Hydromorphone is a pure opioid agonist whose principal therapeutic action is analgesia. Other members of the class known as opioid agonists include substances such as morphine, oxycodone, fentanyl, codeine, and hydrocodone. Pharmacological effects of opioid agonists include anxiolysis, euphoria, feelings of relaxation, respiratory depression, constipation, miosis, cough suppression, and analgesia. Like all pure opioid agonist analgesics, with increasing doses there is increasing analgesia, unlike with mixed agonist/antagonists or non-opioid analgesics, where there is a limit to the analgesic effect with increasing doses. With pure opioid agonist analgesics, there is no defined maximum dose; the ceiling to analgesic effectiveness is imposed only by side effects, the more serious of which may include somnolence and respiratory depression.
Central Nervous System
The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug.
Hydromorphone produces respiratory depression by direct action of brain stem respiratory centers. The respiratory depression involves both a reduction in the responsiveness of the brain stem to increases in carbon dioxide and to electrical stimulation.
Hydromorphone depresses the cough reflex by direct effect on the cough center in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia.
Hydromorphone causes miosis even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of Palladone™ Capsule overdose (see OVERDOSAGE).
Hydromorphone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the duodenum. Digestion of food is delayed in the small intestine and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid induced-effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.
Hydromorphone may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon in humans and other species, rats and dogs. Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.
Administration of a single Palladone™ Capsule dose is characterized by biphasic absorption, a relatively rapid rise to an initial peak concentration, followed by a second broader peak with therapeutic plasma concentrations maintained over the 24-hour dosing interval. The absolute bioavailability of hydromorphone from Palladone™ Capsules has not been determined. Under conditions of multiple dosing, the bioavailability of a once-daily dose of Palladone™ Capsules is equivalent to the same total daily dose of immediate-release hydromorphone given in divided doses every 6 hours. Hydromorphone absorption from Palladone Capsules is pH independent but can be significantly increased in the presence of alcohol (see PHARMACOKINETICS: Drug Interactions). Dose proportionality has been established in terms of Cmax and AUC for the 12 mg and 24 mg dosage strengths. Dosage form proportionality on a dose-adjusted basis has been demonstrated for three 12 mg capsules to one 32 mg capsule.
In a study comparing 12 mg Palladone™ Capsules dosed every 24 hours to 3 mg of immediate-release hydromorphone dosed every 6 hours in healthy human subjects, the two treatments were found to be equivalent in terms of extent of absorption (AUC) (see Figure 1). The extended-release characteristics of Palladone™ Capsules resulted in lower steady-state peak levels (Cmax), higher trough levels (Cmin), and an approximately twofold to threefold reduction in the fluctuation seen with the immediate-release hydromorphone tablets.
Steady-state plasma concentrations with Palladone™ Capsules were achieved within 2 to 3 days after initiation of dosing. This is consistent with the mean apparent terminal elimination half-life for Palladone™ of approximately 18.6 hours. This supports the ability to titrate every 2 to 3 days, as necessary. Hydromorphone did not accumulate significantly after multiple dosing with once-daily administration.
Food had no significant effect on the peak (Cmax), AUC or the elimination of hydromorphone from Palladone™ Capsules (See Figure 2.).
Following intravenous admininstration of hydromorphone, the reported volume of distribution is 295 L (4 L/kg). Hydromorphone is approximately 20% bound to human plasma proteins.
Hydromorphone is metabolized by direct conjugation, or by 6-keto reduction followed by conjugation. Following absorption, hydromorphone is metabolized to the major metabolites hydromorphone-3-glucuronide, hydromorphone-3-glucoside and dihydroisomorphine-6-glucuronide. Also observed were the less prevalent metabolites, dihydroisomorphine-6-glucoside, dihydromorphine and dihydroisomorphine.
Hydromorphone metabolites have been found in plasma, urine and in human hepatocyte test systems. However, it is not known whether hydromorphone is metabolized by the cytochrome P450 enzyme system. Hydromorphone is a poor inhibitor of human recombinant CYP isoforms including CYP1A2, 2A6, 2C8, 2D6, and 3A4 with an IC50 > 50 µM. Therefore, hydromorphone is not expected to inhibit the metabolism of other drugs metabolized by these CYP isoforms.
Full mass balance and recovery studies have not been reported for extended-release hydromorphone products. However, hydromorphone and its metabolites have been recovered in urine following the use of immediate-release hydromorphone. Following intravenous administration of hydromorphone, terminal half-life is approximately 3 hours and clearance is 1.66 L/hr. The apparent terminal half-life with controlled release hydromorphone is about 18.6 hours.
Concomitant administration of H2 receptor blockers (cimetidine, famotidine, ranitidine) or proton pump inhibitors (omeprazole, lansoprazole) showed no significant effect on Palladone™ steady-state pharmacokinetics.
Patients taking Palladone with other opioid analgesics, general anesthetics, phenothiazines, tricyclic antidepressants or other CNS depressants may experience additional CNS depression and therefore, dose adjustments should be considered. Consuming alcohol while taking Palladone Capsules can cause significant increases in peak hydromorphone concentrations.