Oxymorphone

Overview

Oxymorphone (Numorphan®) is an opioid agonist used in dogs and cats as a sedative and analgesic agent. It is effective for the management of moderate to severe pain and has minimal effects on the cardiovascular system. Compared with morphine, oxymorphone causes less histamine release.

One study in dogs and cats found that oxymorphone was comparable to hydromorphone in potency and efficacy for pain control and caused less vomiting than hydromorphone.

Mechanism of Action (MOA): Oxymorphone is a mu-opioid receptor agonist and is approximately 10 times more potent than morphine. Its primary pharmacologic effects are analgesia and sedation, produced by binding to mu-opiate receptors – with activity also described at kappa and delta receptors – and inhibiting the release of neurotransmitters that transmit pain.

Indications

Oxymorphone is used in dogs and cats as a sedative and analgesic agent for the short-term management of moderate to severe pain. It may also be included in anesthetic and sedation protocols as an adjunct to anesthesia.

• Analgesia: Management of moderate to severe pain.
• Sedation: Used alone or in combination with other agents to provide sedation.
• Premedication: Administered as a preanesthetic medication before general anesthesia.

Dosage (Reference)

Dog

Oxymorphone is used in dogs for analgesia, sedation, and as a premedication agent. Doses may be administered alone or in combination with a sedative when additional sedation is required.

Cat

Oxymorphone is used in cats for analgesia, sedation, and as a premedication agent. Doses may be administered alone or in combination with a sedative when additional sedation is required.

Warnings & Precautions

Oxymorphone should be used cautiously in patients with conditions that may increase the risk of respiratory, neurologic, cardiovascular, or gastrointestinal complications.

• Hypersensitivity: Contraindicated in patients with known hypersensitivity to narcotic analgesics.
• Toxic ingestion–associated diarrhea: Contraindicated until the toxin has been eliminated from the gastrointestinal tract.
• Hepatic disease: Severe hepatic disease may prolong the duration of action; use cautiously in affected patients.
• Vomiting risk: Because oxymorphone may cause vomiting, avoid use as a preanesthetic medication in patients with suspected gastric dilation-volvulus, intestinal obstruction, or increased intracerebral or intraocular pressure; pretreatment with maropitant may help prevent vomiting, although this is presumed from data in dogs given hydromorphone.
• Head trauma and neurologic disease: Use extreme caution in patients with head injuries, increased intracranial or intraocular pressure, or acute abdominal conditions, as oxymorphone may obscure the diagnosis or clinical course.
• Respiratory disease: Use with extreme caution in patients with respiratory disease or acute respiratory dysfunction, such as pulmonary edema secondary to smoke inhalation, because respiratory depression may occur.
• Endocrine and renal disorders: Use cautiously in patients with hypothyroidism, severe renal insufficiency, or hypoadrenocorticism.
• Geriatric or debilitated patients: Sensitivity to the effects of oxymorphone, including respiratory depression, is increased in neonatal, debilitated and geriatric patients, and lower doses may be required.
• Seizure disorders: Use cautiously in patients with seizures, as oxymorphone may induce or aggravate seizure activity.
• Hypotension and shock: Use cautiously in hypotensive patients or those in circulatory shock, as decreased cardiac output and blood pressure may occur.
• Bradyarrhythmias: Oxymorphone can cause bradycardia and should be used cautiously in patients with pre-existing bradyarrhythmias.
• Biliary tract disease: Use cautiously in patients with biliary tract impairment, including acute pancreatitis, as sphincter of Oddi spasm may occur.
• Cats: At high doses, concurrent administration with a tranquilizing agent is typically recommended because unpredictable behavioral changes may occur.
• Reduced gut motility: In animals with adynamic ileus, avoid opiates unless specifically indicated; in people, oxymorphone is contraindicated with gastrointestinal obstruction or paralytic ileus.
• Pregnancy and lactation: Opioids cross the placenta and most appear in maternal milk. Oxymorphone given before birth may narcotize newborns, and the effect can be rapidly reversed with naloxone. Because safety has not been established in animals, use only when the maternal benefit outweighs the potential risk to the offspring.
• Controlled substance: In the United States, oxymorphone is a DEA Schedule II (C-II) controlled drug and requires a new written prescription for each refill.
• Human safety: The FDA boxed warning addresses abuse, respiratory depression, neonatal withdrawal syndrome and accidental ingestion by people.
• Scorpion envenomation: Opioid analgesics are contraindicated in patients stung by the scorpions Centruroides sculpturatus Ewing and C gertschi Stahnke, as oxymorphone may potentiate the effect of the venom.

Drug Interactions

Most clinically relevant interactions with oxymorphone involve additive CNS depression, altered analgesic effects, or increased risk of adverse effects. Additional monitoring may be required when used concurrently with the following medications.

• Anticholinergic agents: May increase the risk of urinary retention and constipation.
• Butorphanol, buprenorphine, nalbuphine: May antagonize the effects of oxymorphone.
• Clopidogrel: Oxymorphone may decrease conversion to the active metabolite and reduce antiplatelet effects.
• CNS depressants (e.g., anesthetic agents, antihistamines, barbiturates, gabapentin, phenothiazines, tranquilizers): May increase the risk of CNS and respiratory depression.
• Desmopressin: May increase the risk of water intoxication or hyponatremia.
• Diuretics: May reduce efficacy in patients with congestive heart failure.
• GI prokinetic agents (e.g., cisapride, metoclopramide): Oxymorphone may decrease their effectiveness.
• Magnesium sulfate: May increase the CNS depressant effects of oxymorphone.
• Minocycline (IV): May enhance CNS depressant effects.
• Opioid antagonists (e.g., naloxone, naltrexone): Concurrent use negates opioid effects.
• MAO inhibitors (e.g., amitraz, linezolid, selegiline): Use with extreme caution. Meperidine, a related opioid, is contraindicated in people receiving MAO inhibitors and for at least 14 days afterwards. A study in dogs given selegiline for at least 44 days found no change in the cardiopulmonary response to oxymorphone.
• Skeletal muscle relaxants: Oxymorphone may enhance their effects.
• Phenothiazines (e.g., acepromazine, chlorpromazine): May increase the risk of hypotension and may antagonize analgesic effects.
• Rufinamide: May increase CNS effects, including dizziness and sleepiness.
• Serotonin modulators (e.g., linezolid, methylene blue, metoclopramide, SSRIs, trazodone): May increase serotonin concentrations; monitor for serotonin syndrome.
• Succinylcholine: May enhance opioid-induced bradycardia.
• Tricyclic antidepressants (e.g., amitriptyline, clomipramine): Oxymorphone may exacerbate their effects.
• Warfarin: May potentiate anticoagulant activity.
• Mixing in one syringe: Oxymorphone is physically compatible with acepromazine, atropine, glycopyrrolate and ranitidine, and physically incompatible with barbiturates and diazepam.

Side Effects & Overdose

Side Effects

Oxymorphone has an adverse effect profile similar to hydromorphone and morphine in dogs and cats. Adverse effects are those predictably seen with opioids, and respiratory depression is dose-related.

• Respiratory depression: Dose-related respiratory depression may occur and is more likely during general anesthesia; the respiratory rate may initially rise while oxygenation falls and blood carbon dioxide rises by 10 mm Hg or more.
• Panting: In dogs, panting may occur as a result of changes in thermoregulation, and may be less marked than with hydromorphone but more marked than with morphine.
• Cough suppression: Antitussive effects may occur.
• Bradycardia: May occur secondary to enhanced vagal tone.
• Vomiting: In dogs, vomiting and nausea may occur and are reported more frequently after subcutaneous than after intravenous administration.
• Constipation: May develop due to decreased gastrointestinal motility, and is possible with chronic dosing.
• Urinary retention: May occur because of increased bladder sphincter tone.
• Sedation: A primary pharmacologic effect, and central nervous system depression may be greater than desired.
• High doses in cats: Ataxia, hyperesthesia and behavioral changes such as hyperexcitability or aggression may occur at high doses, and can be unpredictable; concomitant tranquilization is recommended.
• Vocalization and defecation: Both are reported in dogs, alongside vomiting, sedation and panting.
• Other reported effects: Euphoria and confusion are also described, along with peripheral vasodilation, decreased peripheral resistance, baroreceptor inhibition, orthostatic hypotension, syncope and slight decreases in cardiac contractility or blood pressure.
• Tolerance and dependence: Repeated administration over time can lead to tolerance and dependence.

Overdose

Massive overdoses of oxymorphone may result in severe respiratory and central nervous system depression and require immediate supportive care.

• Respiratory depression: May become profound and life-threatening.
• CNS depression: Severe depression of the central nervous system may occur.
• Cardiovascular collapse: May occur in severe overdose cases.
• Hypothermia: Can develop following overdose.
• Skeletal muscle hypotonia: May be observed in severely affected patients.
• Naloxone: Drug of choice for reversal of respiratory depression.
• Monitoring: Patients should be watched closely after naloxone administration, because its effects may wear off before oxymorphone concentrations decline, and the naloxone dose may need to be repeated.
• Respiratory support: Consider mechanical respiratory support in cases of severe respiratory depression.
• Poison control: Consultation with a 24-hour poison control center that gives veterinary-specific information is recommended for a suspected overdose.

Key Notes

Practical clinical points for the use of oxymorphone in dogs and cats:

• Potency: Oxymorphone is approximately 10 times more potent than morphine.
• Cardiovascular effects: Provides analgesia and sedation with minimal effects on the cardiovascular system; in dogs, mean arterial pressure, cardiac output, central venous pressure and systemic vascular resistance were unchanged, while respiratory rate and PaCO2 rose.
• Histamine release: Causes less histamine release than morphine – usually clinically insignificant, though it may matter in critically ill animals; in dogs given a preanesthetic dose, plasma histamine did not rise at all.
• Sedative properties: In dogs, oxymorphone alone provides good sedation at usual clinical doses.
• Hydromorphone comparison: One clinical study in dogs and cats found comparable analgesic potency and efficacy to hydromorphone, with significantly less vomiting. Separately, at the doses used in a feline thermal-threshold study, intravenous hydromorphone produced transient thermal antinociception, whereas intravenous oxymorphone did not produce significant thermal antinociception.
• Epidural administration: Use of a preservative-free product is recommended for epidural administration, and oxymorphone is absorbed systemically from the epidural space more readily than morphine.
• Availability: Manufacture of the injection stopped in 2017 and there is no veterinary-labeled product; it is described as no longer commercially available in the US, and hydromorphone is a commonly used alternative.
• Onset and duration: After 0.1 mg/kg intramuscularly in dogs, onset is 15 minutes and the effect lasts 2 to 4 hours, so frequent administration is needed for continuing pain.
• Pharmacokinetics in dogs: The half-life is 0.8 hours after intravenous and 1 hour after subcutaneous administration, with clearance above 50 mL/kg/min; a high first-pass effect makes oral administration ineffective.
• Metabolism and excretion: Oxymorphone concentrates in the kidneys, liver and lungs with lower concentrations in the central nervous system; it is metabolized in the liver primarily by glucuronidation and excreted by the kidneys.
• Rectal route: Oxymorphone is bioavailable after intramuscular, subcutaneous and rectal administration, but the references give no rectal dose for dogs or cats.
• Pharmacokinetics in cats: The steady-state volume of distribution is 2.5 L/kg, clearance is 26 mL/minute/kg and the elimination half-life is 1.6 to 1.7 hours; bioavailability after buccal administration is 17%.
• Buccal route in cats: In cats, 0.1 mg/kg intravenously and 0.25 mg/kg buccally did not cause significant thermal antinociception, although the authors state the result does not predict usefulness in clinical patients.
• Monitoring: Follow respiratory rate and depth, level of central nervous system depression or excitation, blood pressure (especially with intravenous use), analgesia and cardiac rate.
• Laboratory interference: Opioids can raise plasma amylase and lipase for up to 24 hours after administration, and quinolones may cause a false positive on urine screening tests for oxymorphone.
• Storage: Protect vials from light, keep them at 15°C to 30°C and avoid freezing.
• Anesthetic sparing: Giving oxymorphone may lower the dose requirement for other anesthetics and analgesics, and it is compatible with most anesthetics as part of a multimodal protocol.