Oxycodone and naltrexone

Uses

Naltrexone is used for the treatment of alcohol dependence and for the blockade of the effects of exogenously administered opioids. Naltrexone has not been shown to provide any therapeutic benefit except as part of an appropriate plan of management for the addictions.

Oxycodone is an opioid used in the management of moderate to severe pain.

Oxycodone is indicated for the treatment of moderate to severe pain. There is also an extended release formulation indicated for chronic moderate to severe pain requiring continuous opioid analgesics for an extended period.

Oxycodone and naltrexone is also used to associated treatment for these conditions: Alcohol Dependency, BMI >30 kg/m2, Cholestatic pruritus, Opioid Dependence, Severe PainSevere Pain, Severe, Chronic Pain, Acute, moderate Pain, Acute, severe Pain, Chronic, moderate Pain

How Oxycodone and naltrexone works

Naltrexone is a pure opiate antagonist and has little or no agonist activity. The mechanism of action of naltrexone in alcoholism is not understood; however, involvement of the endogenous opioid system is suggested by preclinical data. Naltrexone is thought to act as a competitive antagonist at mc, κ, and δ receptors in the CNS, with the highest affintiy for the μ receptor. Naltrexone competitively binds to such receptors and may block the effects of endogenous opioids. This leads to the antagonization of most of the subjective and objective effects of opiates, including respiratory depression, miosis, euphoria, and drug craving. The major metabolite of naltrexone, 6-β-naltrexol, is also an opiate antagonist and may contribute to the antagonistic activity of the drug.

The full mechanism of oxycodone is not known. Under conditions of inflammation or hyperalgesia, opioid receptors in the heart, lungs, liver, gastrointestinal tract, and reproductive system are upregulated and transported to nerve terminals. Oxycodone and its active metabolites, noroxycodone, oxymorphone, and noroxymorphone are opioid agonists. These compounds passively diffuse across the blood brain barrier or may be actively transported across by an unknown mechanism. Oxycodone and its active metabolites can selectively bind to the mu opioid receptor, but also the kappa and delta opioid receptors in the central nervous system and periphery, and induce a G protein coupled receptor signalling pathway. Activation of mu opioid receptors inhibits N-type voltage operated calcium channels, inhibiting responses to pain.

Dosage

Oxycodone and naltrexone dosage

Opioid dependence:

• Initially:25 mg; increase to 50 mg daily if no withdrawal signs occur.
• Maintenance: 350 mg wkly given as 50 mg daily or divided in 3 doses (given on 3 days of the wk) for improved compliance.

Adjunct in alcohol dependence: 50 mg daily.

Side Effects

Abdominal pain, nausea, vomiting; anxiety, insomnia, lethargy, headache, musculoskeletal pain; anorexia, diarrhoea, constipation; increased thirst; chest pain; chills, dizziness; sexual dysfunction; rash, liver function abnormalities and reversible idiopathic thrombocytopenia. Inj-site reactions.

Toxicity

In the mouse, rat and guinea pig, the oral LD₅₀s were 1,100-1,550 mg/kg; 1,450 mg/kg; and 1,490 mg/kg; respectively. High doses of naltrexone (generally >1,000 mg/kg) produce salivation, depression/reduced activity, tremors, and convulsions.

Patients experiencing an overdose may present with respiratory depression, sleepiness, stupor, coma, skeletal muscle flaccidity, cold sweat, constricted pupils, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Overdose should be treated by maintaining airway, ventilation, and oxygenation. Oxygen and vasopressor treatment may be necessary to treat circulatory shock and pulmonary edema and defibrillation may be required for cardiac arrest of arrhythmia. Naloxone, nalmefene, or naltrexone may be used to counteract the effects of opioids but patients should be monitored in case further doses are required.

The intraperitoneal LD50 in mice is 320mg/kg, the oral LD50 is 426mg/kg. The oral lowest dose causing toxic effects in humans is 0.14mg/kg and subcutaneously in rats it is 1.53mg/kg.

Oxycodone is pregnancy category B according to the FDA. There is a paucity of data regarding oxycodone use in pregnancy, though animal studies show no teratogenic effects. Rats given oxycodone during lactation showed smaller offspring, though after lactation, they recovered to normal size. Oxycodone is excreted in breast milk and so patients should not breastfeed while taking oxycodone due to risk of sedation and respiratory depression in infants.

No studies on the carcinogenicity of oxycodone have been performed. Oxycodone was genotoxic at 50mcg/mL with metabolic activation and at 400mcg/mL without. It was also clastogenic with metabolic activation at ≥1250mcg/mL. Oxycodone was not found to be genotoxic in other tests. Oxycodone does not affect reproduction and fertility in rats at doses of up to 8mg/kg/day.

Precaution

Hepatic or renal impairment. Monitor LFTs regularly. Patients should be opioid-free for at least 7-10 days prior to initiating naltrexone therapy. Strictly warn patients against the use of opioids while on naltrexone. Monitor for inj-site reactions. Pregnancy, lactation. History of bleeding disorders (including thrombocytopenia).

Interaction

May reduce effects of opiate-containing preparations e.g. those used for cough and cold, diarrhoea and pain. Increased or decreased serum levels with drugs that alter hepatic metabolism. Potentially increased hepatotoxic effects with disulfiram. Increased risk of naltrexone-induced lethargy and somnolence with thioridazine. May increase insulin requirements.

Volume of Distribution

• 1350 L [intravenous administration]

2.6L/kg.

Elimination Route

Although well absorbed orally, naltrexone is subject to significant first pass metabolism with oral bioavailability estimates ranging from 5 to 40%.

Oxycodone has an oral bioavailability of 60% to 87% that is unaffected by food.

The area under the curve is 135ng/mL*hr, maximum plasma concentration is 11.5ng/mL, and time to maximum concentration is 5.11hr in patients given a 10mg oral immediate release dose of oxycodone.

Half Life

4 hours for naltrexone and 13 hours for the active metabolite 6 beta-naltrexol.

The apparent elimination half life of oxycodone is 3.2 hours for immediate release formulations and 4.5 hours for extended release formulations. Noroxycodone has a half life of 5.8 hours, oxymorphone has a half life of 8.8 hours, noroxymorphone has a half life of 9 hours.

Clearance

• ~ 3.5 L/min [after IV administration]

Total plasma clearance is 1.4L/min in adults.

Elimination Route

Both parent drug and metabolites are excreted primarily by the kidney (53% to 79% of the dose), however, urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose and fecal excretion is a minor elimination pathway. The renal clearance for naltrexone ranges from 30 to 127 mL/min and suggests that renal elimination is primarily by glomerular filtration.

Oxycodone and its metabolites are eliminated in the urine. Unbound noroxycodone makes up 23% of the dose recovered in urine and oxymorphone makes up Label Conjugated oxymorphone makes up 10% of the recovered dose. Free and conjugated oxycodone makes up 8.9% of the recovered dose, noroxymorphone makes up 14%, and reduced metabolites make up 18%.

Pregnancy & Breastfeeding use

Pregnancy Category C. Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Contraindication

Patients concurrently dependent on opioids; acute hepatitis or hepatic failure; acute opioid withdrawal; patients on therapeutic opioid analgesics.

Acute Overdose

Symptoms: Clonic-tonic convulsions and respiratory failure.

Management: Supportive and symptomatic.

Storage Condition

Store at 20-25° C.

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