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Sunday, July 27, 2025

Ibuprofen and codeine


Generic Combination: Ibuprofen + Codeine phosphate


Pharmacological Classes
– Ibuprofen: Nonsteroidal anti-inflammatory drug (NSAID)
– Codeine: Opioid analgesic (a weak µ-opioid receptor agonist)


ATC Code: M01AE51
Legal Status: Prescription-only in many countries; OTC in limited low-dose preparations in select regions (e.g., UK: 200 mg ibuprofen + 12.8 mg codeine)


Common Brand Names: Nurofen Plus, Brufen Plus, Ibucod, Neurofen Plus, Cuprofen Plus, Panacod, Advil Plus (varies by country)

Mechanism of Action

This combination leverages the complementary mechanisms of two analgesics:

  1. Ibuprofen: Inhibits cyclooxygenase enzymes (COX-1 and COX-2), reducing prostaglandin synthesis involved in inflammation, fever, and pain signaling. Provides anti-inflammatory, analgesic, and antipyretic effects.

  2. Codeine phosphate: A prodrug converted in the liver to morphine via CYP2D6. Morphine acts on the µ-opioid receptors in the central nervous system, altering the perception and emotional response to pain.

When used together, ibuprofen targets the inflammatory source of pain, while codeine modulates the brain’s perception of that pain, resulting in additive or sometimes synergistic analgesia.

Therapeutic Indications

Short-term relief of acute moderate pain that is not adequately relieved by ibuprofen, paracetamol, or other non-opioid analgesics alone. Typical use cases include:

  • Dental pain or toothache

  • Postoperative pain

  • Musculoskeletal pain (e.g., sprains, strains)

  • Headache and migraine

  • Dysmenorrhea

  • Back pain

  • Neuralgia

Important Restriction:
Use should be limited to short-term (typically <3 days) due to the risk of dependence from codeine.

Available Formulations

Oral Tablets/Capsules

  • Low-dose (commonly OTC in select regions):

    • 200 mg ibuprofen + 12.8 mg codeine phosphate

    • Max 6–8 tablets per day

  • Prescription-strength:

    • 400 mg ibuprofen + 30 mg codeine (varies by country)

    • May be compounded or obtained under medical supervision

Not Available in These Forms:

  • No sustained-release forms of the combination

  • No parenteral formulations

Dosage and Administration

Adults and children over 12 years (UK and Australia):

  • Typical dose: 1–2 tablets every 6–8 hours as needed

  • Maximum: 6–8 tablets in 24 hours

  • Maximum duration: 3 days without medical supervision

Elderly: Use with caution due to increased sensitivity to NSAIDs and opioids; start at lower end of dosing range.

Children under 12:
Contraindicated due to the unpredictable metabolism of codeine and risk of opioid toxicity.

Instructions:

  • Take with food or milk to reduce gastrointestinal irritation

  • Ensure adequate hydration

  • Do not exceed recommended dose or duration

Pharmacokinetics

Ibuprofen:

  • Absorption: Rapid, peak plasma levels in 1–2 hours

  • Half-life: 1.8–2.5 hours

  • Metabolism: Hepatic (CYP2C9)

  • Excretion: Renal

Codeine phosphate:

  • Absorption: Well absorbed orally; onset ~30 minutes

  • Metabolism: Hepatic (CYP2D6 to morphine)

  • Half-life: 3 hours (longer in poor metabolizers)

  • Excretion: Renal, primarily as inactive metabolites

Contraindications

  • Hypersensitivity to ibuprofen, codeine, NSAIDs, or any component

  • Active or history of peptic ulcer or GI bleeding

  • Severe renal, hepatic, or heart failure

  • Asthma or bronchospasm triggered by NSAIDs

  • Pregnancy (especially 3rd trimester) and breastfeeding

  • CYP2D6 ultra-rapid metabolizers (risk of morphine toxicity from codeine)

  • Children <12 years, or adolescents post-tonsillectomy or adenoidectomy

  • Respiratory depression

  • Paralytic ileus

  • Use in combination with other opioid-containing medicines

Special Warnings and Precautions

Ibuprofen Risks:

  • GI effects: Risk of ulceration, bleeding, and perforation (dose and duration dependent)

  • Cardiovascular: May increase risk of thrombotic events, especially at high doses

  • Renal: Can reduce renal perfusion, particularly in hypovolemic states

  • Hepatic dysfunction: Elevated liver enzymes and rare hepatic injury

Codeine Risks:

  • Respiratory depression: Especially in children or ultra-rapid CYP2D6 metabolizers

  • Dependence and misuse: Risk increases with prolonged use or higher doses

  • Sedation and impaired psychomotor performance: Warn patients about driving or operating machinery

  • Tolerance and withdrawal: Can develop with continuous use

Adverse Reactions

Common (1–10%):

  • Nausea, vomiting

  • Constipation

  • Drowsiness, dizziness

  • Dyspepsia, abdominal pain

  • Headache

Uncommon to Rare (<1%):

  • GI bleeding, peptic ulcer

  • Bronchospasm (especially in asthmatics)

  • Skin rash, urticaria

  • Tinnitus

  • Elevated liver enzymes

  • Renal impairment

  • CNS effects: confusion, hallucination, euphoria

  • Dependency (if misused)

Severe:

  • Anaphylaxis

  • SJS/TEN

  • Respiratory depression

  • Acute renal failure

  • Morphine toxicity (in ultra-rapid metabolizers)

Drug Interactions

Ibuprofen Component:

  • Anticoagulants (e.g., warfarin): Increased bleeding risk

  • Antihypertensives (ACEIs, ARBs, beta-blockers): May reduce antihypertensive effect

  • Methotrexate: Enhanced toxicity

  • Lithium: Increased serum levels

  • Diuretics: Decreased diuretic efficacy

  • SSRIs/SNRIs: Increased risk of GI bleeding

Codeine Component:

  • CNS depressants (alcohol, benzodiazepines, sedatives): Increased sedation, respiratory depression

  • MAO inhibitors: Dangerous CNS effects—contraindicated

  • CYP2D6 inhibitors (e.g., fluoxetine, paroxetine): Decreased analgesic efficacy

  • Other opioids: Risk of additive effects, dependency

Monitoring and Laboratory Parameters

  • Renal function (creatinine, BUN)

  • Hepatic enzymes (ALT, AST) with prolonged use

  • Symptoms of GI bleeding (black stools, anemia)

  • Respiratory status if used at higher doses or in sensitive populations

  • Opioid misuse behavior

Use in Special Populations

Pregnancy:

  • Not recommended

    • Ibuprofen: Risk of fetal renal impairment, premature ductus arteriosus closure in 3rd trimester

    • Codeine: Risk of neonatal withdrawal, respiratory depression

Breastfeeding:

  • Contraindicated

    • Codeine is metabolized to morphine and excreted in breast milk → risk of infant sedation or respiratory depression

Elderly:

  • Increased risk of GI bleeding, renal impairment, and CNS effects

  • Start at lowest effective dose and monitor closely

Children <12 years:

  • Contraindicated due to risk of life-threatening respiratory depression and toxicity

Toxicity and Overdose

Symptoms:

  • Ibuprofen: GI upset, metabolic acidosis, renal dysfunction

  • Codeine: Respiratory depression, CNS depression, bradycardia, miosis, hypotension

Management:

  • Supportive care

  • Activated charcoal (within 1 hour)

  • Naloxone for opioid toxicity

  • IV fluids, oxygen, mechanical ventilation if needed

  • Monitor acid-base status and renal function

Clinical Efficacy

  • More effective than either ibuprofen or codeine alone in controlling moderate acute pain

  • Widely used in post-surgical pain, dental pain, and dysmenorrhea

  • Short-term efficacy established in randomized controlled trials; however, not recommended for chronic use

Regulatory Considerations

  • UK MHRA: Restricts OTC use to 3-day treatment only; packaging includes addiction warning

  • EMA/FDA: Require boxed warnings on combination opioids regarding respiratory depression and misuse

  • Australia (TGA): Schedule 3 (pharmacist-only) for low-dose; otherwise Schedule 4 (prescription-only)

Patient Counseling Points

  • Use only for short-term pain relief (≤3 days)

  • Do not exceed the recommended dose or frequency

  • Avoid alcohol and other CNS depressants while taking this medication

  • Take with food to reduce GI upset

  • Watch for signs of GI bleeding (black stools, vomiting blood)

  • Do not drive or operate machinery if drowsy

  • Do not take concurrently with other NSAIDs or opioid medications

  • Risk of addiction: do not share with others or use for emotional distress

Storage and Handling

  • Store below 25°C

  • Keep away from light and moisture

  • Store securely and out of reach of children (risk of accidental overdose)




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