This page shows what was measured, who it was measured in, and what that does not settle.
What Hydrocodone does in the body
Pain severe enough to need an opioid, most often as a combination tablet with paracetamol
Hydrocodone binds the mu-opioid receptor, the same one morphine uses, and turns it on: less pain signal reaching the brain from the spinal cord, and less distress attached to what does get through. It also acts on the cough centre in the brainstem, which is why it was sold as a cough medicine for seventy years. Most of a dose is destroyed by the liver enzyme CYP3A4 into an inactive by-product; a much smaller fraction is converted by a second enzyme, CYP2D6, into hydromorphone, a considerably stronger opioid. The manufacturer’s own label puts that fraction at under 3% of circulating drug and says only that it may contribute to the effect.
What happened in people
Mean two-hour pain reduction of 3.5 points (95% CI 2.9 to 4.2) with hydrocodone 5 mg plus paracetamol 300 mg in 411 randomised emergency department patients — the smallest of four arms, none significantly different
✎ 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.
Chang trial registration — ClinicalTrials.gov NCT02455518 (NCT02455518) · a recorded source, not a stored snapshot
Drug Enforcement Administration. Schedules of Controlled Substances: Rescheduling of Hydrocodone Combination Products From Schedule III to Schedule II. 79 FR… · a recorded source, not a stored snapshot
The limit that matters most
That hydrocodone works chiefly by CYP2D6 conversion to hydromorphone, when the label puts that metabolite under 3% and says only that it may contribute
Where it acts
Mu-opioid receptors of the spinal dorsal horn and brainstem; and the cough centre of the medulla, which is the reason hydrocodone spent decades in cough syrup
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.
What the registries record it as
The substance registry classes this as chemical.
FDA substance registry · 6YKS4Y3WQ7 · read 2026-08-29
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 165 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.
Placebo
A placebo is a dummy treatment given so the real one can be compared with it.
A picture of it, and where the picture fails
A placebo is like a blank control in an experiment.
Where that stops being true. A blank does nothing. People given a placebo often do get better.
What people get wrong. A placebo effect is read as imaginary. The improvement is measured and real.
An inactive intervention matched in appearance to the test intervention, used to control for non-specific effects.
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.
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.
Between-group difference in decline in pain on an 11-point numerical rating scale two hours after a single oral dose, comparing ibuprofen-paracetamol, oxycodone-paracetamol, hydrocodone-paracetamol and codeine-paracetamol in acute extremity pain
✗ The study did not show it
Who was studied
NCT02455518 (Chang et al., JAMA 2017;318:1661-1667)
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
Overall p=0.053; mean two-hour decline 4.3 ibuprofen-paracetamol, 4.4 oxycodone-paracetamol, 3.5 hydrocodone-paracetamol, 3.9 codeine-paracetamol; largest pairwise difference 0.9 (99.2% CI −0.1 to 1.8) against a pre-specified minimum clinically important difference of 1.3
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 in this trial, which the authors identify as a limitation and which matters because the four arms differ substantially in expected adverse-effect profile. 411 of 416 randomised patients were analysed.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral immediate-release tablets, capsules and solution, almost always in fixed combination with paracetamol or ibuprofen; single-entity oral extended-release tablets and capsules; oral antitussive solutions for adults only. Schedule II controlled substance in the United States since 6 October 2014.
Interval reported. Not recorded in this summary
Written into the record, not signed off as a reviewed claim.
Chang trial registration — ClinicalTrials.gov NCT02455518 (NCT02455518) · a recorded source, not a stored snapshot
Drug Enforcement Administration. Schedules of Controlled Substances: Rescheduling of Hydrocodone Combination Products From Schedule III to Schedule II. 79 FR… · a recorded source, not a stored snapshot
Food and Drug Administration. Prescription Drug Products Containing Acetaminophen; Actions To Reduce Liver Injury From Unintentional Overdose. 76 FR 2691, 14… · a recorded source, not a stored snapshot
Advisory committee vote on whether to recommend approval of single-entity extended-release hydrocodone bitartrate without an abuse-deterrent formulation
✗ The study did not show it
Who was studied
NDA 202880 (ZOHYDRO ER) advisory committee review and approval
How many people
13
Study design
Regulatory review, FDA Anesthetic and Analgesic Drug Products Advisory Committee
Compared against
Not recorded for this study
Kind of result
A number that stands in for health
What was found
Vote 11 to 2 against recommending approval, with the committee agreeing the applicant had met the agency’s efficacy and safety standards
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. The FDA approved the product on 25 October 2013 notwithstanding the vote. Drugs@FDA now lists all ZOHYDRO ER strengths under NDA 202880 as discontinued. This row records a regulatory vote rather than a clinical trial and is included because it is the measurement that most directly captures expert judgement on this product.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral immediate-release tablets, capsules and solution, almost always in fixed combination with paracetamol or ibuprofen; single-entity oral extended-release tablets and capsules; oral antitussive solutions for adults only. Schedule II controlled substance in the United States since 6 October 2014.
Interval reported. Not recorded in this summary
Written into the record, not signed off as a reviewed claim.
Chang trial registration — ClinicalTrials.gov NCT02455518 (NCT02455518) · a recorded source, not a stored snapshot
Drug Enforcement Administration. Schedules of Controlled Substances: Rescheduling of Hydrocodone Combination Products From Schedule III to Schedule II. 79 FR… · a recorded source, not a stored snapshot
Food and Drug Administration. Prescription Drug Products Containing Acetaminophen; Actions To Reduce Liver Injury From Unintentional Overdose. 76 FR 2691, 14… · a recorded source, not a stored snapshot
What we know
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.
Start
Hydrocodone
What a person takes: Oral immediate-release tablets, capsules and solution, almost always in fixed combination with paracetamol or ibuprofen; single-entity oral extended-release tablets and capsules; oral antitussive solutions for adults only. Schedule II controlled substance in the United States since 6 October 2014..
The measurement behind this step
Immediate-release combination tablets act within about an hour and are dosed several times a day. The single-entity extended-release products were developed specifically to remove the paracetamol ceiling that limits how much hydrocodone a combination tablet can carry, which is also the reason they attracted the regulatory controversy they did. Extended-release terminal half-life is approximately 7 to 9 hours.
Getting in
Usually arriving inside a paracetamol tablet
Most hydrocodone is dispensed as a combination tablet: five or ten milligrams of opioid alongside three hundred of paracetamol. Single-ingredient slow-release versions exist and are a much smaller part of the picture.
╌╌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
Hydrocodone bitartrate hemipentahydrate in immediate-release combination tablets, or as single-entity extended-release capsules and tablets. Since January 2011 the paracetamol content of a prescription combination unit is capped at 325 mg by FDA action at 76 FR 2691.
Chang trial registration — ClinicalTrials.gov NCT02455518 (NCT02455518) · a recorded source, not a stored snapshot
Drug Enforcement Administration. Schedules of Controlled Substances: Rescheduling of Hydrocodone Combination Products From Schedule III to Schedule II. 79 FR… · a recorded source, not a stored snapshot
Reaching the cell
The liver mostly destroys it, and slightly upgrades it
One enzyme turns most of the dose into an inactive by-product. A second turns a small fraction into a much stronger opioid — under three per cent of what is circulating, according to the manufacturer.
╌╌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
CYP3A4-mediated N-demethylation to inactive norhydrocodone is primary, with contributions from CYP2B6 and CYP2C19. CYP2D6-mediated O-demethylation yields hydromorphone at under 3% of circulating parent. Mean terminal half-life for extended-release hydrocodone is approximately 7 to 9 hours and 99% of a dose is eliminated within 72 hours.
Chang trial registration — ClinicalTrials.gov NCT02455518 (NCT02455518) · a recorded source, not a stored snapshot
Drug Enforcement Administration. Schedules of Controlled Substances: Rescheduling of Hydrocodone Combination Products From Schedule III to Schedule II. 79 FR… · a recorded source, not a stored snapshot
What it acts on
Full agonism at the mu receptor
What reaches the brain binds the same receptor as morphine and turns it fully on.
╌╌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: adenylyl cyclase inhibition, GIRK channel opening, N-type calcium channel closure, neuronal hyperpolarisation and reduced transmitter release.
Chang trial registration — ClinicalTrials.gov NCT02455518 (NCT02455518) · a recorded source, not a stored snapshot
Drug Enforcement Administration. Schedules of Controlled Substances: Rescheduling of Hydrocodone Combination Products From Schedule III to Schedule II. 79 FR… · a recorded source, not a stored snapshot
The change it makes
And at the cough centre, which is a separate circuit
The reflex that makes you cough is generated in the brainstem and carries opioid receptors of its own. That is why the same molecule was a painkiller and a cough syrup for seventy years.
──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
Opioid suppression of the medullary cough centre and of afferent input from airway rapidly adapting receptors. Since 11 January 2018 prescription hydrocodone cough products are labelled for adults 18 and over only, and are not indicated for cough in any paediatric population.
Chang trial registration — ClinicalTrials.gov NCT02455518 (NCT02455518) · a recorded source, not a stored snapshot
Drug Enforcement Administration. Schedules of Controlled Substances: Rescheduling of Hydrocodone Combination Products From Schedule III to Schedule II. 79 FR… · a recorded source, not a stored snapshot
What that does for a person
Two hours later, on the pain scale
In the one randomised head-to-head trial, average pain fell 3.5 points out of ten — the smallest fall of the four tablets tested, and not significantly different from any of them.
──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
Chang 2017: mean two-hour decline in numerical rating scale pain 3.5 (95% CI 2.9 to 4.2) for hydrocodone 5 mg plus paracetamol 300 mg, against 4.3 for ibuprofen 400 mg plus paracetamol 1000 mg, 4.4 for oxycodone-paracetamol and 3.9 for codeine-paracetamol; overall p=0.053 across 411 analysed patients.
Chang trial registration — ClinicalTrials.gov NCT02455518 (NCT02455518) · a recorded source, not a stored snapshot
Drug Enforcement Administration. Schedules of Controlled Substances: Rescheduling of Hydrocodone Combination Products From Schedule III to Schedule II. 79 FR… · a recorded source, not a stored snapshot
What that does for a person
The dose ceiling belongs to the other ingredient
What stops someone taking more combination tablets is usually the liver risk from paracetamol, not the opioid. The regulator capped that ingredient and put a boxed warning on it.
╌╌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
Paracetamol hepatotoxicity is a saturable-conjugation problem: once glucuronidation and sulfation saturate, the reactive intermediate NAPQI depletes glutathione and binds hepatocyte protein. The FDA capped prescription combination units at 325 mg and required a boxed warning, on the stated basis that unintentional overdose is a serious public health problem.
Chang trial registration — ClinicalTrials.gov NCT02455518 (NCT02455518) · a recorded source, not a stored snapshot
Drug Enforcement Administration. Schedules of Controlled Substances: Rescheduling of Hydrocodone Combination Products From Schedule III to Schedule II. 79 FR… · a recorded source, not a stored snapshot
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.
People with acute pain after injury, dental work or surgery; people with long-term pain, where the evidence is much weaker; and formerly children with a cough, which the FDA ended in 2018.
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 hydrocodone bitartrate extended-release tablets in pediatric patients have not been established.”
US prescribing information · f7b55d14-0980-b680-8ceb-7489ff65455e · read 2026-08-30
On older people, the label states: “In a controlled pharmacokinetic study, elderly subjects (greater than 65 years) compared to young adults had similar plasma concentrations of hydrocodone [see Clinical Pharmacology ( 12.3 )] .”
US prescribing information · f7b55d14-0980-b680-8ceb-7489ff65455e · read 2026-08-30
On people who are pregnant, the label states: “Risk 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 · f7b55d14-0980-b680-8ceb-7489ff65455e · read 2026-08-30
On people who are breastfeeding, the label states: “8.3 Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential.”
US prescribing information · f7b55d14-0980-b680-8ceb-7489ff65455e · read 2026-08-30
On people with reduced liver function, the label states: “No adjustment in starting dose with hydrocodone bitartrate extended-release tablets is required in patients with mild or moderate hepatic impairment.”
US prescribing information · f7b55d14-0980-b680-8ceb-7489ff65455e · read 2026-08-30
On people with reduced kidney function, the label states: “No dose adjustment is needed in patients with mild renal impairment.”
US prescribing information · f7b55d14-0980-b680-8ceb-7489ff65455e · read 2026-08-30
Where the result stopped carrying
The head-to-head comparison: hydrocodone-paracetamol had the smallest mean pain reduction of the four tablets tested, including the non-opioid one
The advisory committee vote on Zohydro ER, 11 to 2 against, which the FDA overruled and whose product is now discontinued
The paediatric cough indication, withdrawn by labelling change on 11 January 2018
The original paracetamol strengths, capped at 325 mg per dosage unit with a boxed liver-injury warning in January 2011
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
Prescription only
❝ 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 immediate-release tablets, capsules and solution, almost always in fixed combination with paracetamol or ibuprofen; single-entity oral extended-release tablets and capsules; oral antitussive solutions for adults only. Schedule II controlled substance in the United States since 6 October 2014.
✎ 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: S2, S5, S6.
No source is stored against this line.
What is in the pack
Immediate-release combination tablets act within about an hour and are dosed several times a day.
✎ 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 single-entity extended-release products were developed specifically to remove the paracetamol ceiling that limits how much hydrocodone a combination tablet can carry, which is also the reason they attracted the regulatory controversy they did. Extended-release terminal half-life is approximately 7 to 9 hours.
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
Class boxed warnings for addiction, abuse and misuse; life-threatening respiratory depression; accidental ingestion; neonatal opioid withdrawal syndrome; risks from concomitant benzodiazepines, other CNS depressants and alcohol; the opioid analgesic REMS; and CYP3A4 interaction. Combination products carry an additional boxed warning for hepatotoxicity from paracetamol, and every prescription combination unit has been limited to 325 mg of paracetamol since the FDA action of January 2011. Prescription cough products containing hydrocodone are contraindicated in anyone under 18.
Nobody counted how many people took this and were fine, so this cannot be turned into a rate.
Chang trial registration — ClinicalTrials.gov NCT02455518 (NCT02455518) · a recorded source, not a stored snapshot
Drug Enforcement Administration. Schedules of Controlled Substances: Rescheduling of Hydrocodone Combination Products From Schedule III to Schedule II. 79 FR… · a recorded source, not a stored snapshot
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 immediate-release tablets, capsules and solution, almost always in fixed combination with paracetamol or ibuprofen; single-entity oral extended-release tablets and capsules; oral antitussive solutions for adults only. Schedule II controlled substance in the United States since 6 October 2014.
✎ 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 single-entity extended-release products were developed specifically to remove the paracetamol ceiling that limits how much hydrocodone a combination tablet can carry, which is also the reason they attracted the regulatory controversy they did. Extended-release terminal half-life is approximately 7 to 9 hours.
No source is stored against this line.
What is recorded as being sold
264 products list this as an active ingredient in the United States drug directory. 33 of them contain it and nothing else.
FDA National Drug Code directory · 71930-021 · read 2026-08-29
They are sold as capsule, extended release, liquid, powder, solution, suspension, extended release and syrup, taken oral.
FDA National Drug Code directory · 71930-021 · read 2026-08-29
The regulator's established pharmacologic class for it is opioid agonist [epc] and opioid agonists [moa].
FDA National Drug Code directory · 71930-021 · read 2026-08-29
169 published labels name it as an active ingredient. 3 of them describe this substance alone, which is where its own label text on this page comes from.
US prescribing information · d4caec6d-4af2-4f1c-9add-c0c948b83b16 · read 2026-08-29
Those labels are classed as human prescription drug.
US prescribing information · d4caec6d-4af2-4f1c-9add-c0c948b83b16 · read 2026-08-29
Hydrocodone Bitartrate is oral at 3 DOSAGE FORMS AND STRENGTHS 20 mg film-coated extended-release tablets (white, round, film-coated tablet, “A392” printed in black ink on one side, blank on the other side) 30 mg film-coated extended-release tablets (be…, recorded as fda label in effect 2025-10-07 in the United States.
US prescribing information · f7b55d14-0980-b680-8ceb-7489ff65455e · read 2026-08-30
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. The questions below are for a clinician or pharmacist.
Questions worth asking
Which of the trials of Hydrocodone 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 hydrocodone works chiefly by CYP2D6 conversion to hydromorphone, when the label puts that metabolite under 3% and says only that it may contribute
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 opioid component is what limits how many combination tablets a person can safely take — in practice the paracetamol ceiling binds first
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 an antitussive benefit observed in adults transferred to children, an inference the FDA reversed in January 2018
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 Schedule III placement reflected a lower pharmacological risk rather than an accident of how combination products were classified
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 Hydrocodone 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.
Head to head in an emergency department, it came last
In plain words
Four hundred and eleven people with a moderately to severely painful arm or leg injury were randomly given one of four tablets. Hydrocodone with paracetamol produced the smallest average pain reduction of the four. Ibuprofen with paracetamol, which needs no prescription, was second best.
What was measured
Decline in pain on an 11-point numerical rating scale two hours after a single oral dose
Effect estimate
No reviewed effect estimate exists for this record.
Limits
This entry records a failure.
From the source
Chang and colleagues randomised 416 patients aged 21 to 64 with moderate to severe acute extremity pain at two urban emergency departments in the Bronx, of whom 411 were analysed (mean age 37, 48% women, 60% Latino). Participants received ibuprofen 400 mg plus paracetamol 1000 mg; oxycodone 5 mg plus paracetamol 325 mg; hydrocodone 5 mg plus paracetamol 300 mg; or codeine 30 mg plus paracetamol 300 mg, 104 per group. Baseline mean pain was 8.7 (SD 1.3) on an 11-point numerical rating scale. At two hours the mean decline was 4.3 (95% CI 3.6 to 4.9) for ibuprofen-paracetamol, 4.4 (3.7 to 5.0) for oxycodone-paracetamol, 3.5 (2.9 to 4.2) for hydrocodone-paracetamol and 3.9 (3.2 to 4.5) for codeine-paracetamol, with an overall p of 0.053. The largest pairwise gap, oxycodone against hydrocodone, was 0.9 (99.2% CI −0.1 to 1.8), below the pre-specified minimum clinically important difference of 1.3. Adverse events were not assessed, which the authors state as a limitation.
Written into the record, not signed off as a reviewed claim
137 million prescriptions a year, in the wrong schedule
In plain words
Hydrocodone combination tablets were Schedule III for decades — refillable, prescribable by telephone — while every other strong opioid was Schedule II. The DEA moved them in 2014, without any new pharmacology.
What was measured
Prescriptions of hydrocodone combination products dispensed in the United States in 2013: over 137 million, per the DEA final rule
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
The Drug Enforcement Administration published its final rule on 22 August 2014 at 79 FR 49661, rescheduling hydrocodone combination products from Schedule III to Schedule II of the Controlled Substances Act, effective 6 October 2014. The rule imposed the full regulatory, administrative, civil and criminal controls applicable to Schedule II on everyone handling these products. In its own regulatory impact analysis the DEA states that hydrocodone combination products are the most prescribed opioid drugs in the United States, with over 137 million prescriptions dispensed in 2013. Single-ingredient hydrocodone had always been Schedule II; the combination products were where the volume was, and the schedule they sat in permitted refills and oral prescriptions that Schedule II does not. Nothing about the molecule changed in 2014. What changed was the regulator’s reading of how the schedule had been used.
Source
Drug Enforcement Administration. Schedules of Controlled Substances: Rescheduling of Hydrocodone Combination Products From Schedule III to Schedule II. Final rule, 79 FR 49661, 22 August 2014, effective 6 October 2014
Role in the trial
Not matched to a registered study
Identity check
no open identity hold
Audit mark
verified
Review state
Written into the record, not signed off as a reviewed claim
Approved over its own advisory committee, eleven votes to two
In plain words
The FDA convened its expert advisory committee on the first single-ingredient extended-release hydrocodone. The committee voted 11 to 2 against recommending approval. The agency approved it anyway, in October 2013. The product is now discontinued.
What was measured
That meeting the statutory efficacy and safety standard settles whether an opioid product should reach the market — a position eleven of thirteen advisory committee members rejected for this product
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Zohydro ER, an extended-release hydrocodone bitartrate capsule with no paracetamol and no abuse-deterrent formulation, was reviewed by the FDA Anesthetic and Analgesic Drug Products Advisory Committee, which voted 11 to 2 against recommending approval while agreeing the applicant had met the agency’s efficacy and safety standards; committee members stated that the standards for opioid product approval should be raised given the public health situation. The FDA approved the product on 25 October 2013 under NDA 202880. The approval drew formal objections from members of Congress and from Public Citizen. Drugs@FDA now lists every Zohydro ER product strength under NDA 202880 as discontinued. The instructive point is not that the agency was wrong to overrule its committee — advisory votes are advisory — but that the same evidence supported both a positive regulatory decision and an eleven-to-two vote against, because the committee was weighing something the approval standard does not measure.
Source
FDA Drugs@FDA record for NDA 202880 (ZOHYDRO ER), all strengths listed as discontinued; FDA Anesthetic and Analgesic Drug Products Advisory Committee vote of 11-2 against approval, December 2012
Role in the trial
Not matched to a registered study
Identity check
no open identity hold
Audit mark
contested
Review state
Written into the record, not signed off as a reviewed claim
The ingredient that limits the dose is the paracetamol
In plain words
In a hydrocodone combination tablet, the opioid is a few milligrams and the paracetamol is hundreds. The FDA capped the paracetamol at 325 mg per tablet and put a boxed warning about liver failure on every prescription product containing it.
What was measured
Maximum permitted paracetamol content per dosage unit in a prescription combination product: 325 mg
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
On 14 January 2011 the FDA published notice at 76 FR 2691, "Prescription Drug Products Containing Acetaminophen; Actions To Reduce Liver Injury From Unintentional Overdose", reducing the maximum dosage unit strength of paracetamol in prescription drug products to 325 mg and requiring safety labelling changes including a new boxed warning about the risk of liver damage. The agency’s stated reasoning was that liver damage due to paracetamol overdosing is a serious public health problem and that a lower unit strength provides an increased margin of safety. Manufacturers were given until January 2014. The mechanism of the problem is arithmetic rather than pharmacological: a patient in pain takes more tablets, and the ingredient they exceed first is the one they were not thinking about.
Source
Food and Drug Administration. Prescription Drug Products Containing Acetaminophen; Actions To Reduce Liver Injury From Unintentional Overdose. 76 FR 2691, 14 January 2011
Role in the trial
Not matched to a registered study
Identity check
no open identity hold
Audit mark
verified
Review state
Written into the record, not signed off as a reviewed claim
The prodrug story is much smaller than it is usually told
In plain words
Hydrocodone is often described the way codeine is: inactive until a liver enzyme converts it into something strong. The manufacturer’s own label says the strong metabolite is under 3% of what circulates, and only that it may contribute.
What was measured
That hydrocodone acts chiefly through CYP2D6 conversion to hydromorphone, as codeine acts through conversion to morphine — a claim the label puts at under 3% of circulating drug and qualifies with "may contribute"
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
The Hysingla ER label states that hydrocodone exhibits a complex pattern of metabolism including N-demethylation, O-demethylation and 6-keto reduction; that CYP3A4-mediated N-demethylation to inactive norhydrocodone is the primary metabolic pathway with lower contributions from CYP2B6 and CYP2C19; and that the minor metabolite hydromorphone, under 3% of circulating parent hydrocodone, is mainly formed by CYP2D6-mediated O-demethylation with smaller contributions from CYP2B6 and CYP2C19. It then says only that hydromorphone "may contribute to the total analgesic effect of hydrocodone." That is a much weaker statement than the one made about codeine, whose activity is attributed to morphine conversion outright. Treating hydrocodone as a CYP2D6-dependent prodrug — and therefore predicting failure in poor metabolisers and danger in ultrarapid ones — extends a mechanism established for a different molecule onto a label that declines to make the claim.
Source
HYSINGLA ER (hydrocodone bitartrate extended-release tablets) United States prescribing information, Clinical Pharmacology 12.3 (NDA 206627)
Role in the trial
Not matched to a registered study
Identity check
no open identity hold
Audit mark
contested
Review state
Written into the record, not signed off as a reviewed claim
Seventy years as a cough medicine, ended for anyone under eighteen
In plain words
Hydrocodone syrups were given to children for cough for decades. On 11 January 2018 the FDA required the labels to be changed so the products are for adults only, on the reasoning that the risks outweigh the benefits in children.
What was measured
That an antitussive benefit established in adults by long custom transfers to children — a transfer the FDA reversed in 2018 on benefit-risk grounds
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
The FDA required safety labelling changes for prescription cough and cold medicines containing hydrocodone or codeine, limiting their use to adults aged 18 and over, and required the addition of information on misuse, abuse, addiction, overdose, death and slowed or difficult breathing to the boxed warning. After the changes, these products are no longer indicated to treat cough in any paediatric population. The agency stated that the risks — slowed or difficult breathing, misuse, abuse, addiction, overdose and death — appear greater in children and adolescents under 18, and that the benefit-risk balance no longer supported paediatric use. This is a conclusion shift on an indication that predates the modern trial era: the antitussive use was established by observation and custom rather than by paediatric randomised trials, and it was withdrawn on the harm side of the ledger rather than because the benefit was disproved.
Source
FDA Drug Safety Communication, 11 January 2018: FDA requires labeling changes for prescription opioid cough and cold medicines to limit their use to adults 18 years and older
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
How many documents were read
3 documents were read for this substance.
RNAWiki source record
2 of them state the same proteinBinding, and they agree.
RNAWiki source record
2 of them state the same volumeOfDistribution, and they agree.
RNAWiki source record
Where else this substance is registered
FDA substance identifier (UNII)
6YKS4Y3WQ7
CAS registry number
125-29-1
PubChem compound
5284569
ChEMBL
CHEMBL1457
ChEBI
5779
WHO international nonproprietary name list entry
1700
RxNorm concept
5489
EMA substance identifier
100000084214
European Chemicals Agency number
204-733-9
DrugBank
DB00956
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Suppression classes recorded: S2, S5, S6.
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What is missing or unclear◇Read from sources, not yet reviewed
How this medicine reached us
Kept near the foot of the page. A historical event moves up only when it changes something about this substance today.
What the approval register records
199 approved applications cover products containing this substance. The earliest was NDA005213, approved 19430323 to GENUS.
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What is not here
7 questions this page could not answer
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The older medicine-wide conclusion held in this record
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A full mu-opioid agonist that in a four-arm randomised trial of 411 emergency department patients with acute limb pain produced the smallest two-hour pain reduction of the four combinations tested — 3.5 points against 4.3 for ibuprofen plus paracetamol, with no statistically significant difference between any of them (p=0.053) — and whose 137 million annual prescriptions sat in Schedule III until the DEA moved hydrocodone combination products to Schedule II on 6 October 2014.
Recorded evidence blocks (7)
Q2
On the Hydrocodone label: indicated for what?
"Acetaminophen Injection is indicated for the management of mild to moderate pain in adult and pediatric patients 2 years and older the management of moderate to severe pain with adjunctive opioid analgesics in adult and pediatric patients 2 years and older the reduction of fever in adult and pediatric patients.…": indications and usage on Hydrocodone's label. DailyMed label · 621282f6-75b3-401b-8e1a-c5153a0c9ecd · 2026-06-24
Q3
32 registered trials of Hydrocodone — at which phases?
Registered studies posting no result
18 of 32
32 registered studies of Hydrocodone: 9 phase1, 9 phase3, 5 phase2, 4 na, 2 early phase1, 2 phase4, 1 na or unstated. CLINICALTRIALS_SNAPSHOT · 2026-09-01
Substances that induce or regulate hepatic cytochrome enzyme CYP2E1 may alter the metabolism of acetaminophen and increase its hepatotoxic potential.
drug_interactions
( 7.2 ) 7.1 Effects of Other Substances on Acetaminophen Substances that induce or regulate hepatic cytochrome enzyme CYP2E1 may alter the metabolism of acetaminophen and increase its hepatotoxic potential.
pharmacokinetics
Elimination Metabolism Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: Conjugation with glucuronide, conjugation with sulfate, and oxidation via the cytochrome P450 enzyme pathway, primarily CYP2E1, to form a reactive intermediate metabolite (N-acetyl-p-benzoquinone imine or NAPQI).
clinical_pharmacology
Elimination Metabolism Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: Conjugation with glucuronide, conjugation with sulfate, and oxidation via the cytochrome P450 enzyme pathway, primarily CYP2E1, to form a reactive intermediate metabolite (N-acetyl-p-benzoquinone imine or NAPQI).
Oxycodone hydrochloride, hydrocodone-, Dihydrocodeinone bitartrate, Hycofenix componenet of hydrocodone bitartrate, Hydrocodone bitartrate cii, Hydrocodone bitartrate component of allay, Hydrocodone bitartrate component of anexsia, Hydrocodone bitartrate component of azdone, Hydrocodone bitartrate component of bancap hc, Hydrocodone bitartrate component of codamine, Hydrocodone bitartrate component of co-gesic, Hydrocodone bitartrate component of duradyne dhc, Hydrocodone bitartrate component of flowtuss
Trade name
Dicodid, Hysingla, Hysingla er, Mercodinone, Vantrela er, Zohydro er, Zohydro ER / Hysingla ER / Vantrela ER; also Vicodin, Norco and Lortab in combination with paracetamol
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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