in intracellular calcium in a small proportion of capsaicin-sensitive DRG neurons following direct application. Conversely, PGE2 reproducibly enhanced the capsaicin-elicited calcium response in a substantial proportion of DRG neurons and sensitised silent neurons to become capsaicin responsive, consistent with the prostanoid having a major sensitising effect on nociceptors. With the use of novel potent and selective EP receptor compounds, the EP3 and EP4 receptors were identified as the key receptors responsible for mediating the sensitising effects of PGE2 on sensory neurons.

Management of postoperative pain still depends on the administration of opioids and these drugs are associated with adverse effects eg sedation, nausea and vomiting. Local anaesthetics and NSAIDs are not associated with these adverse effects. Five RCTs have been undertaken: three on the administration of local anaesthetics, and two on NSAIDs. Two models of surgery have been used. As an example of an invasive standardised surgical procedure associated with severe pain, I have studied patients undergoing total abdominal hysterectomy (TAH). I also studied patients undergoing laparoscopy as an example of a minimally invasive technique that is associated with moderate pain. In patients who had TAH, I found that a combination of intraperiotoneal and incisional bupivacaine with epinephrine was associated with significant morphine sparing analgesia. Patients experienced significantly less pain on movement with this technique compared with placebo. Furthermore, in patients having laparoscopic cholecystectomy, I found that intraperitoneal administration of levobupivacine with epinephrine was associated with significantly lower total abdominal pain on inspiration, compared with placebo. However, I was not able to demonstrate significant differences in rescue morphine consumption or adverse effects between the two treatment groups. In another RCT, I did not find that administration of local anaesthetics via the transcervical route during laparoscopic sterilisation was useful for analgesia. I also examined how NSAIDs may be useful for postoperative analgesia. After TAH, rectal diclofenac was found to reduce morphine consumption, improve postoperative analgesia and was associated with reduced sedation and nausea. In another RCT of similar design, I found that iv parecoxib was associated with significant reductions in morphine consumption and pain scores on sitting, compared with placebo. The results of the investigations described in this thesis show that local anaesthetics and NSAIDs are useful as analgesic adjuncts after major and minimally invasive surgery.

One of the key findings of this thesis was the participants' perception of chronic pain impact. Participants' social-situational contexts, coping activities and help seeking approaches determined the degree of impact perceived in the experience of chronic pain. Experience of chronic pain impact was modified to varying degrees by engagement in coping activities e.g. physical and environmental and/or psychological and emotional, modifications and activities. Differences existed between those coping successfully or unsuccessfully as reflected in their overall coping approaches and/or strategies e.g. "active" or "passive". These approaches had positive or negative consequences for the process of adjustment. Expectations of GPs and primary care services were low. Actual experiences of consultations often contrasted with the ideal. Unmet needs and increasing frustration over repeated failed treatments was reported. Many participants moved on to seek help outwith the NHS e.g. CAM, and/or developed personal coping approaches and strategies. Others continued to consult whilst still believing that their GPs' neither did not care nor could not help them. These participants were amongst the most dependent and least evolved in their personal coping. Several typologies emerged from the thematic inductive analysis e.g. coping and consultations styles. Within these typologies, important socioeconomic differences were identified in the participants' ability to adapt e.g. to modify pain impact by developing successful coping strategies, gaining satisfactory health care treatment and obtaining health professional cooperation in or outwith the NHS. Thus, inequalities in pain experience and access to effective treatments were identified.

Background: The biological sciences have contributed an extensive volume of research in efforts to resolve the issue of chronic pain. An expanding body of research, focusing on the psycho-social aspects of chronic pain, is also now evident. Paradigms applied to chronic pain appear to compete and lack an integrative framework. Aims: The original aim of this study was to identify and explore patterns of congruence that exist between service users and providers in relation to beliefs about which treatments for chronic pain are important. At the outset this research took a constructivist position, based within existing research which demonstrates that beliefs about chronic pain and its treatment are individually constructed and that lack of agreement between people with pain and treatment providers may contribute to negative treatment outcomes. As the iterative process of the research unfolded the aims of determining if a complex adaptive systems (CAS) analysis was appropriate for chronic pain and whether recommendations for change could legitimately be generated using a CAS paradigm, emerged. Methods: The literature was reviewed to identify conceptualizations of, and interventions for, chronic pain. Based on this information the Stage one postal survey, gathering service users' and providers' opinions about important treatment components, was designed. The survey also included Skevington's standardised Beliefs About Pain Control Questionnaire (BPCQ). The second stage employed Delphi methodology. A series of iterative questionnaires explored the original questions about congruence of beliefs, perceived impact of disagreement and suggestions for action. As additional information emerging from each Delphi round the analysis employed firstly a constructivist framework and ultimately explored the usefulness ofreframing chronic pain within a CAS framework. Findings: The participants in this study had very little inter and intra-group congruence of beliefs. While service users believed that their decision-making was influenced by four domains of the Chapman's Consciousness model (coherence, purposiveness, affect and self-image) as derived from constructivist theory, service providers stated that affect and self-image were not strong influences. Participants agreed that some action should be taken when there is disagreement about important treatments and the overwhelming majority of recommendations focused on actions the service providers should take. Very few recommendations were made of actions for the service users. Participants' responses in Delphi 3 indicated that chronic pain had a number of elements consistent with a CAS but that more linear and conflicting beliefs were also strong. Discussion and Conclusions: A constructivist perspective in itself proved insufficient to explore chronic pain's resistance to change and the implications of this for intervention. By applying CAS theory to the three key features that emerged from Delphi 1 and 2 (incongruent beliefs, differential access to information and paradoxical beliefs and behaviours) the phenomenon of chronicity was reframed. Interventions, based on complexity science principles, can effect change in the highly interactive systems that constitute the chronic pain experience. A complexity science paradigm can serve as a meta-framework, integrating the currently competing theoretical models employed in chronic pain. The NHS Modernisation Agency, and other researchers and theorists, have provided complexity science based policy statements and recommendations for affecting change in a range of healthcare settings. These can be examined for patterns and examples of how dissent and conflict can be a positive generative force for change. Examples and patterns in turn, can form templates to guide reframing the practice and operating paradigm for chronic pain service delivery.