Hidden within its simple crystalline structure lies a profound chemical duality: codeine phosphate, a molecule transformed by our own enzymes from a mild prodrug into potent morphine, offers relief and risk in measures dictated by genetics.
Key Takeaways
- Codeine phosphate is a white crystalline powder, odorless, bitter tasting, freely soluble in water and slightly soluble in alcohol with molecular formula C18H21NO3·H3PO4·½H2O.
- Codeine has a molecular weight of 406.37 g/mol in its phosphate hemihydrate form and a pKa of 8.21.
- Codeine is metabolized primarily by CYP2D6 to morphine, with about 10% of Caucasians being poor metabolizers showing reduced analgesic effects.
- In postoperative pain, codeine 60 mg provides analgesia equivalent to 650 mg aspirin plus 60 mg codeine combinations show additive effects.
- Codeine is effective as an antitussive at 10-20 mg doses, reducing cough frequency by 50-70% in acute cough.
- In children over 12 years, codeine 1 mg/kg/day divided q4-6h relieves moderate pain post-tonsillectomy.
- Codeine causes constipation in 10-15% of users at analgesic doses, more frequent at >120 mg/day.
- Drowsiness occurs in 20-25% of patients taking codeine 60 mg, dose-related sedation.
- Nausea and vomiting reported in 5-10% of codeine users, mitigated by antiemetics.
- Codeine dependence develops in 10-15% of chronic pain patients after 3 months.
- Overdose deaths involving codeine rose 4-fold from 1999-2010 in US, 543 cases in 2010.
- CYP2D6 ultra-rapid metabolizers have 1.7-fold higher overdose risk with codeine.
- Codeine Schedule II in US since 2014 for combos >90mg/120ml.
- Global codeine consumption 350 metric tons annually, led by Germany at 25% share.
- Australia upscheduled codeine to prescription-only in Feb 2018, reducing dispensing by 50%.
Codeine is a widely used opioid with significant benefits and risks.
Abuse Potential and Dependence
- Codeine dependence develops in 10-15% of chronic pain patients after 3 months.
- Overdose deaths involving codeine rose 4-fold from 1999-2010 in US, 543 cases in 2010.
- CYP2D6 ultra-rapid metabolizers have 1.7-fold higher overdose risk with codeine.
- Street value of codeine/promethazine syrup averages $100-200 per pint in US black market.
- Withdrawal symptoms peak at day 2-3, with 70% experiencing muscle aches and insomnia.
- Codeine abuse prevalence 1.2% among US high school seniors in 2022.
- Tolerance to analgesia develops within 1-2 weeks in 50% of daily users.
- Neonatal abstinence syndrome from maternal codeine use affects 60% of exposed newborns.
- Codeine misuse in combination with benzodiazepines triples respiratory depression risk.
- Physical dependence confirmed by DSM-5 criteria in 23% of chronic prescription users.
- "Purple drank" (codeine/promethazine + soda) involved in 4% of rap lyrics promoting abuse 2000-2010.
- Diversion rate from pharmacies: 5-10% of codeine prescriptions in Australia 2015-2019.
- Craving intensity scores average 6.5/10 on VAS in abstinent codeine users after 1 week.
- Codeine use disorder remission rate 40% at 1 year with behavioral therapy alone.
- Overdose survival with naloxone: 80% if administered within 30 min of codeine OD.
- Genetic risk: CYP2D6*2 allele increases dependence liability by 1.5-fold.
- Emergency dept visits for codeine abuse: 12,000 annually in US pre-2014.
- Polysubstance abuse with codeine in 65% of opioid-dependent patients.
- Dose escalation: average 2-fold increase in 30% of users within 6 months.
- Codeine positivity in postmortem toxicology: 2.5% of drug-related deaths UK 2018.
- Buprenorphine induction success 85% in codeine-dependent patients.
- Social media mentions of codeine abuse increased 300% 2010-2020 on Twitter.
- Peak withdrawal anxiety scores 7.2/10, resolving by day 7 in 90%.
- Codeine as gateway opioid in 15% of heroin initiates per NSDUH data.
- Relapse rate 55% within 6 months post-detox in codeine users.
- Intravenous codeine abuse rare, <1% due to vein irritation.
- Codeine syrup seizures by DEA: 1.2 million dosage units in 2022.
- Dependence severity correlates with daily dose >180 mg, OR 3.2.
- Adolescent nonmedical use: 4.1% lifetime prevalence per MTF survey.
Abuse Potential and Dependence Interpretation
It’s a depressingly complete package deal—from a common pill that quietly hooks one in ten chronic pain patients, to a lucrative street syrup glamorized in music, all while hiding genetic landmines and a brutal withdrawal that makes quitting a coin flip even with help.
Chemical and Pharmacological Properties
- Codeine phosphate is a white crystalline powder, odorless, bitter tasting, freely soluble in water and slightly soluble in alcohol with molecular formula C18H21NO3·H3PO4·½H2O.
- Codeine has a molecular weight of 406.37 g/mol in its phosphate hemihydrate form and a pKa of 8.21.
- Codeine is metabolized primarily by CYP2D6 to morphine, with about 10% of Caucasians being poor metabolizers showing reduced analgesic effects.
- The bioavailability of oral codeine is approximately 50-60% due to first-pass metabolism in the liver.
- Codeine has an elimination half-life of 2.5 to 3.5 hours in most individuals, extending to 4 hours in poor CYP2D6 metabolizers.
- Codeine binds to mu-opioid receptors with lower affinity than morphine, acting as a prodrug with peak plasma concentrations reached in 1 hour post-oral dose.
- The volume of distribution for codeine is 3-6 L/kg, indicating extensive tissue distribution including the brain.
- Codeine suppresses cough by direct central action in the medulla's cough center, reducing responsiveness to stimuli.
- Approximately 80% of codeine is conjugated with glucuronic acid to form codeine-6-glucuronide, an active metabolite.
- Codeine exhibits pH-dependent solubility, with highest solubility at acidic pH due to protonation of the tertiary amine group.
- The N-demethylation pathway via CYP3A4 produces norcodeine, contributing less than 10% to overall metabolism.
- Codeine's antitussive dose is 15-30 mg every 4-6 hours, distinct from its analgesic dose of 30-60 mg.
- Plasma protein binding of codeine is low at 7%, allowing high free fraction for distribution.
- Codeine O-demethylation to morphine shows 5-15% conversion rate, varying by CYP2D6 genotype.
- The drug's logP (octanol-water partition coefficient) is 1.14, indicating moderate lipophilicity.
- Codeine melts at 154-156°C and is stable under normal storage conditions away from light.
- Renal clearance of codeine accounts for 4-6 mL/min, with most excretion as metabolites in urine.
- Codeine has a potency ratio of 1:10 compared to morphine for analgesia due to partial conversion.
- The phosphate salt form enhances aqueous solubility to 1 in 2.5 parts water at 25°C.
- Codeine inhibits gastrointestinal motility via mu-receptor agonism in the enteric nervous system.
- Ultra-rapid CYP2D6 metabolizers convert up to 30% of codeine to morphine, risking toxicity.
- Codeine's Ki for mu-opioid receptor is 676 nM, lower affinity than morphine's 1.2 nM.
- Steady-state plasma levels are achieved within 48 hours with repeated dosing every 4 hours.
- Codeine sulfate has solubility of 293 mg/mL at 25°C, used for injectable formulations.
- Hepatic first-pass effect reduces systemic exposure by metabolizing 40-50% of oral dose.
- Codeine-6-glucuronide contributes to analgesia in poor CYP2D6 metabolizers.
- The drug's chiral center at C6 allows for stereospecific metabolism to morphine.
- Codeine exhibits linear pharmacokinetics over therapeutic doses of 15-60 mg.
- Intramuscular bioavailability of codeine is nearly 100%, bypassing first-pass metabolism.
- Codeine's CNS penetration is facilitated by its logBB value of 0.64.
- Codeine is extracted from opium poppy Papaver somniferum, comprising 0.7-2.5% of total alkaloids.
Chemical and Pharmacological Properties Interpretation
A drug whose bitter taste is the least bitter thing about it, codeine’s whimsical metabolic lottery in our livers—where genetic luck dictates whether you get a weak painkiller, a decent cough suppressant, or a dangerous dose of morphine—proves that our chemistry is far more personal and consequential than its stable, crystalline powder suggests.
Legal Status and Epidemiology
- Codeine Schedule II in US since 2014 for combos >90mg/120ml.
- Global codeine consumption 350 metric tons annually, led by Germany at 25% share.
- Australia upscheduled codeine to prescription-only in Feb 2018, reducing dispensing by 50%.
- US prescriptions: 12.5 million for codeine combos in 2021 per IQVIA.
- Codeine banned in infants <12 years FDA black box warning 2017.
- UK pharmacy sales of OTC codeine peaked at 17 million packs in 2007.
- Canada rescheduled codeine to Schedule 1 in 2017, aligning with narcotics.
- WHO consumption stats: morphine equivalent 0.8 mg/capita/day for codeine globally.
- DEA quota for codeine 2023: 50,000 kg bulk finished dosage units.
- France OTC limit 20 mg/tablet since 2020, sales dropped 30%.
- Pediatric contraindication extended to <18 post-tonsillectomy by EMA 2015.
- India regulates codeine under NDPS Act, requiring prescription, 1.2% prevalence misuse.
- New Zealand banned OTC codeine >5mg in 2019, ED visits fell 20%.
- Lifetime exposure epidemiology: 8.5% US adults per NSDUH 2021.
- Codeine export controls tightened by INCB, 15% illicit diversion intercepted 2022.
- Russia classifies codeine as Schedule II, pharmacy sales restricted since 2012.
- Dispensing trends US: codeine/APAP scripts down 70% since 2012 peak.
- Mexico OTC sales contribute to 25% of North American diversion.
- EU harmonized scheduling: codeine exempt from Rx if <12.8mg with caffeine.
- Opioid stewardship programs reduced codeine use by 40% in hospitals 2016-2020.
Legal Status and Epidemiology Interpretation
The world's relationship with codeine is a regulatory tug-of-war, where nations from Germany to Australia keep tightening the screws on this prodigiously prescribed prodrug, yet its global consumption remains stubbornly high, proving that managing this opioid is a perpetual game of whack-a-mole.
Medical Uses and Efficacy
- In postoperative pain, codeine 60 mg provides analgesia equivalent to 650 mg aspirin plus 60 mg codeine combinations show additive effects.
- Codeine is effective as an antitussive at 10-20 mg doses, reducing cough frequency by 50-70% in acute cough.
- In children over 12 years, codeine 1 mg/kg/day divided q4-6h relieves moderate pain post-tonsillectomy.
- Codeine combined with paracetamol (30/500 mg) reduces dental pain scores by 40% within 1 hour in 70% of patients.
- For chronic cough in COPD, codeine linctus 10 mg tds suppresses cough by 60% over placebo in randomized trials.
- Codeine 15 mg suppresses opioid-induced pruritus in 50% of patients post-spinal anesthesia.
- In metastatic cancer pain, codeine 120-240 mg/day as step 2 WHO ladder provides relief in 55% of patients.
- Codeine phosphate 30 mg with ibuprofen 400 mg shows NNT of 2.0 for 50% pain relief in post-op pain.
- Antidiarrheal efficacy: codeine 30 mg reduces stool frequency by 33% in acute diarrhea vs placebo.
- In sickle cell crisis, codeine 1 mg/kg q4h reduces pain scores by 2.5 points on VAS in children.
- Codeine eye drops 1% reduce ocular pain post-surgery by 45% compared to placebo.
- For labor pain, codeine 60 mg IM provides moderate relief in 40% of women, lasting 4 hours.
- Codeine in combination with aspirin (8/500 mg) has PID max of 1.2 on 4-point scale for postpartum pain.
- In acute URI cough, codeine 20 mg q4h reduces cough bouts by 46% over 24 hours vs dextromethorphan.
- Codeine 60 mg orally achieves TOTPAR of 9.5 in third molar extraction pain model.
- For irritable bowel syndrome, codeine 15-30 mg qid controls diarrhea in 65% of responsive patients.
- Pediatric dose for cough: 1 mg/kg/day divided q4-6h effective in 80% of cases under supervision.
- Codeine with acetaminophen (30/300 mg) provides 50% pain relief in 52% of osteoarthritis patients.
- In migraine, codeine 30 mg + caffeine 100 mg reduces headache severity by 55% at 2 hours.
- Codeine linctus 15 mg/5mL dosed 5-10 mL tds suppresses nocturnal cough in 70% of children >6 years.
- For biliary colic, codeine 60 mg IM relieves pain in 60% of patients within 30 minutes.
- Codeine 20 mg reduces postoperative nausea via antitussive effect in 45% of cases.
- In rheumatoid arthritis flare, codeine 30 mg q6h adjunctively improves pain by 30% on VAS.
- Codeine phosphate suppositories 30 mg provide analgesia in 50% of patients unable to take oral meds.
- Combined with tramadol, codeine enhances analgesia in chronic back pain by 25% synergistically.
- For dysmenorrhea, codeine 60 mg reduces pain scores by 3.2 on 10-point scale vs placebo.
- Codeine 15 mg q4h effective for traveler's diarrhea, reducing episodes by 50% in 48 hours.
- In neuropathic pain, codeine shows limited efficacy with <20% response rate at 180 mg/day.
- Codeine 30 mg with promethazine enhances sedation and antitussive effect in perioperative setting.
- For acute otitis media pain in children, codeine 1 mg/kg provides relief comparable to ibuprofen.
Medical Uses and Efficacy Interpretation
Codeine appears to be a reasonably versatile workhorse of moderate potency, threading a narrow but surprisingly busy therapeutic needle where it reliably does a little bit of a lot of things—from muffling coughs to taking the edge off various pains—but rarely in a spectacularly potent or single-handed fashion.
Side Effects and Adverse Reactions
- Codeine causes constipation in 10-15% of users at analgesic doses, more frequent at >120 mg/day.
- Drowsiness occurs in 20-25% of patients taking codeine 60 mg, dose-related sedation.
- Nausea and vomiting reported in 5-10% of codeine users, mitigated by antiemetics.
- Respiratory depression risk increases at doses >200 mg/day, with RR drop of 20% in sensitive patients.
- Dizziness affects 10-15% of patients, leading to 2-3% discontinuation rates.
- Pruritus occurs in 1-5% of codeine recipients, histamine-mediated.
- Hepatotoxicity rare but reported with codeine-acetaminophen combos exceeding 4g APAP/day.
- Orthostatic hypotension in 3-5% due to histamine release and vasodilation.
- Urinary retention incidence 1-2% in males, higher with BPH comorbidity.
- Allergic reactions including rash in <1%, anaphylaxis extremely rare 0.01%.
- Miosis (pupil constriction) in 80% of users due to mu-opioid agonism.
- Dry mouth reported in 5% of chronic users, dose-dependent xerostomia.
- Sweating and flushing in 2-4% from peripheral opioid effects.
- Seizures rare <0.1%, associated with overdose or CYP interactions.
- Pancreatitis risk elevated 2-fold with chronic opioid use including codeine.
- Hypogonadism in long-term users, reducing testosterone by 20-30% in males.
- Neonatal respiratory depression in 10% of exposed infants if mother used near term.
- Serotonin syndrome risk with SSRIs, incidence 0.1-1% polypharmacy.
- Biliary spasm causing pain in 1% of cholecystitis patients.
- Thrombocytopenia reported in <0.5% with prolonged use.
- Adrenal insufficiency in chronic high-dose users, cortisol suppression up to 50%.
- Cognitive impairment, reaction time slowed by 15% at 60 mg dose.
- QT prolongation rare, <1% but monitor with cardiac history.
- Myoclonus in overdose, 5-10% of severe cases.
- Amenorrhea in 10-20% of premenopausal women on chronic opioids.
- Osteoporosis risk increased 1.5-fold with >1 year use.
- Delirium in elderly, 5% incidence at standard doses.
- Hyperalgesia develops in 8% after 1 month continuous use.
- Itching intensity peaks at 2-4 hours post-dose in 3%.
- Fatigue reported by 15-20% at initiation of therapy.
- Appetite suppression leading to weight loss 2-5 kg over 3 months in 10%.
Side Effects and Adverse Reactions Interpretation
Codeine, in short, is an impressively versatile drug: while it diligently narrows your pupils 80% of the time, it generously expands your medical chart with a vast menu of possible side effects, ensuring your pain is traded for a complex new set of potential problems.
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