Usage
- Milnacipran is prescribed for the management of fibromyalgia in adults.
- Pharmacological classification: Serotonin-Norepinephrine Reuptake Inhibitor (SNRI).
- Mechanism of Action: Milnacipran increases the levels of both serotonin and norepinephrine in the brain by inhibiting their reuptake at nerve terminals. This action is believed to contribute to its analgesic and mood-improving effects in fibromyalgia.
Alternate Names
- International Nonproprietary Name (INN): Milnacipran
- Brand names: Savella
How It Works
- Pharmacodynamics: Milnacipran’s primary effect is to increase the synaptic concentrations of serotonin and norepinephrine, neurotransmitters involved in pain signaling and mood regulation. The precise mechanism by which this alleviates fibromyalgia symptoms is not fully understood but it is believed that altered pain processing in the central nervous system is a major factor.
- Pharmacokinetics:
- Absorption: Milnacipran is well-absorbed after oral administration, with peak plasma concentrations reached within 2-3 hours. Food intake may slightly delay absorption but does not significantly affect overall bioavailability.
- Metabolism: Milnacipran undergoes extensive metabolism in the liver, primarily via conjugation. Cytochrome P450 enzymes play a minor role in its metabolism.
- Elimination: Milnacipran is primarily eliminated through renal excretion, with a small portion excreted in the feces. The elimination half-life is approximately 8 hours, which supports twice-daily dosing.
- Mode of Action: Milnacipran inhibits the reuptake transporters for serotonin and norepinephrine, increasing their availability in the synaptic cleft. This leads to enhanced neurotransmission in pathways relevant to pain modulation and mood.
- Receptor binding, enzyme inhibition, or neurotransmitter modulation: Primarily inhibits serotonin and norepinephrine reuptake transporters. It has a three-fold higher selectivity for norepinephrine reuptake inhibition compared to serotonin.
- Elimination pathways: Predominantly renal excretion of unchanged drug and metabolites.
Dosage
Standard Dosage
Adults:
- Initial: 12.5 mg orally once daily on day 1.
- Days 2-3: 12.5 mg orally twice daily.
- Days 4-7: 25 mg orally twice daily.
- Maintenance: 50 mg orally twice daily.
- Maximum: 200 mg orally per day (100 mg twice daily) if tolerated.
- Administration: Oral, with or without food. Food intake may improve tolerability.
Children:
- Safety and efficacy not established in patients younger than 18 years. Not recommended for pediatric use.
Special Cases:
- Elderly Patients: Renal function should be assessed prior to initiation. Consider lower starting doses due to age-related decline in renal function. Monitor for hyponatremia.
- Patients with Renal Impairment:
- Mild (CrCl 50-80 mL/min): No dosage adjustment necessary.
- Moderate (CrCl 30-49 mL/min): Use with caution.
- Severe (CrCl 5-29 mL/min): Reduce maintenance dose by 50% (25 mg twice daily). May increase to 50 mg twice daily if tolerated.
- End-stage renal disease (ESRD): Not recommended.
- Patients with Hepatic Dysfunction:
- Mild to moderate impairment: No adjustment required.
- Severe impairment: Use with caution.
- Patients with Comorbid Conditions: Caution should be exercised in patients with uncontrolled narrow-angle glaucoma, hypertension, cardiovascular disease, or seizure disorders. Monitor blood pressure and heart rate regularly.
Clinical Use Cases
Milnacipran is specifically indicated for fibromyalgia management. It is not indicated for other clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
- Renal and hepatic impairment: As described above.
- Co-administration with CYP450 inhibitors or inducers: Close monitoring for adverse events and dose adjustments based on clinical response.
Side Effects
Common Side Effects
- Nausea, headache, constipation, dizziness, insomnia, hot flashes, increased sweating, vomiting, palpitations, increased heart rate, dry mouth, hypertension.
Rare but Serious Side Effects
- Serotonin syndrome, suicidal thoughts/behavior (especially in young adults), neuroleptic malignant syndrome-like reactions, hyponatremia (especially in elderly), severe allergic reactions, seizures, hepatotoxicity, abnormal bleeding (especially with concomitant use of anticoagulants or NSAIDs), angle-closure glaucoma (in predisposed individuals).
Long-Term Effects
- Potential for withdrawal symptoms upon discontinuation after prolonged use. Tapering is recommended.
Adverse Drug Reactions (ADR)
- Serotonin syndrome, neuroleptic malignant syndrome-like reactions, suicidal thoughts/behavior, severe allergic reactions, hepatotoxicity.
Contraindications
- Concurrent or recent (within 14 days) use of MAOIs.
- Concurrent use of linezolid or intravenous methylene blue.
- Uncontrolled narrow-angle glaucoma.
Drug Interactions
- MAOIs: Contraindicated due to the risk of serotonin syndrome and hypertensive crisis.
- Serotonergic drugs (e.g., SSRIs, SNRIs, triptans, tricyclic antidepressants, buspirone, fentanyl, lithium, tramadol, tryptophan, St. John’s wort): Increased risk of serotonin syndrome.
- Drugs that impair serotonin metabolism (e.g., linezolid, methylene blue): Increased risk of serotonin syndrome.
- Drugs that affect blood pressure or heart rate: Caution advised as milnacipran can cause hypertension and tachycardia.
- CYP450 interactions: Limited potential.
- Alcohol: Moderate consumption is advised.
- Anticoagulants/NSAIDs: Increased risk of bleeding.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: C. Use only if the potential benefit outweighs the risk to the fetus. Neonates exposed in the third trimester may experience withdrawal symptoms or serotonin syndrome.
- Breastfeeding: Milnacipran is present in breast milk. Caution is advised, especially when nursing a newborn or preterm infant. Consider the risks and benefits.
Drug Profile Summary
- Mechanism of Action: SNRI - Inhibits serotonin and norepinephrine reuptake.
- Side Effects: Nausea, headache, constipation, dizziness, insomnia, serotonin syndrome (rare), suicidal thoughts.
- Contraindications: MAOIs, linezolid, intravenous methylene blue, uncontrolled narrow-angle glaucoma.
- Drug Interactions: MAOIs, serotonergic drugs, alcohol.
- Pregnancy & Breastfeeding: Category C, caution advised.
- Dosage: 100 mg/day (50 mg twice daily), titrated up to 200 mg/day if needed.
- Monitoring Parameters: Blood pressure, heart rate, liver function tests, symptoms of serotonin syndrome and suicidal ideation.
Popular Combinations
Milnacipran is not typically used in combination with other drugs for fibromyalgia. Co-administration with other serotonergic agents should be approached with caution due to the risk of serotonin syndrome.
Precautions
- General Precautions: Monitor blood pressure, heart rate, liver enzymes, and mental status. Screen for suicidal ideation.
- Specific Populations: As outlined above.
- Lifestyle Considerations: Advise patients to avoid or limit alcohol consumption.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Milnacipran?
A: The recommended starting dose is 12.5 mg once daily, gradually increasing to a maintenance dose of 100 mg/day (50 mg twice daily). The maximum dose is 200 mg/day. Dosage adjustments may be necessary for patients with renal impairment.
Q2: How does Milnacipran work for fibromyalgia?
A: Milnacipran increases serotonin and norepinephrine levels, which are believed to play a role in pain processing and mood regulation, although the exact mechanism in fibromyalgia isn’t fully understood.
Q3: What are the most common side effects of Milnacipran?
A: The most common side effects include nausea, headache, constipation, dizziness, dry mouth, insomnia, increased sweating and palpitations.
Q4: Is Milnacipran safe to take during pregnancy or breastfeeding?
A: Milnacipran is a Pregnancy Category C drug. Use only if the benefit clearly outweighs the risk. Caution is advised during breastfeeding.
Q5: What are the serious side effects I should be aware of?
A: Serious side effects can include serotonin syndrome, neuroleptic malignant syndrome, suicidal thoughts, allergic reactions, seizures and liver problems.
Q6: What drugs should not be taken with Milnacipran?
A: MAOIs are contraindicated. Concomitant use of other serotonergic drugs or drugs that impair serotonin metabolism should be approached with caution.
Q7: Can Milnacipran be used to treat depression?
A: While Milnacipran is an SNRI like many antidepressants, it is not currently approved for the treatment of major depressive disorder. It’s specifically indicated for fibromyalgia management.
Q8: How long does it take for Milnacipran to start working?
A: Some patients may experience improvement within a few weeks, but it can take up to several months for the full effects to be realized.
Q9: What should I do if I miss a dose of Milnacipran?
A: Take the missed dose as soon as you remember. If it is close to the time for your next dose, skip the missed dose and return to your regular schedule. Do not take a double dose to make up for a missed one.
Q10: What are the symptoms of Milnacipran withdrawal?
A: Withdrawal symptoms can include nausea, dizziness, headache, irritability, anxiety, and insomnia. It is important to taper off the drug slowly under medical supervision to minimize these effects.
