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This thesis presents data relating to the use of hydromorphone for the treatment of acute and chronic pain. The work was done in order to obtain European product licences for both immediate-release and a controlled-release oral formulations. Hydromorphone is a semi-synthetic derivative of morphine which possesses pharmacologic properties qualitatively similar to those produced by morphine, although it is a more water- soluble molecule and is approximately five-times more potent than morphine. As with all strong opioids, hydromorphone has the potential to produce physical or psychological dependence. Hydromorphone has been credited with a lack of active metabolites in contrast to morphine, which has an active metabolite, morphine-6-glucuronide. For the immediate-release tablet, hydromorphone is rapidly absorbed after oral administration and undergoes extensive first-pass metabolism, resulting in oral bioavailability of 18.7%. Elimination is multiphasic; there is a rapid decline in plasma concentrations within the first 3 hours after dosing followed by slower elimination phase. The earlier distribution/elimination element is thought to determine hydromorphone's duration of action, whereas the longer elimination half-life of around 15 hours is of less relevance in the clinical setting. Cmax and AUC(0-24h) for hydromorphone immediate-release are proportional to dose level and there is a statistically significant effect of food, but the effects observed are not clinically relevant. Sex had little effect on the pharmacokinetics of oral immediate-release hydromorphone and age also had little effect. Renal impairment produced changes in the pharmacokinetics of hydromorphone as did moderate hepatic impairment, both producing an increase in hydromorphone bioavailabihty. The controlled-release formulation achieves a very flat profile of release compared with the immediate-release, with Tmax being observed at times in excess of 12 hours. Dose- proportional pharmacokinetics were confirmed and marginally increased bioavailability demonstrated compared with the immediate-release formulation. The effect of food to increase bioavailability is not likely to be clinically significant. Several published controlled studies of oral hydromorphone in patients with a variety of acute or chronic painful conditions have demonstrated the analgesic efficacy of hydromorphone. Nevertheless, novel studies demonstrating efficacy and safety were requested, therefore, three major studies were conducted to evaluate hydromorphone's efficacy and safety in acute and chronic pain models. The first of these was a double-blind, single dose, placebo-controlled, multicentre dose- ranging study of 205 postoperative knee replacement patients receiving either 2, 4 or 6 mg single doses of immediate-release hydromorphone. The principal measure of efficacy was the sum of the pain intensity differences (SPID) for pain at rest, using self-reported pain on an 11-point numerical scale over a six-hour period. Hydromorphone 4 and 6 mg were significantly more effective in reducing pain at rest compared with placebo (p=0.03 for both comparisons). There was no statistically significant difference between hydromorphone 2mg and placebo. This thesis presents three large, multinational positive studies confirming the efficacy and safety of hydromorphone in both acute and chronic pain models. (Abstract shortened by ProQuest.). |
