No abstract

Respiratory depression limits the use of opioid analgesia. Although well described clinically, the specific mechanisms of opioid action on respiratory control centres in the brain have, until recently, been less well understood. This article reviews the mechanisms of opioid-induced respiratory depression, from the cellular to the systems level, to highlight gaps in our current understanding, and to suggest avenues for further research. The ultimate aim of combating opioid-induced respiratory depression would benefit patients in pain and potentially reduce deaths from opioid overdose. By integrating recent findings from animal studies with those from human volunteer and clinical studies, further avenues for investigation are proposed, which may eventually lead to safer opioid analgesia.

Despite improvements in the clinical management of aneurysmal subarachnoid haemorrhage over the last decade, delayed cerebral ischaemia (DCI) remains the single most important cause of morbidity and mortality in those patients who survive the initial bleed. The pathological mechanisms underlying DCI are still unclear and the calcium channel blocker nimodipine remains the only therapeutic intervention proven to improve functional outcomes after SAH. The recent failure of the drug clazosentan to improve functional outcomes despite reducing vasoconstriction has moved the focus of research into DCI away from cerebral artery constriction towards a more multifactorial aetiology. Novel pathological mechanisms have been suggested, including damage to cerebral tissue in the first 72 h after aneurysm rupture ('early brain injury'), cortical spreading depression, and microthrombosis. A greater understanding of the significance of these pathophysiological mechanisms and potential genetic risk factors is required, if new approaches to the prophylaxis, diagnosis, and treatment of DCI are to be developed. Furthermore, objective and reliable biomarkers are needed for the diagnosis of DCI in poor grade SAH patients requiring sedation and to assess the efficacy of new therapeutic interventions. The purpose of this article is to appraise these recent advances in research into DCI, relate them to current clinical practice, and suggest potential novel avenues for future research.