Quartette

**Generic name:**
Butalbital, Acetaminophen, Caffeine, Codeine Phosphate

**Drug class:**
Combination analgesic; barbiturate derivative; opioid analgesic; adjuvant caffeine

**Dosage form:**
Capsules (butalbital 50 mg / acetaminophen 300 mg / caffeine 40 mg / codeine phosphate 30 mg)

**Root of administration:**
Oral

**Dose:**
Typical adult dose: 1–2 capsules every 4 hours as needed for pain relief; do not exceed 6 capsules in 24 hours
Pediatric use: not recommended for children under 12 years; use with caution (risk of respiratory depression)

**Mechanism of action:**
Butalbital produces CNS depression by enhancing GABAergic transmission; acetaminophen provides analgesia and antipyresis via central COX inhibition; caffeine acts as a vasoconstrictor and adenosine receptor antagonist to enhance analgesic efficacy; codeine is metabolized to morphine and exerts mu-opioid receptor agonism, reducing pain transmission

**Drug usage cases:**
– Tension‐type headache
– Migraine headache
– Muscular headache
– Off-label: rebound headache prevention (with caution)
– Off-label: cluster headache adjunctive therapy (limited evidence)

**Drug contra indications:**
– Hypersensitivity to any component (butalbital, acetaminophen, caffeine, codeine)
– Significant respiratory depression or acute asthma
– Porphyria
– Severe hepatic impairment or active liver disease
– Concurrent monoamine oxidase inhibitors (or within 14 days)
– Severe CNS depression or severe hypotension
– Known or suspected gastrointestinal obstruction, including paralytic ileus
– Patients with a history of substance use disorder (opioids or barbiturates)

**Side effects:**
– Drowsiness, sedation, dizziness
– Nausea, vomiting
– Constipation
– Lightheadedness
– Euphoria or dysphoria
– Dependence, tolerance, withdrawal symptoms
– Respiratory depression (dose-related)
– Hypotension, bradycardia (rare)
– Hepatotoxicity (with excessive acetaminophen or chronic use)
– Urinary retention
– Headache rebound or medication overuse headache

**Warnings:**
– Risk of abuse, addiction, and misuse; assess patient risk prior to prescribing
– Monitor for signs of respiratory depression, especially in opioid-naïve patients
– Avoid alcohol and other CNS depressants concurrently
– Limit total daily acetaminophen to ≤ 4 g to reduce hepatotoxicity risk
– Use caution in elderly or debilitated patients; reduce dose if needed
– Sudden discontinuation may precipitate withdrawal; taper gradually
– Risk of medication‐overuse headache with frequent use (> 3 days/week)
– Contains codeine; genetic variability in CYP2D6 metabolism may lead to higher morphine levels
– May cause orthostatic hypotension; advise patients to rise slowly

**Use during pregnancy or breastfeeding:**
Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Chronic use in pregnancy may lead to neonatal opioid withdrawal syndrome. Butalbital and codeine cross the placenta. Acetaminophen is generally considered safer but high doses risk hepatotoxicity. Breastfeeding is not recommended during treatment due to risk of opioid‐induced sedation and respiratory depression in the neonate; if used, monitor infant for signs of excessive drowsiness and breathing difficulties.