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Opportunely, six recent clinical trial data from several continents have uniformly provided dramatic evidence of the potent, dose-related and highly significant efficacy of NI, with minimal or manageable accompanying toxicity and safety concerns. The opiate-free lifestyle is attained significantly more often with NI adjusted O.R. = 6.00 (95% C.I. 3.86\u20139.50), P &lt; 10\n                    <jats:sup>-10<\/jats:sup>\n                    . Other drug use and drug craving are also rapidly reduced. The optimum manner in which to commence NI remains to be established. Of particular relevance is the relative safety of NI compared to the chronic opiate agonists (COA) usually employed, as the long-term toxicity of COA is only just being elucidated. Large population-based studies have found elevated rates of cardiovascular disease, six cancers, liver and respiratory disease, and all-cause mortality in COA. Whilst opiates have been shown to trigger numerous molecular pathways, the most interesting is the demonstration that the opiate morphinan's nucleus binds to the endotoxin groove of the TLR4-MD2 heterodimer. This has the effect of triggering a low grade endotoxaemic-like state, which over time may account for these protean clinical findings, an effect which is reversed by opiate antagonists. This emerging evidence suggests an exciting new treatment paradigm for OD and a corresponding increase in the role of NI in treatment.\n                  <\/jats:p>","DOI":"10.4137\/sart.s9031","type":"journal-article","created":{"date-parts":[[2012,9,30]],"date-time":"2012-09-30T02:30:18Z","timestamp":1348972218000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Epidemiologic and Molecular Pathophysiology of Chronic Opioid Dependence and the Place of Naltrexone Extended-Release Formulations in its Clinical Management"],"prefix":"10.4137","volume":"6","author":[{"given":"Albert Stuart","family":"Reece","sequence":"first","affiliation":[{"name":"School of Psychiatry and Clinical Neurosciences, University of Western Australia."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2012,9,27]]},"reference":[{"key":"bibr1-SART.S9031","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1965.03090080008002"},{"key":"bibr2-SART.S9031","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2011.11071121"},{"key":"bibr3-SART.S9031","unstructured":"Joint United Nations Program on HIV\/AIDS (UNAIDS). 2008 Report on the global AIDS epidemic. 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