No abstract

Traditionally, opioids have been administered as fixed doses at fixed dose intervals. This approach has been largely ineffective. Patient-controlled analgesia (PCA) and upgraded traditional approaches incorporating flexibility in dose size and dose interval, and titration for an effect in individual patients with the monitoring of pain and sedation scores, can greatly improve the efficacy of opioid administration. Optimising opioid use, therefore, entails optimising the titration process. Opioids have similar pharmacodynamic properties but have widely different kinetic properties. The most important of these is the delay between the blood concentrations of an opioid and its analgesic or other effects, which probably relate to the delay required for blood and brain and spinal cord (CNS) equilibrium. The half-lives of these delays range from approximately 34 minutes for morphine to 1 minute for alfentanil. The titration is influenced by the time needed after an initial dose before it is safe to administer a second dose and the duration of the effects of a single dose, which varies widely between opioids, doses and routes of administration. To compare opioids and routes of administration, we examined the relative CNS concentration profiles of opioids - the CNS concentration expressed as a percentage of its maximum value. The relative onset was the defined as the time the relative CNS concentration first rose to 80% of maximum, while the relative duration was defined as the length of time the concentration was above 80%. For an intravenous bolus dose, the relative onset varies from approximately 1 for alfentanil to 6 minutes for morphine, while their relative durations are approximately 2 and 96 minutes, respectively. Although all of the common opioids, perhaps with the exception of alfentanil, have kinetic and dynamic properties suitable for use in PCA with intravenous bolus doses, the long relative duration of morphine makes it particularly suited to an upgraded traditional approach using staff administered intramuscular or subcutaneous doses. There is a clear kinetic preference for regimens with a rapid onset and short duration (e.g. intravenous PCA) for coping with incident pain. It is shown that, in general, titration is improved by the more frequent administration of smaller doses, but it is important to use additional doses to initially 'load' a patient. The titration of opioids should always be accompanied by the monitoring of pain and sedation scores and ventilation.

T helper (Th)17 cells might contribute to immunemediated renal injury. Thus, we sought to define the time course of IL-17A-induced kidney damage and examined the relation between Th17 and Th1 cells in a model of crescentic anti-glomerular basement membrane glomerulonephritis. Renal injury and immune responses were assessed in wild-type and in IL-17A-deficient mice on days 6, 14, and 21 of disease development. On day 6, when mild glomerulonephritis developed, IL-17A-deficient mice were protected from renal injury. On day 14, when more severe disease developed, protection from renal injury due to IL-17A deficiency was less evident. On day 21, when crescentic glomerulonephritis was fully established, disease was enhanced in IL-17A ؊/؊ mice, with increased glomerular T-cell accumulation and fibrin deposition, and augmented Th1 responses. Mice lacking the Th17-promoting cytokine, IL-23 (p19), also developed more severe disease than wild-type animals on day 21. In contrast, mice deficient in the key Th1-promoting cytokine, IL-12 (p35), had decreased Th1 and increased Th17 responses and developed less severe crescentic glomerulonephritis than wild-type animals. These studies show that IL-17A contributes to early glomerular injury, but it attenuates established crescentic glomerulonephritis by suppressing Th1 responses. They provide further evidence that Th1 cells mediate crescentic injury in this model and that Th1 and Th17 cells counterregulate each other during disease development.