This page shows what was measured, who it was measured in, and what that does not settle.
What Codeine Anhydrous does in the body
Mild to moderate pain where an opioid is appropriate and other treatments have not worked
Codeine on its own barely binds the opioid receptor. It becomes a painkiller only because a liver enzyme called CYP2D6 strips a methyl group off it and turns roughly one part in twelve into morphine. Everything that follows is morphine pharmacology. The catch is that the number of working copies of the CYP2D6 gene varies: people with none get almost no pain relief, and people with extra copies convert far more than expected and can reach a morphine overdose from an ordinary tablet. That is why the drug is now forbidden in young children, and why the same tablet is close to useless in one adult and dangerous in another.
What happened in people
Number needed to treat of 12 (95% CI 8.4 to 18) for at least 50% postoperative pain relief with codeine 60 mg, from 33 studies and 2,411 participants
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The recorded finding that sits closest to something a person would notice. Written into the record, not signed off, and it carries no population or interval.
That a stated codeine dose produces comparable exposure across patients, when the label’s own prevalence figures for CYP2D6 ultra-rapid metabolism range from 1% to above 10% by ancestry
Where it acts
The liver, where CYP2D6 converts a small fraction of the dose into morphine, and then the mu-opioid receptors of the spinal cord and brainstem where that morphine acts
Kind of result
Symptoms and quality of life
Supervision
Professional supervision is normally required. A regulator classifies this substance in a way that restricts how it is supplied.
Where each sentence above came from
No recorded sentence describes the change this makes in a way that stands on its own. The page opens with what it is taken for instead, and the recorded explanation follows below.
Shown as the opening line on this page.
A limit recorded against this substance. Not signed off as a reviewed claim.
The four opening statements run to 157 words.
Words this page uses
Four words worth knowing first
Chosen from what this page shows, with each one explained before the word it depends on.
Comparator
A comparator is whatever the treatment was measured against.
A picture of it, and where the picture fails
It is like the other runner in a race.
Where that stops being true. A race has one winner. A study can show both arms improved.
What people get wrong. Results are read without asking what the other group got. Beating nothing is not beating a treatment.
The control condition against which the experimental intervention is assessed.
Randomisation
Randomisation means chance decides who gets which treatment.
A picture of it, and where the picture fails
It is like a coin toss deciding the groups.
Where that stops being true. A coin toss is fair once. Fairness here comes from doing it for everyone.
What people get wrong. It is thought to make groups identical. It makes them similar on average, including on things nobody measured.
Allocation of participants to arms by a chance process, so that unmeasured factors are balanced in expectation.
Absolute difference
An absolute difference is how many more people in a hundred were affected.
A picture of it, and where the picture fails
It is like counting heads in two rooms of a hundred.
Where that stops being true. Heads are easy to count. Study results carry a margin of error too.
What people get wrong. It is confused with a percentage change, which can look far larger.
The arithmetic difference in event rates between arms.
Confidence interval
A confidence interval is the range the true answer is likely to sit in.
A picture of it, and where the picture fails
It is like a weather forecast giving a range rather than one number.
Where that stops being true. A forecast range covers tomorrow. This one covers what the study could resolve.
What people get wrong. The middle number is read as the answer. A range crossing zero means no change is still possible.
An interval estimate that would contain the true parameter in a stated proportion of repeated studies.
What happened in people◇Read from sources, not yet reviewed
What happened in people
Each card is one study: the exact question it asked, who was in it, and whether it showed what it set out to show.
At least 50% pain relief over four to six hours after a single oral 60 mg dose of codeine in established moderate to severe postoperative pain
✓ The study showed what it set out to show
Who was studied
Cochrane CD008099 — pooled single-dose placebo-controlled trials
How many people
2411
Study design
Systematic review and meta-analysis of randomised, double-blind, placebo-controlled single-dose trials
Compared against
A dummy treatment
Kind of result
A number that stands in for health
What was found
NNT 12 (95% CI 8.4 to 18) across all surgery types; 26% responded on codeine 60 mg against 17% on placebo; NNT 21 (12 to 96) after dental surgery
Repeated elsewhere
Replicated
What this does not prove. Meeting one endpoint in one population does not carry to other goals or other people.
The limits of this study, and where it came from
Main limit. Only 27 participants across the whole review received codeine 90 mg, so nothing can be said about a higher dose. More participants reported adverse events on codeine than placebo, though not significantly and none serious. The review long predates the paediatric contraindications and says nothing about them.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral tablets and solution as codeine sulfate or phosphate; very commonly in fixed combination with paracetamol, aspirin or butalbital; prescription antitussive solutions for adults only. Schedule II as a single ingredient in the United States, with certain combinations in Schedules III and V.
Interval reported. 95% CI 8
Written into the record, not signed off as a reviewed claim.
Between-group difference in decline in pain on an 11-point numerical rating scale two hours after a single oral dose, codeine 30 mg plus paracetamol 300 mg against three comparators in acute extremity pain
✗ The study did not show it
Who was studied
NCT02455518 (Chang et al., JAMA 2017;318:1661-1667) — codeine arm
How many people
416
Study design
Randomised clinical trial, two urban emergency departments
Compared against
Not recorded for this study
Kind of result
What a body can do day to day
What was found
Mean two-hour decline 3.9 (95% CI 3.2 to 4.5) for codeine-paracetamol against 4.3 for ibuprofen-paracetamol; overall p=0.053 across four arms
Repeated elsewhere
Unreplicated
What this does not prove. A study that did not show an effect does not show that no effect exists anywhere.
The limits of this study, and where it came from
Main limit. Adverse events were not assessed, and CYP2D6 genotype was not measured — so the trial reports a population average for a drug whose defining property is that the population average describes almost nobody.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral tablets and solution as codeine sulfate or phosphate; very commonly in fixed combination with paracetamol, aspirin or butalbital; prescription antitussive solutions for adults only. Schedule II as a single ingredient in the United States, with certain combinations in Schedules III and V.
Interval reported. 95% CI 3
Written into the record, not signed off as a reviewed claim.
RNAWiki holds 2 written-up human studies for this substance, each with the question it asked.
How we know it
Each card names the study, the number of people and what the study set out to measure.
What this does not prove
These summaries were written by a person and have not been signed off as reviewed claims.
Why it matters
A study that failed is as informative as one that worked, and both are here.
What we still do not know
No reviewed claim exists, so no exact population, effect size or interval is published yet.
What it changes in the body◇Read from sources, not yet reviewed
The path through the body
From what a person takes to what changes. A solid line is a step measured in people. A dashed line is a step nobody has measured that way.
Where a source records it acting
Brainstem: Produces respiratory depression by direct action on brain stem respiratory centers, as recorded in the label pharmacodynamics
US prescribing information · 010905f9-3bcb-4b50-9fe8-a3ad0010f14c · read 2026-08-27
Intestines: Causes a reduction in gastrointestinal motility; digestion of food in the small intestine is delayed and propulsive contractions are decreased
US prescribing information · 010905f9-3bcb-4b50-9fe8-a3ad0010f14c · read 2026-08-27
Start
Codeine Anhydrous
What a person takes: Oral tablets and solution as codeine sulfate or phosphate; very commonly in fixed combination with paracetamol, aspirin or butalbital; prescription antitussive solutions for adults only. Schedule II as a single ingredient in the United States, with certain combinations in Schedules III and V..
The measurement behind this step
Absorbed well by mouth with plasma half-lives of codeine and its metabolites of approximately 3 hours, and about 90% of a dose excreted renally, of which roughly 10% is unchanged codeine. The pharmacokinetics that matter are not codeine’s own but those of the morphine formed from it, whose rate of appearance depends on CYP2D6 activity and can be abolished by a CYP2D6 inhibitor.
Getting in
A methyl group away from morphine
Codeine is morphine with one small chemical group attached. That group is what stops it binding the opioid receptor properly, and removing it is the entire mechanism.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Codeine is morphine 3-methyl ether, C18H21NO3. Its own affinity for the mu-opioid receptor is orders of magnitude below morphine’s. The 3-O-methyl group blocks the phenolic hydroxyl that morphine uses to anchor in the receptor pocket.
One enzyme decides how much drug you actually took
CYP2D6 converts about one part in twelve of the dose into morphine. How many working copies of that gene you carry — none, one, two or more — decides whether the tablet does nothing or too much.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
The label records 70 to 80% glucuronidation to codeine-6-glucuronide, about 5 to 10% O-demethylation by CYP2D6 to morphine, and about 10% N-demethylation by CYP3A4 to inactive norcodeine. Ultra-rapid metaboliser prevalence ranges from 1 to 2% in East Asian populations to above 10% in Oceanian, North African, Middle Eastern, Ashkenazi Jewish and Puerto Rican populations.
Everything that follows is morphine pharmacology at the mu-opioid receptor, at whatever concentration the conversion produced.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Full agonism at the Gi/o-coupled mu-opioid receptor by the morphine formed, plus a contribution from morphine-6-glucuronide, which the label notes has analgesic activity in humans. Norcodeine and morphine-3-glucuronide are not considered analgesic; the activity of codeine-6-glucuronide in humans is stated as unknown.
Across every placebo-controlled surgical trial, 26% of people on 60 mg reached at least half pain relief, against 17% on placebo. That gap is the drug.
──Measured in people. Written by a person from the study named beside the step. Not signed off as a reviewed claim.
The measurement behind this step
Cochrane CD008099: NNT 12 (95% CI 8.4 to 18) across 33 studies and 2,411 participants; 21 (12 to 96) after dental surgery; 6.8 (4.6 to 13) after other surgery. Mean time to rescue medication 2.7 hours on codeine against 2.0 on placebo.
In someone with extra copies of the enzyme, an ordinary dose converts far more completely and can produce a morphine overdose. That is how children died after tonsil surgery.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Boxed warning: life-threatening respiratory depression and death have occurred in children who received codeine, most cases following tonsillectomy or adenoidectomy, many with evidence of CYP2D6 ultra-rapid metabolism. Contraindicated in all children under 12 and after tonsillectomy or adenoidectomy under 18.
Restricted, and partly replaced by the same problem
Codeine prescribing to children dropped a quarter after the 2017 restriction. Tramadol prescribing to children rose a fifth — and tramadol depends on the same enzyme.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Interrupted time series over 1.92 million paediatric codeine prescriptions: immediate 26% fall in codeine dispensing to children (IRR 0.742, 95% CI 0.684 to 0.806) and immediate 22% rise in tramadol (IRR 1.223, 95% CI 1.068 to 1.401) after April 2017.
No suggested links are held for this record, so nothing is hidden from this path.
What we know
The record describes 6 steps from taking it to an effect in a person.
How we know it
Each step names the study behind it in the technical detail beside it.
What this does not prove
A change inside the body is a reason to look. It is not a result in a person.
Why it matters
A reader can see exactly where the chain stops being measured in people.
What we still do not know
No reviewed claim binds any of these steps to a named population.
What is missing or unclear◇Read from sources, not yet reviewed
Were people like you studied?
RNAWiki cannot tell whether a study fits you. It can show who was in it, and where the result stops carrying.
Who was studied
People similar to this profile were included.
Adults with mild to moderate pain, and adults with a cough. Not children under 12 at all, not anyone under 18 after tonsillectomy or adenoidectomy, and not recommended in breastfeeding.
Who is missing from the studies
Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
What the label states about particular groups
On pediatric, the label states: “The safety and effectiveness of codeine sulfate tablets in pediatric patients have not been established.”
US prescribing information · 5819bdf7-300e-45b8-8f3a-447b53656293 · read 2026-08-30
On older people, the label states: “Elderly patients (aged 65 years or older) may have increased sensitivity to codeine.”
US prescribing information · 5819bdf7-300e-45b8-8f3a-447b53656293 · read 2026-08-30
On people who are pregnant, the label states: “R i sk Summary: Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.4 )] .”
US prescribing information · 5819bdf7-300e-45b8-8f3a-447b53656293 · read 2026-08-30
On people who are breastfeeding, the label states: “R i sk Summary: Codeine and its active metabolite, morphine, are present in human milk.”
US prescribing information · 5819bdf7-300e-45b8-8f3a-447b53656293 · read 2026-08-30
On people with reduced liver function, the label states: “No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of codeine in this patient population are unknown.”
US prescribing information · 5819bdf7-300e-45b8-8f3a-447b53656293 · read 2026-08-30
On people with reduced kidney function, the label states: “Codeine pharmacokinetics may be altered in patients with renal failure.”
US prescribing information · 5819bdf7-300e-45b8-8f3a-447b53656293 · read 2026-08-30
Where the result stopped carrying
Paediatric use, contraindicated outright in every child under 12 and after tonsillectomy or adenoidectomy under 18
The dental-surgery indication in particular, where the pooled NNT is 21 with a confidence interval reaching 96
Codeine 90 mg, on which the entire randomised literature comprises 27 participants
The assumption that a prodrug is inherently safer than the active drug it becomes
This is a scope explorer, not a diagnosis engine.
It shows who was studied so you can see whether people similar to you were included.
RNAWiki cannot tell whether a study fits you. It can show who was in it.
What it would be like to take◇Read from sources, not yet reviewed
Why it might seem to do nothing
A real effect and a noticed effect are different things. These are the recorded reasons the two come apart.
It was studied in different people
The people in the studies were not much like the reader.
On this record: Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
The evidence may simply be wrong
Small early studies often do not hold up.
On this record: RNAWiki has not yet published a reviewed conclusion for this use.
Other reasons RNAWiki checked and found nothing for (11)
It was studied for a different goal
The studies measured something else entirely. Nothing in this record points to this reason.
A different form was studied
The studied form is not the form on the shelf. Nothing in this record points to this reason.
There was nothing to correct
Where a level is already normal, topping it up may change nothing. Nothing in this record points to this reason.
Something else had to happen too
In the studies it was paired with training, a diet or another treatment. Nothing in this record points to this reason.
The change is too small to feel
A real change can still sit below what a person notices. Nothing in this record points to this reason.
Day-to-day swing hides it
Sleep, food, stress and time of day move most numbers more than this would. Nothing in this record points to this reason.
Not enough time yet
The studies ran longer than the person has waited. Nothing in this record points to this reason.
It was not taken as studied
Missed days change the result, and studies count them. Nothing in this record points to this reason.
Something else changed at the same time
Two changes at once cannot be told apart afterwards. Nothing in this record points to this reason.
The product may not be what it says
Contents of a sold product are not always what the label states. Nothing in this record points to this reason.
No recorded reason
RNAWiki has nothing stored that would explain it. Nothing in this record points to this reason.
None of these is a reason to take more. Taking more is not a step this page ever suggests.
What it would be like to take◇Read from sources, not yet reviewed
What taking it involves
The recorded facts about getting hold of it and using it. Nothing here is a suggestion about what you should do.
How it is supplied
Withdrawn
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
Read from the recorded approval status.
No source is stored against this line.
Form and route
Oral tablets and solution as codeine sulfate or phosphate; very commonly in fixed combination with paracetamol, aspirin or butalbital; prescription antitussive solutions for adults only. Schedule II as a single ingredient in the United States, with certain combinations in Schedules III and V.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form and route recorded on this substance.
No source is stored against this line.
Who oversees it
Professional supervision is normally required. A regulator classifies this substance in a way that restricts how it is supplied.
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
Suppression classes recorded: S1, S2, S5, S6, S8.
No source is stored against this line.
What is in the pack
Absorbed well by mouth with plasma half-lives of codeine and its metabolites of approximately 3 hours, and about 90% of a dose excreted renally, of which roughly 10% is unchanged codeine.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
Recorded notes on how this is sold. The rest of the recorded wording: The pharmacokinetics that matter are not codeine’s own but those of the morphine formed from it, whose rate of appearance depends on CYP2D6 activity and can be abolished by a CYP2D6 inhibitor.
No source is stored against this line.
Where it is registered
Regulatory records are listed in the technical disclosure at the foot of this page.
# Counted from records
Where this came from
A count of rows RNAWiki holds. It describes our records, not your body.
Register entries are stored per jurisdiction and shown with their dates.
No source is stored against this line.
Why people stop
Not recorded.
∅ Nothing recorded
Where this came from
RNAWiki holds nothing here and says so rather than guessing.
No record of why people stopped taking it is stored for this substance.
No source is stored against this line.
What it would be like to take◇Read from sources, not yet reviewed
What can go wrong
Sorted by where each line came from. A regulator's label and a report somebody sent in are not the same kind of fact.
·Worth asking a clinician aboutWritten into the record from the studies named on this page
Boxed warnings for addiction, abuse and misuse; life-threatening respiratory depression; accidental ingestion; concomitant benzodiazepines and other CNS depressants; neonatal opioid withdrawal syndrome; the opioid analgesic REMS; ultra-rapid metabolism of codeine in children; and the complexity of CYP3A4 and CYP2D6 interactions. Contraindicated in all children under 12, for post-operative management under 18 after tonsillectomy or adenoidectomy, in significant respiratory depression, in acute or severe asthma without monitoring, with monoamine oxidase inhibitors or within 14 days of them, and in known or suspected gastrointestinal obstruction. Breastfeeding is not recommended.
Nobody counted how many people took this and were fine, so this cannot be turned into a rate.
Over a long time. No completed tested study window is recorded, so long-term effects are not established by the registry record.
Groups the studies covered thinly. Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
What is missing or unclear◇Read from sources, not yet reviewed
Does the exact form matter?
Evidence belongs to the exact thing that was tested. A different salt, a different mixture or a different preparation is a different question.
The form that was studied
Oral tablets and solution as codeine sulfate or phosphate; very commonly in fixed combination with paracetamol, aspirin or butalbital; prescription antitussive solutions for adults only. Schedule II as a single ingredient in the United States, with certain combinations in Schedules III and V.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form used in the studies cited on this page.
No source is stored against this line.
What is sold
A recorded note compares this form with the others that are sold. It is kept below, word for word.
§ A fixed RNAWiki sentence
Where this came from
Wording RNAWiki always uses, not a finding about this substance.
The recorded note, unchanged: The pharmacokinetics that matter are not codeine’s own but those of the morphine formed from it, whose rate of appearance depends on CYP2D6 activity and can be abolished by a CYP2D6 inhibitor.
No source is stored against this line.
What is recorded as being sold
127 products list this as an active ingredient in the United States drug directory. 17 of them contain it and nothing else.
FDA National Drug Code directory · 71335-2818 · read 2026-08-29
They are sold as capsule, liquid, powder, solution, syrup and tablet, taken oral.
FDA National Drug Code directory · 71335-2818 · read 2026-08-29
The regulator's established pharmacologic class for it is full opioid agonists [moa] and opioid agonist [epc].
FDA National Drug Code directory · 71335-2818 · read 2026-08-29
95 published labels name it as an active ingredient. 2 of them describe this substance alone, which is where its own label text on this page comes from.
US prescribing information · eadc80fa-13c3-471a-a22f-6fe7e1ab290f · read 2026-08-29
Those labels are classed as human otc drug and human prescription drug.
US prescribing information · eadc80fa-13c3-471a-a22f-6fe7e1ab290f · read 2026-08-29
Codeine sulfate is tablets at Tablets: 15 mg, 30 mg, and 60 mg, recorded as prescription opioid product; fda label in effect 2025-12-22 in the United States.
US prescribing information · 010905f9-3bcb-4b50-9fe8-a3ad0010f14c · read 2026-08-27
Recorded price in US: 0.68106–1.23549 USD per one unit as the pricing file counts it — a tablet, capsule, patch or single item, across 5 priced products whose strengths and pack forms differ, as of 2026-08-26, paid by retail pharmacies buying the product, as surveyed by the Centers for Medicare & Medicaid Services. It is not a list price, an insurance price, or what anyone pays at a counter..
Recorded source · 2026-08-26 · read 2026-08-28
Evidence carries across two names for one substance. It does not carry across a salt, a mirror form or a mixture.
What it would be like to take◇Read from sources, not yet reviewed
What you could measure
This one is decided with a clinician, so this section holds questions to ask rather than a plan to run.
Self-experiment planning is not offered for a prescription or clinician-supervised medicine, withdrawn medicine. The questions below are for a clinician or pharmacist.
Questions worth asking
Which of the trials of Codeine Anhydrous studied people like me?
What was measured, and for how long?
Was the result a laboratory value or a health outcome?
What would we watch for, and when would we stop?
Tracking can show whether something changed for you. It cannot show what caused it.
RNAWiki records evidence. It does not say whether this substance is right for you.
What is missing or unclear◇Read from sources, not yet reviewed
Claims that go past the evidence
Things said about this substance that sound reasonable, and the exact step that is missing between the evidence and the claim.
✗Goes past the evidence
That a stated codeine dose produces comparable exposure across patients, when the label’s own prevalence figures for CYP2D6 ultra-rapid metabolism range from 1% to above 10% by ancestry
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That codeine is a mild opioid and therefore appropriate for children — the position held for most of a century and now a contraindication
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That restricting codeine in children reduces the underlying hazard, when the commonest substitute carries the same CYP2D6 dependency
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That the 2006 Lancet breastfeeding case report settles the breastfeeding question; the report now carries an editorial expression of concern, though the label warning rests on separate grounds
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
What is missing or unclear◇Read from sources, not yet reviewed
What nobody knows yet
Open questions, each with why it is open and what would close it.
Missing populations
Which groups were under-represented in the studies has not been recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing long-term data
No completed tested study window is recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
No reviewed conclusion
RNAWiki has not yet published a reviewed conclusion for this use.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing interaction studies
No interaction was found in the registers checked. Not finding one is not the same as showing there is none.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Formulation uncertainty
Several salts, forms or products of Codeine Anhydrous are recorded. Results from one form may not transfer to another.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Mechanism not reviewed
No reviewed mechanism story exists for this substance.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
What happened in people◇Read from sources, not yet reviewed
Check any of this yourself
Every line above traced back to the study it came from. This is the technical layer, and the vocabulary changes here.
Every line above can be traced to the study named beside it. Follow the link and read it.
A number needed to treat of twelve, and twenty-one after dental surgery
In plain words
Pooling every placebo-controlled trial of a single 60 mg dose after surgery, twelve people had to take codeine for one extra person to get at least half their pain relieved. After dental surgery it was twenty-one. Twenty-six per cent responded on codeine; seventeen per cent responded on placebo.
What was measured
Number needed to treat for at least 50% pain relief over four to six hours with codeine 60 mg against placebo
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Derry, Moore and McQuay included 35 studies in which 1,223 participants received codeine 60 mg, 27 received codeine 90 mg and 1,252 received placebo. Across all surgery types (33 studies, 2,411 participants) codeine 60 mg gave a number-needed-to-treat for at least 50% pain relief over four to six hours of 12 (95% CI 8.4 to 18). At least 50% pain relief was achieved by 26% on codeine 60 mg against 17% on placebo. After dental surgery the NNT was 21 (12 to 96) across 15 studies and 1,146 participants; after other surgery it was 6.8 (4.6 to 13) across 18 studies and 1,265 participants. The NNT to prevent rescue medication within four to six hours was 11 (6.3 to 50), with mean time to rescue 2.7 hours on codeine against 2.0 on placebo. More participants reported adverse events on codeine than placebo, though the difference was not significant and none were serious. For scale, the same Cochrane programme puts ibuprofen 200 mg plus paracetamol 500 mg at an NNT of 1.6.
Written into the record, not signed off as a reviewed claim
Children died, and the drug was contraindicated in an entire age group
In plain words
Children given codeine after routine tonsil surgery stopped breathing and died. Post-mortem work showed they carried extra copies of the gene that turns codeine into morphine. Codeine is now forbidden in every child under twelve.
What was measured
That codeine is a mild opioid safe for routine paediatric use — a position held for most of a century and reversed to a contraindication in every child under 12
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Ciszkowski, Madadi, Phillips, Lauwers and Koren reported a post-tonsillectomy death in a child with an ultrarapid-metaboliser CYP2D6 genotype in the New England Journal of Medicine in 2009. The FDA added a boxed warning in 2013 contraindicating codeine after tonsillectomy or adenoidectomy in children, and on 20 April 2017 issued a Drug Safety Communication contraindicating codeine in all children under 12, contraindicating tramadol under 12 and after tonsillectomy or adenoidectomy under 18, warning against both in adolescents with obesity or conditions predisposing to respiratory depression, and recommending against breastfeeding on either drug. The current Codeine Sulfate Tablets label carries all of this: contraindication in all children younger than 12 and for post-operative management under 18 after tonsillectomy or adenoidectomy, with the boxed warning stating that life-threatening respiratory depression and death have occurred in children who received codeine, that most reported cases followed those operations, and that many of the children had evidence of ultra-rapid metabolism due to a CYP2D6 polymorphism.
Written into the record, not signed off as a reviewed claim
The breastfeeding case report now carries an expression of concern
In plain words
A 2006 Lancet case report of a newborn who died of morphine poisoning through breast milk became one of the most cited reasons for warning mothers off codeine. In February 2026 The Lancet published an expression of concern about that report.
What was measured
That a single 2006 case report established the breastfeeding hazard — the report is now under an editorial expression of concern, while the label’s warning and the underlying pharmacogenetic mechanism stand on separate evidence
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Koren, Cairns, Chitayat, Gaedigk and Leeder reported in The Lancet in 2006 the death of a breastfed neonate whose mother, prescribed codeine, was a CYP2D6 ultrarapid metaboliser. On 14 February 2026 (published online 3 February 2026) the editors of The Lancet issued an Expression of Concern regarding that report. An expression of concern is not a retraction and does not by itself invalidate the finding; it signals that the editors have unresolved questions about the work. The regulatory position does not rest on that single paper — the current codeine label states independently that at least one death was reported in a nursing infant exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metaboliser, and the pharmacological mechanism is the same one demonstrated in the post-tonsillectomy deaths. But a reader tracing the breastfeeding warning back to its most-cited source should know what has happened to that source.
Written into the record, not signed off as a reviewed claim
Restricting codeine in children pushed prescribers to a drug with the same defect
In plain words
After the 2017 FDA communication, codeine dispensing to children fell by a quarter. Tramadol dispensing to children rose by a fifth — and tramadol depends on the same enzyme, which is exactly why the same communication restricted it too.
What was measured
Immediate level change in codeine and tramadol dispensing rates to children after April 2017, by segmented regression
Effect estimate
No reviewed effect estimate exists for this record.
Limits
This entry records a failure.
From the source
Renny, Jent, Townsend and Cerdá ran an interrupted time series with segmented regression on 2014-2019 opioid dispensing to patients under 18 from the IQVIA Longitudinal Prescription Database, which covers 86% to 92% of United States retail pharmacy prescriptions, comprising about 1.92 million codeine prescriptions for children and 2.40 million for adolescents plus 514,090 tramadol prescriptions for children and 1.06 million for adolescents. After April 2017, codeine dispensing to children fell immediately by 26% (IRR 0.742, 95% CI 0.684 to 0.806) with a sustained 5% monthly decline (IRR 0.950, 95% CI 0.944 to 0.955), and to adolescents by 17% (IRR 0.829, 95% CI 0.762 to 0.898). Tramadol dispensing to children rose immediately by 22% (IRR 1.223, 95% CI 1.068 to 1.401), followed by a sustained 3% decline; adolescent tramadol dispensing showed no immediate change. The 2017 communication restricted both drugs for the same reason. The prescribing response treated it as a restriction on one.
Written into the record, not signed off as a reviewed claim
The population spread of the converting enzyme is enormous
In plain words
The proportion of people who convert codeine unusually fast ranges from about one in a hundred to more than one in ten depending on ancestry. Nobody knows their own status, and the prescription is written as though everyone were average.
What was measured
That a stated codeine dose produces a broadly similar effect from patient to patient — contradicted by the label’s own account of CYP2D6 phenotype prevalence and by the deaths that account was written to explain
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
The Codeine Sulfate Tablets label states that some individuals are ultra-rapid metabolisers because of a specific CYP2D6 genotype such as the gene duplications denoted *1/*1xN or *1/*2xN, and that the prevalence of this phenotype varies widely: estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and possibly greater than 10% in certain groups including Oceanian, Northern African, Middle Eastern, Ashkenazi Jewish and Puerto Rican populations. These individuals convert codeine to morphine more rapidly and completely, producing higher than expected serum morphine, and may have life-threatening or fatal respiratory depression even at labelled dosage. The label concludes that ultra-rapid metabolisers should not use codeine. The inference embedded in ordinary prescribing is that a fixed milligram dose produces a broadly comparable exposure across patients. For this molecule that inference is false by design, and the label says so while offering no routine way to identify the affected patients before the first dose.
Source
Codeine Sulfate Tablets United States prescribing information, Warnings and Precautions 5.6 CYP2D6 Genetic Variability (NDA 022402)
Role in the trial
Not matched to a registered study
Identity check
no open identity hold
Audit mark
caution
Review state
Written into the record, not signed off as a reviewed claim
In a randomised emergency department comparison, it was not distinguishable
In plain words
Given to people with a painful arm or leg injury, codeine plus paracetamol reduced pain by 3.9 points out of ten at two hours. Ibuprofen plus paracetamol reduced it by 4.3. The difference was not statistically or clinically significant.
What was measured
Decline in pain on an 11-point numerical rating scale two hours after codeine-paracetamol against three comparators
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Chang and colleagues randomised 416 emergency department patients aged 21 to 64 with moderate to severe acute extremity pain, of whom 411 were analysed, to one of four single-dose combinations. Baseline mean pain was 8.7 (SD 1.3) on an 11-point numerical rating scale. Mean two-hour decline was 3.9 (95% CI 3.2 to 4.5) for codeine 30 mg plus paracetamol 300 mg, 4.3 (3.6 to 4.9) for ibuprofen 400 mg plus paracetamol 1000 mg, 4.4 (3.7 to 5.0) for oxycodone-paracetamol and 3.5 (2.9 to 4.2) for hydrocodone-paracetamol; the overall between-group p was 0.053 and the largest pairwise difference was 0.9, below the pre-specified minimum clinically important difference of 1.3. Adverse events were not assessed. A single-dose two-hour endpoint is a narrow question, and it is the question a person in an emergency department is actually asking.
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The older medicine-wide conclusion held in this record
Written for a clinical reader, and about the medicine as a whole rather than about one indication, population and set of trials. RNAWiki does not treat it as a programme conclusion and no reviewer has signed it off in that form. It is here word for word because it is what the record holds.
A prodrug of which only 5 to 10% becomes morphine, at a rate set by CYP2D6 gene copy number, giving a Cochrane number-needed-to-treat of 12 (95% CI 8.4 to 18) for at least half pain relief after surgery — 26% responding against 17% on placebo — and a boxed warning built out of children who died after tonsillectomy because their copy of the enzyme worked too well.
Recorded evidence blocks (9)
Q2
On the Codeine Anhydrous label: indicated for what?
"Codeine sulfate tablets are indicated for the management of mild to moderate pain, where treatment with an opioid is appropriate and for which alternative treatments are inadequate. L i m i t ations of Use: Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration…": indications and usage on Codeine Anhydrous's label. DailyMed label · 5819bdf7-300e-45b8-8f3a-447b53656293 · 2026-01-16
Q3
28 registered trials of Codeine Anhydrous — at which phases?
3 hours; The plasma half-lives of codeine and its metabolites have been reported to be approximately 3 hours.
metabolismpharmacokinetics
E li mi nation: Codeine is metabolized by conjugation to codeine-6-glucuronide (70% to 80%), by O -demethylation to morphine (5% to 10%), and by N -demethylation to norcodeine (~10%).
recorded 2026-01-16 · last checked 2026-09-04
Q7
Which 20 trials of Codeine Anhydrous posted no result?
Posted no result
20 of 20 completed trials
Registrations
NCT00174538, NCT00378937, NCT01010139, NCT00456898, NCT01009853 and NCT01009892, and 14 more
Completion dates
oldest 2005-12; newest 2024-05-17
Show the evidence
Trial
NCT00174538
2005-12
NCT00378937
2006-02
NCT01010139
2006-09
NCT00456898
2007-03
NCT01009853
2008-01
NCT01009892
2008-01
14 further recorded trials
NCT01010152
2008-01
NCT01009697
2008-04
NCT01322204
2013-03-06
NCT01845194
2013-10
NCT01672112
2015-01
NCT00921700
2015-04
NCT01788254
2015-05
NCT02625753
2015-10
NCT02737059
2017-05-10
NCT03239821
2018-04-30
NCT03784105
2018-12-14
NCT05770960
2019-05-09
NCT05626140
2022-07-31
NCT04641338
2024-05-17
Q8
At the median, Codeine Anhydrous's trials enrolled 40 people — anything larger?
Median enrolment
40
Largest enrolment
720
Registered trials counted
28
Q9
Codeine Anhydrous and CYP3A4 and CYP2D6: shared by which compounds?
Table 1: Clinically Significant Drug Interactions with Codeine Sulfate Tablets Inhibitors of CYP3A4 C li n i cal Impact: The concomitant use of codeine sulfate tablets with CYP3A4 inhibitors, may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions…
drug_interactions
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower codeine levels, greater norcodeine levels, and less metabolism via CYP2D6 with resultant lower morphine levels [see Clinical Pharmacology ( 12.3 ) ] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to codeine.
drug_interactions
Intervention: If concomitant use of CYP3A4 inhibitor is necessary, consider dosage reduction of codeine sulfate tablets until stable drug effects are achieved.
drug_interactions
If a CYP3A4 inhibitor is discontinued, consider increasing the codeine sulfate tablets dosage until stable drug effects are achieved.
drug_interactions
CY P 3A4 Inducers C li n i cal Impact: The concomitant use of codeine sulfate tablets and CYP3A4 inducers can result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels [see Clinical Pharmacology ( 12.3 ) ] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence [see…
drug_interactions
After stopping a CYP3A4 inducer, as the effects of the inducer decline, codeine plasma concentrations may increase with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels [see Clinical Pharmacology ( 12.3 ) ] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
2 more recorded rows
Interaction statementdrug_interactions
Intervention: If concomitant use of a CYP3A4 inducer is necessary, evaluate patients at frequent intervals for reduced efficacy and signs of opioid withdrawal and consider increasing the codeine sulfate tablets dosage as needed.
Interaction statementdrug_interactions
If a CYP3A4 inducer is discontinued, consider codeine sulfate tablets dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation.
ChEMBL 37 — CC BY-SA 3.0 Unported · ClinicalTrials.gov — US Government work · mixed register set; per-register licences in docs/specs/corpus-20k-sources.md · openFDA / DailyMed — US Government work
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