Head-to-head clinical analysis & difference comparison: details on mechanism of action, dosing, half-life, interactions, and maternal-fetal safety.
ADVIL PM vs ACETAMINOPHEN AND HYDROCODONE BITARTRATE
Clinician-reviewed, head-to-head comparison of mechanism, dosing, pharmacokinetics, and safety profiles.
Last clinically reviewed: July 2026 · OpiCalc Medical Review Team
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase (COX) enzymes, reducing prostaglandin synthesis. Diphenhydramine is a first-generation antihistamine that antagonizes histamine H1 receptors, causing sedation.
Acetaminophen: analgesic and antipyretic effects via inhibition of cyclooxygenase (COX) and activation of descending serotonergic pathways; central action. Hydrocodone: mu-opioid receptor agonist; activates G-protein coupled receptors to modulate pain perception and emotional response.
Temporary relief of occasional sleeplessness associated with minor aches and pains
Moderate to moderately severe pain,Cough suppression (hydrocodone; off-label)
Two caplets (ibuprofen 200 mg, diphenhydramine citrate 38 mg) orally at bedtime as needed for insomnia. Maximum: 2 caplets in 24 hours.
1-2 tablets (containing 5-10 mg hydrocodone and 300-325 mg acetaminophen) orally every 4-6 hours as needed for pain; maximum 8 tablets per day.
Ibuprofen: 2-4 hours (terminal); clinical context: steady state achieved in 1 day, not affected by renal impairment. Diphenhydramine: 4-8 hours (terminal); clinical context: prolonged in hepatic impairment.
Acetaminophen: 2-3 hours in adults; prolonged in hepatic impairment (up to 5 hours). Hydrocodone: 3.8-4.5 hours (range 3-5 hours) in healthy adults; prolonged in elderly or hepatic/renal impairment. Clinical context: repeated dosing may require extended intervals in renal impairment.
Ibuprofen is primarily metabolized via hepatic oxidation by CYP2C9. Diphenhydramine is metabolized via hepatic N-demethylation and oxidation, primarily by CYP2D6.
Acetaminophen: primarily via glucuronidation (UGT1A1, UGT1A6, UGT1A9) and sulfation; minor CYP2E1 oxidation to NAPQI (toxic metabolite). Hydrocodone: CYP3A4 and CYP2D6; N-demethylation to norhydrocodone; O-demethylation to hydromorphone (CYP2D6).
Ibuprofen: Renal (90% as metabolites and conjugates, <10% unchanged); Diphenhydramine: Renal (primarily as metabolites, ~1% unchanged). Fecal excretion is negligible for both.
Acetaminophen: primarily renal excretion of conjugated metabolites (glucuronide and sulfate) with approximately 5% excreted unchanged. Hydrocodone: renal excretion as unchanged drug and metabolites (O-demethylated and N-demethylated); total renal excretion accounts for about 60-70% of dose (parent and metabolites). Biliary/fecal elimination is minimal.
Ibuprofen: >99% bound to albumin; Diphenhydramine: 78-85% bound to albumin.
Acetaminophen: 10-25% bound, nonspecific binding to albumin. Hydrocodone: 25-50% bound, primarily to albumin and alpha-1-acid glycoprotein.
Ibuprofen: 0.1-0.2 L/kg; small Vd consistent with high protein binding. Diphenhydramine: 4.5-8.5 L/kg; large Vd indicating extensive tissue distribution.
Acetaminophen: 0.8-1.0 L/kg, indicating distribution into total body water; clinically relevant for loading dose calculations. Hydrocodone: 3.0-4.0 L/kg, suggesting extensive tissue distribution; higher Vd may require higher loading doses but has no clinical target.
Ibuprofen: 80-100% (oral); Diphenhydramine: 50-70% (oral) due to first-pass metabolism.
Acetaminophen: oral bioavailability 85-95% (first-pass metabolism minimal). Hydrocodone: oral bioavailability about 25-45% due to first-pass hepatic metabolism; significant interindividual variability.
Avoid use in GFR <30 m L/min. For GFR 30-59 m L/min, limit to single dose and avoid chronic use. No adjustment needed for GFR ≥60 m L/min.
GFR 10-50 m L/min: administer every 6 hours; GFR <10 m L/min: administer every 8 hours; avoid in severe impairment due to acetaminophen metabolite accumulation.
Contraindicated in Child-Pugh Class C. In Child-Pugh Class B, reduce dose by 50% (max 1 caplet) and monitor for toxicity. No adjustment for Child-Pugh Class A.
Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50% or extend interval; Child-Pugh C: use with caution, avoid if possible, consider alternative therapy.
Not recommended for children under 12 years. For age ≥12 years, same adult dose: 2 caplets at bedtime.
Dosing based on hydrocodone component: 0.1-0.2 mg/kg/dose every 4-6 hours; maximum daily acetaminophen limit: 75 mg/kg/day; not recommended for children <2 years.
Start with lowest effective dose (1 caplet) at bedtime to minimize anticholinergic and GI adverse effects. Avoid in elderly with cognitive impairment or high fall risk.
Initiate at lowest effective dose, typically 1 tablet (2.5-5 mg hydrocodone) every 6 hours; monitor for respiratory depression and acetaminophen toxicity; avoid in frail elderly with hepatic impairment.
NSAIDs cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. NSAIDs are contraindicated in the setting of coronary artery bypass graft (CABG) surgery.
Addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion of acetaminophen; neonatal opioid withdrawal syndrome; interaction with alcohol; risk of medication errors.
Cardiovascular thrombotic events,Gastrointestinal bleeding, ulceration, and perforation,Renal toxicity,Sedation and impaired cognitive function,Anticholinergic effects,Avoid use with other NSAIDs or antihistamines,Use caution in elderly, renal impairment, hepatic impairment, and pregnancy
Hepatotoxicity from acetaminophen overdose; respiratory depression; increased intracranial pressure; CNS depression; elderly/debilitated patients; renal impairment; opioid-induced hyperalgesia; serotonin syndrome; interaction with CNS depressants; risk of adrenal insufficiency; severe hypotension; use in patients with gastrointestinal obstruction; convulsion risk; severe hepatic impairment; urinary retention; acute abdominal conditions; hypothyroidism; prostatic hypertrophy; adrenocortical insufficiency; pregnancy/lactation; pediatric use; geriatric use; renal impairment; hepatic impairment.
Hypersensitivity to ibuprofen, diphenhydramine, or any component of the formulation,History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs,Perioperative pain in the setting of coronary artery bypass graft (CABG) surgery,Neonates and premature infants (due to diphenhydramine),Concurrent use with other diphenhydramine products or sedatives
Hypersensitivity to acetaminophen or hydrocodone; significant respiratory depression; acute or severe bronchial asthma; upper airway obstruction; known or suspected gastrointestinal obstruction; paralytic ileus; concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days; severe hepatic impairment (acetaminophen toxicity risk); acute alcoholism.
Take with food or milk to reduce GI upset. Avoid alcohol and grapefruit juice. Caffeine may enhance CNS stimulation and should be limited.
Avoid alcohol consumption during therapy; ethanol increases acetaminophen hepatotoxicity risk and enhances CNS depression. Grapefruit juice may inhibit CYP2D6 (minor effect) but no significant clinical interaction. No other specific food restrictions.
Pregnancy Category C/D (after 30 weeks). First trimester: Potential risk of miscarriage and cardiac defects (limited data with NSAIDs). Second trimester: Avoid unless clearly needed; possible oligohydramnios, premature closure of ductus arteriosus, and fetal renal impairment. Third trimester: Contraindicated after 30 weeks due to risk of premature ductus arteriosus closure and persistent pulmonary hypertension.
First trimester: Acetaminophen considered low risk; hydrocodone is a pregnancy category C drug. Data from retrospective studies suggest a small increased risk of certain congenital malformations (e.g., neural tube defects, cleft palate) with first trimester opioid use, but absolute risk is low. Second trimester: Low risk as above. Third trimester: Prolonged use of hydrocodone can cause neonatal opioid withdrawal syndrome (NOWS); acetaminophen is safe. Use only if benefit outweighs risk.
Diphenhydramine and ibuprofen are excreted into breast milk. M/P ratio not established. Both drugs are considered compatible with breastfeeding in low doses, but theoretical risk of infant sedation (diphenhydramine) and gastrointestinal effects (ibuprofen). Max daily dose for mother should not exceed recommended limits. Monitor infant for drowsiness and poor feeding.
Acetaminophen excretion in breast milk is low (M/P ratio ~0.9). Hydrocodone is excreted in small amounts (M/P ratio ~2.1). The relative infant dose is estimated to be 2.5-3.5% of maternal weight-adjusted dose for hydrocodone. Monitor infant for sedation and respiratory depression. Consider benefit to mother and potential neonatal opioid withdrawal if used chronically.
No specific dose adjustment recommended for ibuprofen or diphenhydramine in pregnancy. However, due to altered pharmacokinetics (increased volume of distribution, renal clearance), standard doses may be less effective. Avoid use if possible, especially after 30 weeks. Use lowest effective dose for shortest duration.
During pregnancy, increased plasma volume and enhanced hepatic clearance may reduce serum concentrations of both drugs. However, dosing adjustments are not routinely recommended due to risk of undertreatment. Use the lowest effective dose of hydrocodone for the shortest duration. For acetaminophen, maximum daily dose should not exceed 3000 mg to avoid hepatotoxicity.
Advil PM combines ibuprofen (NSAID) and diphenhydramine (antihistamine). Avoid concomitant use with other NSAIDs or CNS depressants (including alcohol). Use lowest effective dose for shortest duration. Contraindicated in severe hepatic/renal impairment, active GI bleeding, or during third trimester of pregnancy. May cause morning drowsiness due to antihistamine.
Acetaminophen-hydrocodone is contraindicated in severe respiratory depression, acute or severe bronchial asthma, and known hypersensitivity. Monitor for respiratory depression, especially in elderly or debilitated patients. Avoid use with other acetaminophen-containing products to prevent hepatotoxicity. Hydrocodone is a prodrug metabolized by CYP2D6 to hydromorphone; CYP2D6 ultrarapid metabolizers may experience toxicity. Use with caution in patients with head injury, increased intracranial pressure, or severe hepatic impairment. Naloxone is the reversal agent for opioid effects; acetylcysteine for acetaminophen overdose.
Take only one tablet before bedtime; do not exceed recommended dose.,Avoid alcohol and other sedatives while using this medication.,Do not use for more than 10 days for pain or 3 days for fever unless directed by a doctor.,May cause drowsiness; avoid driving or operating machinery until you know how the drug affects you.,Not for use in children under 12 years of age or during pregnancy/breastfeeding without consulting a healthcare provider.,Report signs of stomach bleeding (e.g., black/tarry stools, vomiting blood) or allergic reactions (e.g., facial swelling, difficulty breathing).
Take exactly as prescribed; do not increase dose or frequency without consulting your doctor.,Avoid alcohol and other CNS depressants (e.g., benzodiazepines, sedatives) as they increase risk of severe drowsiness and respiratory depression.,Do not exceed 4000 mg of acetaminophen per day from all sources; check labels of other medications.,This medication may cause dizziness or drowsiness; avoid driving or operating heavy machinery until you know how it affects you.,Store securely out of reach of others, especially children, as misuse can cause overdose and death.,Do not stop abruptly; withdrawal may occur. Taper under medical supervision.,Contact emergency if you experience trouble breathing, extreme drowsiness, or signs of allergic reaction.,Report any history of substance abuse, as this medication has abuse potential.
No interactions on record
"Hydrocodone, an opioid agonist, and scopolamine, an anticholinergic agent, both exhibit central nervous system (CNS) depressant effects. When co-administered, their combined activity can lead to additive CNS depression, resulting in enhanced sedation, respiratory depression, and cognitive impairment. This interaction may also increase the risk of constipation and urinary retention due to additive anticholinergic effects from both drugs."
"Pargyline, a monoamine oxidase inhibitor (MAOI), irreversibly inhibits the metabolism of amines, leading to increased intraneuronal stores of norepinephrine. Hydrocodone, a semisynthetic opioid, can release these stored catecholamines, potentially causing a hypertensive crisis, serotonin syndrome, or CNS excitation. Coadministration may also result in excessive sedation and respiratory depression due to additive CNS depressant effects, requiring immediate clinical attention."
"Hydrocodone, an opioid agonist, and oxprenolol, a non-selective beta-adrenoceptor antagonist, are both central nervous system (CNS) depressants. Their combined use can lead to additive CNS depression, resulting in excessive sedation, respiratory depression, hypotension, and bradycardia. This interaction is particularly dangerous in patients with compromised cardiac or respiratory function, potentially leading to coma or death."
Explore head-to-head clinical comparisons of other medications in the same therapeutic classes.
Common clinical questions about ADVIL PM vs ACETAMINOPHEN AND HYDROCODONE BITARTRATE, answered by our medical review team.
ADVIL PM is a NSAID/Sedative Combination that works by Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase (COX) enzymes, reducing prostaglandin synthesis. Diphenhydramine is a first-generation antihistamine that antagonizes histamine H1 receptors, causing sedation.. ACETAMINOPHEN AND HYDROCODONE BITARTRATE is a Opioid Agonist that works by Acetaminophen: analgesic and antipyretic effects via inhibition of cyclooxygenase (COX) and activation of descending serotonergic pathways; central action. Hydrocodone: mu-opioid receptor agonist; activates G-protein coupled receptors to modulate pain perception and emotional response.. They differ in pharmacokinetic profiles, FDA-approved indications, and side effect profiles.
Potency comparisons between ADVIL PM and ACETAMINOPHEN AND HYDROCODONE BITARTRATE depend on the specific clinical indication. These are agents from distinct pharmacological classes and are not directly interchangeable by dose. A physician or clinical pharmacist should guide any therapeutic switching decisions.
The standard adult dose of ADVIL PM is: Two caplets (ibuprofen 200 mg, diphenhydramine citrate 38 mg) orally at bedtime as needed for insomnia. Maximum: 2 caplets in 24 hours.. The standard adult dose of ACETAMINOPHEN AND HYDROCODONE BITARTRATE is: 1-2 tablets (containing 5-10 mg hydrocodone and 300-325 mg acetaminophen) orally every 4-6 hours as needed for pain; maximum 8 tablets per day.. Dosing should always be individualized based on indication, renal and hepatic function, age, and other patient factors.
No direct drug-drug interaction has been formally documented between ADVIL PM and ACETAMINOPHEN AND HYDROCODONE BITARTRATE in current clinical databases. However, individual patient risk factors including other medications, organ function, and comorbidities should always be evaluated by a qualified healthcare provider.
The maternal-fetal safety profiles differ. ADVIL PM is classified as Category C. Pregnancy Category C/D (after 30 weeks). First trimester: Potential risk of miscarriage and cardiac defects (limited data with NSAIDs). Second trimester: Avoid unless clearly neede. ACETAMINOPHEN AND HYDROCODONE BITARTRATE is classified as Category D/X. First trimester: Acetaminophen considered low risk; hydrocodone is a pregnancy category C drug. Data from retrospective studies suggest a small increased risk of certain congenital. Always consult a maternal-fetal medicine specialist before taking either drug during pregnancy or lactation.