Morphine and naltrexone

Uses

This medication is used to help relieve moderate to severe pain. Morphine belongs to a class of drugs known as opioid (narcotic) analgesics. It works in the brain to change how your body feels and responds to pain.

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.

Morphine and naltrexone is also used to associated treatment for these conditions: Pain, Chronic, Severe PainAlcohol Dependency, BMI >30 kg/m2, Cholestatic pruritus, Opioid Dependence, Severe Pain

How Morphine and naltrexone works

Morphine-6-glucuronide is responsible for approximately 85% of the response observed by morphine administration. Morphine and its metabolites act as agonists of the mu and kappa opioid receptors. The mu-opioid receptor is integral to morphine's effects on the ventral tegmental area of the brain. Morphine's activation of the reward pathway is mediated by agonism of the delta-opioid receptor in the nucleus accumbens, while modification of the respiratory system and addiction disorder are mediated by agonism of the mu-opioid receptor.

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.

Dosage

Morphine and naltrexone dosage

Oral-Moderate to severe pain:5-20 mg 4 hrly. Extended-release: 5-20 mg 12 hrly. Dosage is dependent on the severity of pain.

Intraspinal-Moderate to severe pain:Initially, 5 mg epidural inj; after 1 hr, additional doses of 1-2 mg may be given up to a total dose of 10 mg/24 hr if pain relief is unsatisfactory. A dose of 20-30 mg daily may be required in some patients. Liposomal inj: 10-20 mg depending on the type of surgery.

Intrathecal-Moderate to severe pain: 0.2-1 mg once daily or 1-10 mg daily for patients with opioid tolerance. Some patients may require a dose of up to 20 mg daily.

Intravenous-Acute pulmonary oedema:

• Adult: 5-10 mg via slow inj at 2 mg/min.
• Elderly: Half of the usual adult dose.

Intravenous-

Pain associated with myocardial infarction:

• Adult: 5-10 mg at 1-2 mg/min followed by a further 5-10 mg as necessary.
• Elderly: Half of the usual adult dose.

Parenteral-

• Moderate to severe pain:5-20 mg; 2.5-10 mg via slow IV inj over 4-5 min with patient in recumbent position or a starting dose of 1-2 mg/hr via continuous IV infusion (max: 100 mg/day; 4 g/day in cancer patients). Doses may be adjusted according to severity of pain and patient's response.
• Premedication in surgery:Up to 10 mg, given 60-90 min before operation.

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.

May be taken with or without food. May be taken with meals to reduce GI discomfort.

Side Effects

Nausea, vomiting, constipation, abdominal pain, dry mouth, anorexia, taste disturbance, dyspepsia, resp depression, sedation, dizziness, confusion, insomnia, headache, somnolence, involuntary muscle contractions, hyperhidrosis, rash, pruritus, asthenic conditions, HTN, bronchospasm, seizures, amenorrhoea, rhabdomyolysis, nystagmus.

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

The LD₅₀ is 0.78µg/mL in males and 0.98µg/mL in females.

Patients experiencing an overdose present with respiratory depression, somnolence, skeletal muscle flaccidity, cold and clammy skin, miosis, and mydriasis. Symptoms of overdose can progress to pulmonary edema, bradycardia, hypotension, cardiac arrest, and death. Treat overdose with symptomatic and supportive treatment which may include the use of oxygen, vasopressors, and naloxone.

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.

Precaution

Patient with impaired resp function, severe bronchial asthma, convulsive disorders, acute alcoholism, delirium tremens, raised intracranial pressure, hypotension with hypovolaemia, cardiac arrhythmias, severe cor pulmonale, history of substance abuse, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, prostatic hypertrophy, adrenocortical insufficiency, toxic psychoses. Opioid dependent patients. Renal and hepatic impairment. Pregnancy and lactation.

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

Additive depressant effects with other CNS depressants (e.g. sedatives, hypnotics, general anaesth, phenothiazines, other tranquilisers). May enhance the neuromuscular blocking action of skeletal muscle relaxants. Reduced analgesic effect with mixed agonist/antagonist opioid analgesics (e.g. pentazocine, nalbuphine, buprenorphine). Increased plasma concentrations with cimetidine. May reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. May delay the absorption of mexiletine. May antagonise the GI effect of cisapride, domperidone and metoclopramide. May produce hyperpyrexia and CNS toxicity with dopaminergics.

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

The volume of distribution of morphine is 5.31L/kg. Morphine-6-glucuronide has a volume of distribution of 3.61L/kg.

• 1350 L [intravenous administration]

Elimination Route

Morphine is absorbed in the alkaline environments of the upper intestine and rectal mucosa. The bioavailability of morphine is 80-100%. There is significant first-pass metabolism, therefore oral doses are 6 times larger than parenteral doses to achieve the same effect. Morphine reaches steady-state concentrations after 24-48 hours. Parenteral morphine has a T_max of 15 minutes and oral morphine has a T_max of 90 minutes, with a C_max of 283nmol/L. The AUC of morphine is 225-290nmol*h/L.

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

Half Life

Morphine has a half life of 2-3 hours.

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

Clearance

The apparent clearance of intravenous or subcutaneous morphine is 1600 mL/min.

• ~ 3.5 L/min [after IV administration]

Elimination Route

70-80% of an administered dose is excreted within 48 hours. Morphine is predominantly eliminated in the urine with 2-10% of a dose recovered as the unchanged parent drug. 7-10% of a dose of morphine is eliminated in the feces.

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.

Pregnancy & Breastfeeding use

Parenteral or oral: C, D (if prolonged use/high doses at term)

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

Resp depression, obstructive airway disease, delayed gastric emptying, acute abdomen, heart failure secondary to chronic lung disease, known or suspected paralytic ileus, phaeochromocytoma. Concurrent admin with MAOIs or within 2 wk after treatment.

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

Special Warning

Renal Impairment: Dosage may need to be reduced.

Hepatic Impairment: Dosage may need to be reduced.

Acute Overdose

Symptoms: Resp depression, pinpoint pupils, extreme somnolence progressing to stupor and coma, skeletal muscle flaccidity, cold and clammy skin and sometimes bradycardia and hypotension. Apnoea, circulatory collapse, and cardiac arrest may occur in severe cases.

Management: Re-establish adequate resp exchange through provision of a patent airway and institution of assisted or controlled ventilation. Oxygen, IV fluid, vasopressors and other supportive measures may be employed as necessary. Naloxone may be given as antidote.

Symptoms: Clonic-tonic convulsions and respiratory failure.

Management: Supportive and symptomatic.

Storage Condition

Inj/oral preparations: Store between 15-30°C. Liposomal inj: Store between 2-8°C. Supp: Store below 25°C. Protect from light.

Store at 20-25° C.

Innovators Monograph

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