September 5, 2015
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Mechanism Of Action

Hydromorphone, a semi-synthetic morphine derivative, is a hydrogenated ketone of morphine. Hydromorphone is principally an agonist of mu-receptors, showing a weak affinity for κ-receptors. Comparing relative binding affinity for mu-and κ-opioid receptors, hydromorphone binds more specifically to mu-receptors than structurally related morphine. As an opioid agonist, the principle therapeutic action of hydromorphone is analgesia. The precise mechanism of action of opioid analgesics is not known but the effects are thought to be mediated through opioid-specific receptors located predominantly in the central nervous system (CNS). Interaction with the mu-opioid receptor subtype is believed to be responsible for most of hydromorphone's clinical effects. There is no intrinsic limit to the analgesic effect of hydromorphone. Clinically, however, dosage limitations are imposed by the adverse effects, primarily respiratory depression, sedation, nausea, and vomiting, which can result from high doses.


CNS Depressant/Alcohol Interaction

Additive pharmacodynamic effects may be expected when PALLADONE is used in conjunction with alcohol, other opioids, legal or illicit drugs that cause central nervous system depression.

Effects on the Central Nervous System

Hydromorphone produces dose-related respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation.

Hydromorphone depresses the cough reflex by direct effect on the cough center in the medulla.

Hydromorphone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomic. Marked mydriasis, rather than miosis, may be seen due to severe hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Gastric, biliary and pancreatic secretions are decreased by hydromorphone. Hydromorphone causes a reduction in motility associated with an increase in tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm. The end result is constipation. Hydromorphone also can cause an increase in biliary tract pressure as a result of spasm of the sphincter of Oddi.

Effects on the Cardiovascular System

Hydromorphone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Release of histamine may be induced by hydromorphone and can contribute to opioid-induced hypotension.

Manifestations of histamine release or peripheral vasodilation may include pruritus, flushing, red eyes, and sweating.

Effects on the Endocrine System

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.

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.



PALLADONE is an extended-release formulation of hydromorphone. Administration of a single PALLADONE 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 has not been determined. Under conditions of multiple dosing, the bioavailability of a once-daily dose of PALLADONE is equivalent to the same total daily dose of immediate-release hydromorphone given in divided doses every 6 hours. 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 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 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.

Figure 1: Steady-State Plasma Hydromorphone Concentration-Time Curves

Steady-State Plasma Hydromorphone Concentration-Time Curves - Illustration

Steady-state plasma concentrations with PALLADONE 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. 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 (see Figure 2).

Figure 2: Single-Dose Palladone™ Pharmacokinetic Profiles

Single-Dose Palladone™ Pharmacokinetic Profiles - Illustration

Food Effect

The pharmacokinetics of PALLADONE is not affected by food as indicated by bioequivalence when administered under fed and fasting conditions. Therefore, PALLADONE may be administered without regard to meals.


Following intravenous administration 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-3glucuronide, 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.

Specific Populations

Geriatric Patients

Age-related increases in exposure in clinical studies were observed between geriatric and younger adult subjects. Greater sensitivity of some older individuals cannot be excluded. Dosages should be adjusted according to the clinical situation.

Pediatric Patients

The safety and effectiveness of PALLADONE have not been established in patients below the age of 18.


Pharmacokinetics of hydromorphone from PALLADONE is comparable in men and women.


The pharmacokinetics of hydromorphone in African Americans and Caucasians in the clinical population were comparable.

Hepatic Impairment

PALLADONE was not studied in patients with severe hepatic insufficiency and is not recommended for use in such patients. Start patients with moderate hepatic impairment on 25% of the usual dose of PALLADONE and closely monitor for respiratory and central nervous system depression during dose titration. Consider alternate analgesic therapy for patients with severe hepatic impairment [see DOSAGE AND ADMINISTRATION and Specific Populations].

Renal Impairment

In patients with mild renal impairment, based on calculated creatinine clearance, the concentrations of hydromorphone in plasma were slightly higher than in subjects with normal renal function. Start patients with moderate renal impairment on 50% of the usual PALLADONE dose for patients with normal renal function and closely monitor for respiratory and central nervous system depression during dose titration. As PALLADONE is only intended for once-daily administration, consider use of an alternate analgesic that may permit more flexibility with the dosing interval in patients with severe renal impairment [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].

Drug Interaction/Alcohol Interaction

A pharmacokinetic study in healthy subjects showed that co-ingestion of a 12 mg PALLADONE capsule with 240 mL (8 ounces) of 40% (80 proof) alcohol resulted in an average peak hydromorphone concentration approximately six times greater than when taken with water. One subject in this study experienced a 16-fold increase when the drug was ingested with 40% alcohol compared with water. In certain subjects, 8 ounces of 4% alcohol (equivalent to 2/3 of a typical serving of beer) resulted in almost twice the peak plasma hydromorphone concentration than when the drug was ingested with water.

This pharmacokinetic study was an open-label, four-arm, crossover design study and included twenty-four healthy adult subjects who were tested under fasted conditions and 24 healthy adult subjects who were tested under standardized fed conditions. Subjects were pretreated with naltrexone to block the opiate effects, and then administered one of the following four treatments:

Group A PALLADONE, 12 mg + 240 mL of 40% ethanol
Group B PALLADONE, 12 mg + 240 mL of 20% ethanol
Group C PALLADONE, 12 mg + 240 mL of 4% ethanol
Group D PALLADONE, 12 mg + 240 mL of water

Plasma was sampled and analyzed for hydromorphone concentration at appropriate intervals. Each subject received each of the four treatments, thereby acting as his or her own control (Group D).

The effects of alcohol co-ingestion were more marked in the fasted state and are summarized below.

Pharmacokinetic Outcomes Resulting from Co-ingestion of PALLDONE with Different Concentrations of Alcohol (fasted state)

Ratio 40* Ratio 20** Ratio 4†
Cmax ‡ Mean 6 2 1
Range 1 to 16 1 to 6 1 to 2
AUC*** Mean 1.3 1 1
Range 0.6 to 3.4 0.4 to 1.5 0.5 to 1.9
*Ratio of values when co-ingested with 240 mL of 40% ethanol compared to co-ingestion with 240 mL of water, i.e. if the peak plasma concentration was 6 ng/mL when administered with alcohol and 1 ng/mL when administered with water, this ratio would be 6
**Ratio of values (as above) when co-ingested with 240 mL of 20% ethanol compared to coingestion with 240 mL of water
†Ratio of values (as above) when co-ingested with 240 mL of 4% ethanol compared to co-ingestion with 240 mL of water
‡Peak plasma concentration
***Measure of total drug exposure

In the fed state, the mean peak plasma concentration ratio (40% alcohol:water) was 3.5 with a maximum of 6.

In summary, the study showed that ingesting PALLADONE with alcohol in clinically relevant amounts results in significantly higher peak plasma concentrations of hydromorphone. The effect is more pronounced with increasing concentrations of alcohol and in a fasted state.

The effects of co-ingestion of smaller volumes and with other concentrations of alcohol have not been studied.

Clinical Studies

The efficacy of PALLADONE was established in a double-blind, randomized, parallel group, multicenter, placebo-controlled, four-week trial of patients with pain that was present for at least one month. The majority of these patients experienced moderate to severe pain due to musculoskeletal disorders while maintained on one or more opioid analgesics, often in addition to non-opioid analgesics. Two hundred twenty-one patients with chronic moderate to severe pain were randomized to receive once daily 12 mg PALLADONE capsule or placebo after they had demonstrated that they needed approximately 12 mg of immediate-release hydromorphone (in addition to non-opioid medication) around-the-clock to improve their pain control. Patients randomized to PALLADONE maintained adequate analgesia for a significantly longer period of time (P < 0.0001) than patients randomized to placebo.

Last reviewed on RxList: 5/1/2014
This monograph has been modified to include the generic and brand name in many instances.

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