Oxymorphone
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Mechanism of action
Oxymorphone is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of oxymorphone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with oxymorphone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.
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 are thought to play a role in the analgesic effects of this drug.
Pharmacodynamics
Effects on the Central Nervous System
Oxymorphone produces 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 both increases in carbon dioxide tension and electrical stimulation.
Oxymorphone 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 origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.
Effects on the Gastrointestinal Tract and Other Smooth Muscle
Oxymorphone causes a reduction in motility associated with an increase in smooth muscle 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, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED).
Effects on the Cardiovascular System
Oxymorphone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating and/or orthostatic hypotension.
Effects on the Endocrine System
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans
[see Adverse Reactions ( 6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.
Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date
[see Adverse Reactions ( 6.2)].
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.
Concentration–Efficacy Relationships
The minimum effective analgesic concentration varies widely among patients, especially among patients who have been previously treated with extended-release opioid agonists. The minimum effective analgesic concentration of oxymorphone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance
[see Dosage and Administration ( 2.1, 2.3)].
Concentration–Adverse Reaction Relationships
There is a relationship between increasing oxymorphone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions
[see Dosage and Administration (2.1
,2.3
,2.7
)].
Pharmacokinetics
Absorption
Absorption
The absolute oral bioavailability of oxymorphone is approximately 10%. Studies in healthy volunteers reveal predictable relationships between oxymorphone hydrochloride tablets dosage and plasma oxymorphone concentrations.
Steady-state levels were achieved after three days of multiple dose administration. Under both single-dose and steady-state conditions, dose proportionality has been established for 5 mg, 10 mg and 20 mg doses of oxymorphone hydrochloride tablets, for both peak plasma levels (C
max) and extent of absorption (AUC) (see Table 3).
Table 3: Mean (±SD) Oxymorphone Hydrochloride Tablets Pharmacokinetic Parameters
Regimen
Dosage
C
max
(ng/mL)
ACU
(ng·hr/mL)
T
1/2
(hr)
Single Dose
5 mg
10 mg
20 mg
1.10±0.55
1.93±0.75
4.39±1.72
4.48±2.07
9.10±3.40
20.07±5.80
7.25±4.40
7.78±3.58
9.43±3.36
Multiple Dose
a
5 mg
10 mg
20 mg
1.73±0.62
3.51±0.91
7.33±2.93
4.63±1.49
10.19±3.34
21.10±7.59
NA
NA
NA
NA = not applicable
aResults after 5 days of every 6 hours dosing.
After oral dosing with 40 mg of oxymorphone hydrochloride tablets in healthy volunteers under fasting conditions or with a high-fat meal, the C
maxand AUC were increased by approximately 38% in fed subjects relative to fasted subjects. As a result, oxymorphone hydrochloride tablets should be dosed at least one hour prior to or two hours after eating
[see Dosage and Administration (
2.3
)].
Distribution
Formal studies on the distribution of oxymorphone in various tissues have not been conducted.
Oxymorphone is not extensively bound to human plasma proteins; binding is in the range of 10% to 12%.
Elimination
Oxymorphone Hydrochloride Tablets half-life ranges from approximately 9-11 hours after a single oral dose (5-40 mg).
Metabolism
Oxymorphone is highly metabolized, principally in the liver, and undergoes reduction or conjugation with glucuronic acid to form both active and inactive products. The two major metabolites of oxymorphone are oxymorphone-3-glucuronide and 6-OH-oxymorphone. The mean plasma AUC for oxymorphone-3-glucuronide is approximately 90-fold higher than the parent compound. The pharmacologic activity of the glucuronide metabolite has not been evaluated. 6-OH-oxymorphone has been shown in animal studies to have analgesic bioactivity. The mean plasma 6-OH-oxymorphone AUC is approximately 70% of the oxymorphone AUC following single oral doses but is essentially equivalent to the parent compound at steady-state.
Excretion
Because oxymorphone is extensively metabolized, <1% of the administered dose is excreted unchanged in the urine. On average, 33% to 38% of the administered dose is excreted in the urine as oxymorphone-3-glucuronide and 0.25% to 0.62% is excreted as 6-OH-oxymorphone in subjects with normal hepatic and renal function. In animals given radiolabeled oxymorphone, approximately 90% of the administered radioactivity was recovered within 5 days of dosing. The majority of oxymorphone-derived radioactivity was found in the urine and feces.
Specific Populations
Age: Geriatric Population
The plasma levels of oxymorphone administered as an extended-release tablet were about 40% higher in elderly (≥65 years of age) than in younger subjects
[see Use in Specific Populations (
8.5
)].
Sex:
The effect of sex on the pharmacokinetics of oxymorphone hydrochloride tablets has not been studied. In a study with an extended-release formulation of oxymorphone, there was a consistent tendency for female subjects to have slightly higher AUC
ssand C
maxvalues than male subjects. However, sex differences were not observed when AUC
ssand C
maxwere adjusted by body weight.
Hepatic Impairment
The liver plays an important role in the pre-systemic clearance of orally administered oxymorphone. Accordingly, the bioavailability of orally administered oxymorphone may be markedly increased in patients with moderate to severe liver disease. The effect of hepatic impairment on the pharmacokinetics of oxymorphone hydrochloride tablets has not been st …
External links
Source: DailyMed — Oxymorphone ↗
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