Codeine

in TYLENOL #3

Open Codeine in the interactive console ↗

What it isWeak opioid requiring CYP2D6 conversion to morphine; mild to moderate pain and cough.

Why this oneIt is one of few opioids used as both an analgesic and antitussive, but offers little advantage over direct-acting alternatives.

What limits itCYP2D6 variation makes it inactive or toxic; avoid after pediatric tonsil or adenoid surgery and during breastfeeding.

FDA-approved for

pain (~1950)
cough (~1950)

FDA label

Read the full label on DailyMed ↗

BOXED WARNING Addiction, abuse, misuse (overdose/death). Life-threatening respiratory depression. Accidental ingestion (even one dose) can be fatal, especially in children. Concomitant benzodiazepines/CNS depressants: profound sedation, respiratory depression, coma, death. Neonatal opioid withdrawal syndrome with prolonged use in pregnancy. Ultra-rapid CYP2D6 metabolism: life-threatening respiratory depression/death in children (contraindicated <12 yr and post-tonsillectomy/adenoidectomy <18 yr). Acetaminophen hepatotoxicity (doses >4,000 mg/day).

FDA dosing	Population	Start	Target	Max
Mild-to-moderate pain	Adult	300-600 mg acetaminophen / 30-60 mg codeine q4h PRN	1-2 tablets q4h PRN (15/300 or 30/300); 1 tablet q4h PRN (60/300)	Codeine 360 mg/day; acetaminophen 4,000 mg/day

Renal Undefined

Hepatic Undefined

Maximum codeine 360 mg and acetaminophen 4,000 mg per 24 hours

Instructions

Use the lowest effective dose for the shortest duration
Do not abruptly discontinue in physically dependent patients; taper (e.g., by 10-25% of daily dose every 2-4 weeks)
Do not exceed 4,000 mg/day acetaminophen; avoid other acetaminophen-containing products
Advise access to an opioid overdose reversal agent (naloxone/nalmefene)

Contraindications

Children younger than 12 years
Postoperative management in children <18 yr after tonsillectomy and/or adenoidectomy
Significant respiratory depression
Acute or severe bronchial asthma in an unmonitored setting or without resuscitative equipment
MAOIs (concurrently or within 14 days)
Known or suspected gastrointestinal obstruction, including paralytic ileus

Cautions

Life-threatening respiratory depression
Ultra-rapid CYP2D6 metabolizers (esp. children)
Neonatal opioid withdrawal syndrome
Interactions with CNS depressants
Opioid-induced hyperalgesia and allodynia
Severe hypotension
Gastrointestinal adverse reactions
Seizures
Adrenal insufficiency
Serotonin syndrome with concomitant serotonergic drugs
Acetaminophen hepatotoxicity
Withdrawal on abrupt discontinuation

Adverse reactions

Drowsiness/sedation
Lightheadedness; dizziness
Nausea; vomiting
Constipation
Sweating
Shortness of breath
Hypotension; palpitations
Pruritus; rash

Pregnancy Prolonged use can cause neonatal opioid withdrawal syndrome; use only if potential benefit justifies potential fetal risk

Lactation Undefined

⚠ BOXED WARNINGS

Addiction, abuse and misuse
Life-threatening respiratory depression
Ultra-rapid metabolism and death in children
Risk from concomitant use with benzodiazepines

Cost, est. cash$10–$300/month

Generic entry2014

Classes and tags

Clinical profile

Therapeutic safety burden3 / 4

Overdose danger4 / 4

Weight-gain liability0 / 4

Sedation liability2 / 4

QT / Torsades0 / 4

Direct muscarinic antagonism0 / 4

Embryofetal risk2 / 4

Legacy pregnancy categoryC

Defining liabilityRespiratory depression, dependence and overdose; risk rises sharply with sedatives or impaired clearance.

Active metabolites

Morphine

Mechanism of action: Codeine ballicule

Codeine ballicule: receptor binding, kinetics and half-life diagram

Open Codeine in the interactive console ↗

Memory aids: mascots and interaction avatars

Codeine — mascot mnemonic cartoon — **“Coding (Morphine)”**
metabolized to morphine
rabbit is the morphine mascot
“purple drank” is a concoction containing morphine cough syrup

CYP2D6 substrate

CYP3A4 substrate

Open Codeine in the interactive console ↗