No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

This thesis has used qualitative interviews to generate knowledge about the use of Transcutaneous Electrical Nerve Stimulation (TENS) by patients with chronic musculoskeletal pain. This knowledge can inform the selection of appropriate outcome measures which are relevant to the patients' use of TENS, and can be used to focus the design of future TENS evaluations. Methods Semi-structured interviews were used to explore the perceived benefits of TENS reported by secondary ca re pain clinic patients with chronic musculoskeletal pain. The data were analysed using an ind uctive thematic analysis and a parallel, theo retical thematic analysis was undertaken to faci litate linking against other datasets and outcome measures. Two other forms of data generation were used to ens ure that a comprehensive understanding of the perceived benefits of TENS was developed. The analysis was compared with outcome measures used previously for TENS evaluations in chronic pain and chronic low back pain findings & impli ca tions The analysis indicated that TENS should be considered as a complex intervention, with benefits which extend beyond pain relief, including a red uction in muscle sensations (such as tension and spasm), and di straction from pain as separate benefits. Patients reported using TENS in a strategic manner, for example in order to manage pain fl are-ups, ach ieve functiona l goals, enhance rest periods and reduce medication. This indicates that outcomes need to be contextualised to the specific strategy of use. The benefits re ported by TENS users had a low degree of match against previously used outcome measures. This indicates that these previously used outcome measures have limi ted ca pacity to capture patient-reported benefits. An alte rna tive a pproach to outcome measurement is developed, which has the potential to test elements of the analysis developed in t hi s thesis, as well as enhancing the sensitivity of future TENS evaluations.

Since the discovery of the powerful analgesic epibatidine in 1974 from the Ecuadorian poison frog Epipedobates tricolor, there has been global interest in the synthesis of analogue molecules. Epibatidine has the unique 7-azabicyclo[2.2.1]heptane structure with a chloropyridyl ring at the 2-positon. Epibatidine acts at the nicotinic acetylcholine receptor (nAChR) and the aim of this work is to produce target compounds retaining therapeutic potential but with higher nAChR sub-type selectivity and lower toxicity. The only naturally occurring compound to have the 2-azabicyclo[2.1.1]hexane system is the nonproteinogenic amino acid 2,4-methanoproline. This alternative bicyclic framework opens the route to the construction of pioneering epibatidine analogues. The intramolecular [2+2] photocycloaddition method was employed to construct the rigid 2-azabicyclo[2.1.1]hexane skeleton. Successful nucleophilic substitution at a methylene attached to the bridgehead position of the 2-azabicyclo[2.1.1]hexane ring system opened the way to construction of innovative derivatives. These have a wider range of functional groups attached at the 1-positon via a methylene 'spacer' and provide access to epibatidine analogues containing heterocyclic substituents and to further homologation. Mechanistic studies indicate that displacements with loss of a nucleofuge require thermal activation but proceed without the rearrangement initially anticipated in such a strained bicyclic structure. A unique tricyclic carbamate has been isolated; nucleophilic attack on this carbamate leads directly to the isolation of N-deprotected substitution products with concomitant decarboxylation. The analogues produced in this study are currently being pharmacologically tested and the results will determine the course of future synthetic approaches towards original targets.