Metamizole

Usage

Metamizole, a non-narcotic analgesic, antipyretic, and spasmolytic, is prescribed for moderate to severe acute pain and fever, including postoperative pain, renal colic, and headache. It has weak anti-inflammatory properties and does not belong to the NSAID class, although often grouped with them. Its pharmacological classifications include pyrazolone, analgesic, antipyretic, and spasmolytic.

Metamizole’s mechanism of action involves inhibiting prostaglandin synthesis, primarily through a combination of cyclooxygenase (COX)-1 and COX-2 inhibition as well as COX-3 inhibition and potentially via cannabinoid receptors. However, the exact mechanism is not fully understood. It also appears to affect the endogenous opioid system.

Alternate Names

Metamizole is also known as dipyrone, noramidopyrine, and metamizol. Brand names include Novalgin, Optalgin, Analgin, Baralgin, and others.

How It Works

Pharmacodynamics: Metamizole reduces pain by inhibiting prostaglandin synthesis in the central nervous system. It lowers fever by acting on the hypothalamic heat-regulating center. Its spasmolytic action is exerted on smooth muscle, relieving spasms.

Pharmacokinetics:

• Absorption: Rapidly and almost completely absorbed after oral administration. The active metabolite, 4-methyl-amino-antipyrine (MAA), reaches peak plasma concentration approximately 1 hour after oral intake.
• Metabolism: Metabolized in the liver to several metabolites, including 4-methyl-amino-antipyrine (MAA) and 4-formyl-amino-antipyrine (FAA). MAA is the primary active metabolite.
• Elimination: Excreted mainly via the kidneys (around 90%, mostly as metabolites) and to a lesser extent in feces (about 10%).

Mode of Action: Primarily inhibits prostaglandin synthesis through a combination of COX-1, COX-2, and potentially COX-3 enzyme inhibition, but exact mechanism isn’t fully elucidated. It may also involve the endogenous cannabinoid and opioid systems.

Receptor Binding/Enzyme Inhibition: Inhibits COX-1, COX-2, and potentially COX-3 enzymes and possibly TRPA1 channels. Potential interaction with the cannabinoid and opioid systems.

Elimination Pathways: Primarily renal excretion (about 90% as metabolites). Minor elimination through feces (about 10%).

Dosage

Standard Dosage

Adults:

• Oral: 500-1000 mg every 6-8 hours, with a maximum daily dose of 4000 mg.
• Intravenous/Intramuscular: 500-1000 mg every 6-8 hours, with a maximum daily dose not exceeding 5000 mg (slow intravenous injection over 5 minutes or via IM injection).

Children:

• Oral: 8-16 mg/kg body weight every 6-8 hours. Use age-appropriate formulations like oral drops or solutions.
• Pediatric safety: Monitor carefully, especially for agranulocytosis. Not recommended for children less than 3 months or weighing less than 5 kg.

Special Cases:

• Elderly Patients: Start with lower doses and titrate cautiously. Monitor renal function.
• Patients with Renal Impairment: Dose reduction may be required. Monitor closely. Contraindicated in severe renal impairment.
• Patients with Hepatic Dysfunction: Use with caution and at lower doses. Monitor liver function. Contraindicated in severe hepatic impairment.
• Patients with Comorbid Conditions: Adjust dose according to individual needs and associated conditions like cardiovascular disease.

Clinical Use Cases

The use of metamizole in these clinical settings should be approached with caution due to its potential side effects, particularly agranulocytosis. Alternative analgesics should be considered whenever possible. If metamizole is used:

• Intubation/Surgical Procedures/Mechanical Ventilation/ICU Use: IV administration is preferred, following the adult dosage guidelines (500-1000 mg every 6-8 hours, not to exceed 5000 mg daily).
• Emergency Situations: IV administration is recommended, following adult guidelines.

Dosage Adjustments

Adjust dosage based on individual patient factors such as renal or hepatic impairment, age, and other medical conditions. Genetic polymorphisms affecting drug metabolism should be taken into account if known.

Side Effects

Common Side Effects

• Nausea, vomiting
• Dizziness, vertigo
• Rash
• Hypotension

Rare but Serious Side Effects

• Agranulocytosis
• Aplastic anemia
• Anaphylaxis
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Acute kidney injury
• Liver dysfunction

Long-Term Effects

Chronic complications are rare, but long-term use increases the risk of blood disorders.

Adverse Drug Reactions (ADR)

Agranulocytosis, aplastic anemia, anaphylactic shock, and severe skin reactions require immediate intervention.

Contraindications

• Hypersensitivity to metamizole or other pyrazolone derivatives.
• History of agranulocytosis or blood dyscrasias.
• Acute intermittent porphyria.
• Glucose-6-phosphate dehydrogenase deficiency.
• Severe hepatic or renal impairment.
• Third trimester of pregnancy and breastfeeding.
• Children under 3 months of age or weighing less than 5 kg.

Drug Interactions

• Anticoagulants/Antiplatelets: Increased bleeding risk.
• Antihypertensives: Enhanced hypotensive effect.
• Chlorpromazine: Severe hypothermia.
• Cyclosporine: Reduced cyclosporine levels.
• Methotrexate: Increased myelosuppression.
• Oral contraceptives, MAOIs, Allopurinol: Enhanced metamizole effects.
• Barbiturates, Glutethimide, Phenylbutazone: Reduced metamizole efficacy.
• Alcohol: May potentiate side effects.

Pregnancy and Breastfeeding

• Pregnancy: Contraindicated during the third trimester due to risk of renal impairment and premature closure of the ductus arteriosus in the fetus. Use with caution in the first and second trimesters.
• Breastfeeding: Contraindicated as metamizole is excreted in breast milk and can cause adverse effects in infants.

Drug Profile Summary

• Mechanism of Action: Inhibits prostaglandin synthesis (COX-1, COX-2, potentially COX-3), possible involvement of opioid and cannabinoid systems.
• Side Effects: Nausea, vomiting, dizziness, rash, hypotension, rarely agranulocytosis, aplastic anemia.
• Contraindications: Hypersensitivity, blood dyscrasias, porphyria, G6PD deficiency, severe liver/kidney disease, third-trimester pregnancy, breastfeeding.
• Drug Interactions: Anticoagulants, antihypertensives, chlorpromazine, cyclosporine.
• Pregnancy & Breastfeeding: Contraindicated in third trimester and during breastfeeding.
• Dosage: Adults: 500-1000 mg every 6-8 hours (max 4000 mg/day oral, 5000mg/day IV/IM); Children: 8-16 mg/kg/dose every 6-8 hours.
• Monitoring Parameters: Complete blood count (if symptoms suggestive of blood disorders occur), renal function, and liver function if used long-term or at higher doses.

Popular Combinations

Metamizole is sometimes combined with opioids or other analgesics for increased pain relief. Combinations must be used cautiously due to potential interactions and additive side effects.

Precautions

• Screen for allergies, blood disorders, liver/kidney dysfunction before initiating treatment.
• Pregnant Women: Avoid use during the third trimester. Exercise caution in other trimesters.
• Breastfeeding Mothers: Contraindicated.
• Children & Elderly: Start with lower doses and monitor closely.
• Lifestyle Considerations: Avoid alcohol, monitor for signs of blood disorders.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Metamizole?

A: Adults: 500-1000 mg every 6-8 hours, max 4000 mg/day oral or 5000mg/day IV/IM. Children: 8-16 mg/kg/dose every 6-8 hours. Adjust for renal/hepatic impairment.

Q2: What are the serious side effects of Metamizole?

A: Agranulocytosis, aplastic anemia, anaphylaxis, severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis).

Q3: Is Metamizole safe during pregnancy?

A: Contraindicated in the third trimester. Caution advised in other trimesters.

Q4: Can Metamizole be used in patients with kidney disease?

A: Use with caution and dose adjustment in mild to moderate impairment. Contraindicated in severe renal dysfunction.

Q5: What are the common drug interactions with Metamizole?

A: Anticoagulants, antihypertensives, chlorpromazine, cyclosporine, methotrexate.

Q6: How does Metamizole work?

A: Primarily by inhibiting prostaglandin synthesis; exact mechanism not fully understood but involves COX-1 and COX-2 inhibition, possibly COX-3 inhibition and also involves endogenous cannabinoid and opioid systems.

Q7: What should patients be advised regarding Metamizole use?

A: Report any signs of infection (fever, sore throat), unusual bleeding or bruising, allergic reactions. Avoid alcohol.

Q8: What are the alternatives to Metamizole for pain and fever management?

A: Other analgesics (paracetamol, ibuprofen, opioids), depending on the cause and severity of the pain or fever.

Q9: Is Metamizole available worldwide?

A: Banned in some countries (e.g., US, UK, Japan). Available in others under various brand names.