This page shows what was measured, who it was measured in, and what that does not settle.
What Tramadol does in the body
Moderate to severe pain, as an opioid
Tramadol itself barely touches the opioid receptor. The liver converts part of each dose into a metabolite called M1 that binds it roughly two hundred times more tightly, and how much M1 you make depends on a liver enzyme whose activity varies from almost none to several times normal between people. On top of that, tramadol blocks the reuptake of noradrenaline and serotonin, which adds pain relief through the brain’s own descending damping system — and adds the risk of seizures and of serotonin syndrome. That dual mechanism is why the drug was described for years as something gentler than an opioid, and it is also why an overdose is only partially reversed by naloxone.
What happened in people
4% absolute improvement in osteoarthritis pain against placebo (95% CI 3% to 5%) across 8 randomised trials and 3,972 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.
Remains one of the most prescribed analgesics in the world, in the position that the evidence assembled here does not support as a distinct category
Where it acts
Mu-opioid receptors in the brain and spinal cord, reached mainly by the metabolite the liver makes; and the monoamine transporters of the descending pain-modulating pathways
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
16 registered substances share the start of this name, which is why a search for it can return more than one thing.
FDA substance registry · 26J30IC20Q · 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 144 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.
Stand-in result
A stand-in result is a number measured because the real result takes too long.
A picture of it, and where the picture fails
It is like judging a journey by the speedometer rather than by arriving.
Where that stops being true. Speed does predict arrival. Many stand-in results do not predict the real one.
What people get wrong. A stand-in result is often reported as the result itself.
A surrogate endpoint substituted for a clinical endpoint, valid only where the substitution has been shown to hold.
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.
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.
Pathway
A pathway is a chain of steps inside a cell, each one setting off the next.
A picture of it, and where the picture fails
A pathway is like a row of dominoes.
Where that stops being true. Dominoes fall one way. Pathways loop back and can switch themselves off.
What people get wrong. Changing one step is read as changing the outcome. Other steps often absorb it.
An ordered series of molecular interactions producing a defined cellular change.
What happened in people◇Read from sources, not yet reviewed
What was measured, goal by goal
One row for each goal a registered study measured something for. One column for each kind of thing that could be measured.
Registered studies list 40 outcome measures that RNAWiki could read. A registered study says what someone planned to measure. It does not say what they found. 0 of the matched studies tested this substance, and 0 posted a result.
There is no single score. A strong test result and a weak life result are different facts.
Goals down the side, kinds of measurement across the top. Each cell says what kind of thing was registered, not what was found.
Goal
Life outcome
What a body can do
How a person feels
A test result
A step in the body
Harms
How long
Who was studied
Pain
∅Nothing in the sources checkedNo registered study lists a life outcome for this goal.
∅Nothing in the sources checkedNo registered study lists a performance measure for this goal.
…Waiting for a reviewer13 registered symptom measure.
∅Nothing in the sources checkedNo registered study lists a test result for this goal.
∅Nothing in the sources checkedNo registered study lists a body-step measure for this goal.
—Not recordedHarms were not a registered measure for this goal.
—Not recordedNo finished study window is recorded.
…Waiting for a reviewerWho was studied is listed further down the page.
Recovery
∅Nothing in the sources checkedNo registered study lists a life outcome for this goal.
∅Nothing in the sources checkedNo registered study lists a performance measure for this goal.
∅Nothing in the sources checkedNo registered study lists a symptom measure for this goal.
∅Nothing in the sources checkedNo registered study lists a test result for this goal.
∅Nothing in the sources checkedNo registered study lists a body-step measure for this goal.
—Not recordedHarms were not a registered measure for this goal.
—Not recordedNo finished study window is recorded.
…Waiting for a reviewerWho was studied is listed further down the page.
Which registered measures put each goal on this table
Pain
vas pain scoring; pressure pain threshold area under the curve; analgesic efficacy; pain assessed by visual analogue scale; pain perception during the procedure; pain vas; pain scores; pain during the procedure
Recovery
recovery time of sensory block; recovery time of motor block
Sorted by fixed word lists, version v1. A name the rules do not recognise stays unsorted rather than moving to the nearest column.
What each mark on this table means
∅ Nothing in the sources checked
No registered study lists a life outcome for this goal.
… Waiting for a reviewer
13 registered symptom measure.
— Not recorded
Harms were not a registered measure for this goal.
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.
Pain reduction and physical function against placebo or active control in hip or knee osteoarthritis
✗ The study did not show it
Who was studied
Cochrane CD005522 — pooled randomised trials of tramadol in osteoarthritis
How many people
6496
Study design
Systematic review and meta-analysis of 22 randomised controlled trials
Compared against
Not recorded for this study
Kind of result
What a body can do day to day
What was found
Tramadol alone: 4% absolute improvement in pain (95% CI 3% to 5%; 8 studies, 3,972 participants) and 4% in physical function (2% to 6%). Responders improving by 20%: 15 of 100 on tramadol against 10 of 100 on placebo for pain, 21 against 16 for function. Adverse events risk ratio 1.34 (1.24 to 1.46)
Repeated elsewhere
Replicated
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. High risk of selection bias — only 4 of 22 trials reported both adequate sequence generation and allocation concealment. High risk of attrition bias in 10 of 22. Most trials were funded by the pharmaceutical industry. Doses from 37.5 mg to 400 mg daily were pooled and mean duration was two months.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral immediate-release tablets, extended-release tablets and capsules, an oral solution, and fixed combinations with acetaminophen
Interval reported. 95% CI 3% to 5%; 8 studies, 3,972 participants) and 4% in physical function (2% to 6%)
Written into the record, not signed off as a reviewed claim.
All-cause mortality within one year of an initial prescription, tramadol against five other analgesics
✗ The study did not show it
Who was studied
Tramadol and all-cause mortality in osteoarthritis (JAMA 2019;321:969-982)
How many people
88902
Study design
Sequential propensity-score-matched cohort study, UK general practice, 2000-2016
Compared against
Not recorded for this study
Kind of result
Living longer, or avoiding a major event
What was found
Tramadol 23.5 against naproxen 13.8 deaths per 1,000 person-years, hazard ratio 1.71 (95% CI 1.41 to 2.07); against diclofenac 1.88 (1.51 to 2.35); against celecoxib 1.70 (1.33 to 2.17); against etoricoxib 2.04 (1.37 to 3.03); against codeine 0.94 (0.83 to 1.05), not significant
Repeated elsewhere
Partially Replicated
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. Observational. The authors state the findings may be susceptible to confounding by indication and that further research is needed to determine causality — tramadol is plausibly prescribed to frailer patients in whom NSAIDs are avoided. The null codeine comparison is the result least explicable by that bias.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral immediate-release tablets, extended-release tablets and capsules, an oral solution, and fixed combinations with acetaminophen
Interval reported. 95% CI 1
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 happened in people◇Read from sources, not yet reviewed
How close this is to real life
The top step is something a person would feel or care about. The bottom is a guess from software. Filled steps are where evidence exists for this substance.
□Living longer, or avoiding a major eventNo evidence recorded. Death, a heart attack, a stroke, a hospital stay.No registered study measures this.
□What a body can do day to dayNo evidence recorded. Walking, dressing, breathing, recovering.No registered study measures this.
□Measured performanceNo evidence recorded. How much was lifted, how far was run, how fast.No registered study measures this.
■Symptoms and quality of lifeEvidence recorded. Pain, tiredness, mood, sleep, as the person rated it.15 registered measures of this kind.
■A number that stands in for healthEvidence recorded. Cholesterol, blood sugar, bone density. A stand-in, not the thing itself.1 registered measure of this kind.
■A step measured inside a personEvidence recorded. Something measured in human tissue or human cells.A human record sits on the stored organism ladder.
■AnimalsEvidence recorded. Mice, rats, dogs. Useful for ideas, not proof about people.Stored records in Mouse. A result in animals says what to test next. It does not say what happens in people.
■Cells in a dishEvidence recorded. Cells or chemistry on a bench, far from a whole body.Stored mechanism abstracts describe steps measured in cells or tissue.
□A guess from softwareNo evidence recorded. Nobody measured it. RNAWiki never publishes one as a finding.RNAWiki stores no prediction for this record. Software can suggest a link. RNAWiki does not publish one as a finding.
Higher on these steps means closer to something a person would feel. It does not mean better done.
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
Tramadol
What a person takes: Oral immediate-release tablets, extended-release tablets and capsules, an oral solution, and fixed combinations with acetaminophen.
The measurement behind this step
Absorbed orally and converted by CYP2D6 to the active O-desmethyl metabolite M1, with a parallel CYP3A4 route to inactive N-desmethyl products. Because activity depends on that conversion, exposure to the active species varies substantially with CYP2D6 phenotype and with any CYP2D6 or CYP3A4 inhibitor or inducer — an interaction the boxed warning describes as complex and requiring consideration of both parent drug and metabolite. Extended-release tablets must be swallowed whole; chewing or crushing exposes the patient to a potentially fatal dose.
Getting in
What you swallow is not what acts
Tramadol itself binds the opioid receptor only weakly. The liver converts part of the dose into a metabolite called M1, which binds it about two hundred times more tightly.
──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
The label states that opioid activity is due to both low-affinity binding of the parent compound and higher-affinity binding of the O-desmethyl metabolite M1, that M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in mu-opioid binding in animal models, and that the relative contribution of each depends on plasma concentrations.
How much you make depends on an enzyme that varies enormously
CYP2D6 does the conversion, and people range from having almost none of it to several working copies. The same tablet therefore delivers very different opioid doses to different people.
╌╌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
M1 formation is CYP2D6-dependent, spanning poor, intermediate, extensive and ultra-rapid metaboliser phenotypes. The boxed warning records deaths in children who received tramadol, some after tonsillectomy or adenoidectomy, with at least one documented ultra-rapid metaboliser, and adds that the effects of CYP3A4 inducers, CYP3A4 inhibitors and CYP2D6 inhibitors are complex and require consideration of both parent and metabolite.
M1 acts on the opioid receptor like any other opioid
Once formed, the metabolite works the way opioids work — damping the pain signal in the brain and spinal cord, and damping the drive to breathe alongside 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
Mu-opioid receptor agonism in central pain pathways. The boxed warning covers addiction, abuse and misuse; life-threatening respiratory depression on initiation or dose increase; fatal overdose from accidental ingestion of a single extended-release dose; and neonatal opioid withdrawal syndrome after prolonged use in pregnancy.
Separately, tramadol blocks the reuptake of noradrenaline and serotonin, strengthening the brain’s own descending pain-damping pathways. That is a real second mechanism and it is not an opioid one.
╌╌Measured in animals. A result in animals says what to test next. It does not say what happens in people.
The measurement behind this step
The label states that tramadol inhibits reuptake of noradrenaline and serotonin in vitro, as have some other opioid analgesics, and that these mechanisms may contribute independently to the overall analgesic profile. It also states that tramadol-induced analgesia is only partially antagonised by naloxone in several animal tests — the direct evidence that part of the effect is non-opioid.
Which is where the seizures and the serotonin syndrome come from
The second mechanism was presented as the reason tramadol is gentler. It is the reason tramadol causes seizures at ordinary doses and can trigger serotonin syndrome with common antidepressants.
╌╌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
Section 5.10: the increased risk of seizures is present within the recommended dosage range, rising with higher doses and with SSRIs, SNRIs, tricyclics, MAO inhibitors, neuroleptics, other opioids and other threshold-lowering drugs. Section 5.9: serotonin syndrome, potentially life-threatening, from concomitant serotonergic drugs, with discontinuation directed if suspected.
What was measured, and what was assumed for nineteen years
Measured: a 4% absolute improvement in osteoarthritis pain, and one-year mortality 71% higher than naproxen but identical to codeine. Assumed: that it was categorically safer than other opioids, until the DEA scheduled it in 2014.
╌╌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
Cochrane CD005522: 4% absolute pain improvement (95% CI 3% to 5%), 15 of 100 responders against 10 of 100 on placebo, adverse event risk ratio 1.34. JAMA 2019: hazard ratio for one-year all-cause mortality 1.71 against naproxen, 1.88 against diclofenac, 2.04 against etoricoxib, 0.94 against codeine. Federal Register 79 FR 37623: schedule IV effective 18 August 2014.
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 it would be like to take◇Read from sources, not yet reviewed
Felt, measured, or meaningful
Three different things that get called the same word. Registered studies measured all three, and mixing them is how a blood test becomes a health claim.
Felt
Things a person could notice without a test.
vas pain scoring
pressure pain threshold area under the curve
clinical global impression improvement
pain assessed by visual analogue scale
swiss spinal stenosis questionnaire
pain perception during the procedure
pain vas
pain scores
pain during the procedure
efficacy of pain management
and 5 more.
Measured
Things only a test, a scale or a device shows.
concentration of o desmethyltramadol
Meaningful
Things that change how a life goes, not only a number.
No registered study measured anything of this kind.
A registered study says what someone planned to measure. It does not say what they found. A number moving is not the same as a life going better. The two are shown apart here.
Felt, but not shown to help. A person notices a change. No study showed it leads anywhere good.
Measured, but not felt. A number moves. The person notices nothing. Both can be true.
Measured, but not shown to matter. A number moves in the good direction. Nobody showed that lives went better.
Matters, but takes years. The result that counts may take longer than anyone would keep watching.
Names that fit none of the three (24)
physiological effects
physiologic measures
satisfaction
nausea
sedation
discrimination effects assessed by operant responses
discrimination effects assessed by distribution
discrimination effects assessed by discrete choice
requiring rescue medication
cmax
analgesic efficacy
who tolerate qutenza treatment
clinician administered ptsd scale
adverse events
respiratory insufficiency
postoperative intravenous opioid dose
qtc interval
opioid requirement in the first 24 h postoperatively
incidence of postoperative nausea and vomiting
intraoperative bleeding
These are harms, study-process measures, or names the rules did not recognise. They are shown rather than dropped.
What it would be like to take◇Read from sources, not yet reviewed
How long anything takes
Nine different lengths of time that get confused with each other. None of them is worked out from another.
Before anything is noticed.RNAWiki does not store this separately, and never works it out from another figure on this page.
Before a test result moves.RNAWiki does not store this separately, and never works it out from another figure on this page.
Before performance moves.RNAWiki does not store this separately, and never works it out from another figure on this page.
How long the result was watched.No finished study window is recorded for a study that tested this substance.
How long people took it.How long people actually took it is not stored. The study window is not the same thing.
How long people were followed.Follow-up length is not stored separately. It is never read off the study window, which would be a different thing.
How fast the body clears it. approximately 7.9 hours (tramadol); 8.8 hours (M1 metabolite) hours
Read from the label, which states: “The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 after administration of tramadol hydrochloride extended-release tablets are approximately 7.9 and 8.8 hours, respectively.”
How long effects linger.RNAWiki does not store this separately, and never works it out from another figure on this page.
Beyond the studies. Nothing is recorded about the long term.
The longest finished study sets the edge of what anyone measured.
A study window is not how long people took it, and neither is how long they were followed. Where RNAWiki holds only one of the three, it shows one.
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 pain severe enough to require an opioid where alternatives are inadequate. Contraindicated in children under 12, and in anyone under 18 after tonsillectomy or adenoidectomy, because of deaths from respiratory depression in ultra-rapid metabolisers.
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 CONZIP in pediatric patients have not been established.”
US prescribing information · a65b4d05-3a1c-4aa1-848a-d20ac9aaf62f · read 2026-08-30
On older people, the label states: “Eight hundred and twelve elderly (65 years of age or older) subjects were exposed to CONZIP in clinical trials.”
US prescribing information · a65b4d05-3a1c-4aa1-848a-d20ac9aaf62f · read 2026-08-30
On people who are pregnant, the label states: “Tramadol was evaluated in pre- and post-natal studies in rats.”
US prescribing information · a65b4d05-3a1c-4aa1-848a-d20ac9aaf62f · read 2026-08-30
On people who are breastfeeding, the label states: “Risk Summary CONZIP is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied.”
US prescribing information · a65b4d05-3a1c-4aa1-848a-d20ac9aaf62f · read 2026-08-30
On people with reduced liver function, the label states: “Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver.”
US prescribing information · a65b4d05-3a1c-4aa1-848a-d20ac9aaf62f · read 2026-08-30
On people with reduced kidney function, the label states: “CONZIP has not been studied in patients with renal impairment.”
US prescribing information · a65b4d05-3a1c-4aa1-848a-d20ac9aaf62f · read 2026-08-30
Where the result stopped carrying
Efficacy in osteoarthritis: the pooled randomised benefit is described by its own systematic review as no important benefit
Unscheduled status, ended by the DEA in August 2014
Paediatric use, now contraindicated under 12 and under 18 after tonsillectomy or adenoidectomy after deaths in ultra-rapid metabolisers
The premise of a seizure-free opioid: the label states the increased seizure risk is present within the recommended dosage range
Its position as a category between NSAIDs and opioids — its one-year mortality is indistinguishable from codeine’s
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 for a different goal
The studies measured something else entirely.
On this record: Some registered studies measured things that match no goal on this page.
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 (10)
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, extended-release tablets and capsules, an oral solution, and fixed combinations with acetaminophen
✎ 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: S5, S6.
No source is stored against this line.
What is in the pack
Absorbed orally and converted by CYP2D6 to the active O-desmethyl metabolite M1, with a parallel CYP3A4 route to inactive N-desmethyl products.
✎ 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: Because activity depends on that conversion, exposure to the active species varies substantially with CYP2D6 phenotype and with any CYP2D6 or CYP3A4 inhibitor or inducer — an interaction the boxed warning describes as complex and requiring consideration of both parent drug and metabolite. Extended-release tablets must be swallowed whole; chewing or crushing exposes the patient to a potentially fatal dose.
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
Full opioid boxed warning: addiction, abuse and misuse leading to overdose and death; life-threatening respiratory depression, especially on initiation or dose increase; fatal overdose from accidental ingestion of even one extended-release dose, especially by a child; profound sedation, respiratory depression, coma and death with benzodiazepines, other central nervous system depressants or alcohol; neonatal opioid withdrawal syndrome; a REMS education requirement; and paediatric contraindications arising from CYP2D6 ultra-rapid metabolism. Additional labelled risks include seizures within the recommended dose range, serotonin syndrome, opioid-induced hyperalgesia, adrenal insufficiency, severe hypotension and suicide risk. Contraindicated in children under 12 and in anyone under 18 after tonsillectomy or adenoidectomy.
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 immediate-release tablets, extended-release tablets and capsules, an oral solution, and fixed combinations with acetaminophen
✎ 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: Because activity depends on that conversion, exposure to the active species varies substantially with CYP2D6 phenotype and with any CYP2D6 or CYP3A4 inhibitor or inducer — an interaction the boxed warning describes as complex and requiring consideration of both parent drug and metabolite. Extended-release tablets must be swallowed whole; chewing or crushing exposes the patient to a potentially fatal dose.
No source is stored against this line.
What is recorded as being sold
162 products list this as an active ingredient in the United States drug directory. 146 of them contain it and nothing else.
FDA National Drug Code directory · 71610-006 · read 2026-08-29
They are sold as capsule, capsule, extended release, powder, solution, tablet and tablet, coated, taken oral.
FDA National Drug Code directory · 71610-006 · 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 · 71610-006 · read 2026-08-29
115 published labels name it as an active ingredient. 99 of them describe this substance alone, which is where its own label text on this page comes from.
US prescribing information · a65b4d05-3a1c-4aa1-848a-d20ac9aaf62f · read 2026-08-29
Those labels are classed as human prescription drug.
US prescribing information · a65b4d05-3a1c-4aa1-848a-d20ac9aaf62f · read 2026-08-29
TRAMADOL HYDROCHLORIDE is extended-release tablets at Extended-release tablets 100 mg, 200 mg, and 300 mg, recorded as prescription product; fda label in effect 2025-11-20 in the United States.
US prescribing information · 004de5a4-80f8-4040-a6ea-be5e99352a36 · read 2026-08-27
Recorded price in US: 0.02453–3.33462 USD per one unit as the pricing file counts it — a tablet, capsule, patch or single item, across 29 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. The questions below are for a clinician or pharmacist.
Questions worth asking
Which of the trials of Tramadol 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 tramadol is categorically safer than other opioids because the parent compound binds the mu receptor weakly — the active species is the metabolite, which does not
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 it is an appropriate first-line option for knee osteoarthritis, a guideline position the mortality study was designed to examine
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 dual mechanism reduces risk, when it is the source of the seizure and serotonin syndrome risks that no pure opioid carries in the same way
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 naloxone fully reverses a tramadol overdose, when the label records that its analgesia is only partially antagonised by naloxone
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 Tramadol 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.
It was an unscheduled opioid in the United States for nineteen years
In plain words
Tramadol was approved in 1995 and was not a controlled substance. It could be prescribed and refilled without any of the rules that apply to other opioids. The DEA placed it into schedule IV effective 18 August 2014.
What was measured
Regulatory status of tramadol under the Controlled Substances Act, before and after 18 August 2014
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
The final rule placing tramadol into schedule IV was published at 79 Federal Register 37623 on 2 July 2014, Docket DEA-351, effective 18 August 2014. It placed 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol, including its salts, isomers and salts of isomers, into schedule IV of the Controlled Substances Act, imposing the regulatory controls and administrative, civil and criminal sanctions applicable to schedule IV substances on everyone who handles it. For nineteen years before that, tramadol’s regulatory status carried the implication that it was categorically different from other opioids — an implication its own label does not support. Section 12.1 describes it as an opioid agonist whose activity comes from mu-opioid receptor binding by the parent compound and, far more strongly, by the metabolite M1. The scheduling decision did not follow new pharmacology; it followed accumulated evidence of abuse and dependence in a drug that had been positioned as the safe intermediate step.
Source
Schedules of Controlled Substances: Placement of Tramadol Into Schedule IV. Final rule, Drug Enforcement Administration. Federal Register 2014;79(127):37623-37630, Docket DEA-351, effective 18 August 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
In osteoarthritis the randomised benefit is a 4% absolute improvement
In plain words
Pooled across 22 randomised trials, tramadol improved osteoarthritis pain by 4% more than placebo. Fifteen people in a hundred improved meaningfully, against ten in a hundred on placebo. The review’s own phrase is "no important benefit".
What was measured
Absolute improvement in pain and physical function against placebo, responder proportions at a 20% improvement threshold, and adverse event risk ratio
Effect estimate
No reviewed effect estimate exists for this record.
Limits
This entry records a failure.
From the source
The Cochrane review included 22 randomised trials, 21 in meta-analysis, covering 3,871 participants on tramadol alone or with another analgesic and 2,625 on placebo or active control. Doses ranged from 37.5 mg to 400 mg daily and were pooled; mean trial duration was two months; participants were predominantly women with hip or knee osteoarthritis, mean age 63, with moderate to severe pain. Moderate quality evidence — downgraded for risk of bias — showed tramadol alone gave a 4% absolute improvement in pain over placebo (95% CI 3% to 5%; 8 studies, 3,972 participants) and tramadol with acetaminophen 4% (2% to 6%; 2 studies, 614 participants). Expressed as responders, 15 of 100 on tramadol improved by 20% against 10 of 100 on placebo. Physical function showed the same 4% absolute improvement, with 21 of 100 improving by 20% against 16 of 100. Adverse events were more common: risk ratio 1.34 (1.24 to 1.46) for tramadol alone and 1.91 (1.32 to 2.76) for the combination. The review noted a high risk of selection bias, with only four of 22 trials reporting both adequate sequence generation and allocation concealment, a high risk of attrition bias in ten trials, and that most trials were funded by the pharmaceutical industry.
Written into the record, not signed off as a reviewed claim
One-year mortality was 71% higher than naproxen — and identical to codeine
In plain words
A propensity-matched study of 88,902 osteoarthritis patients over 50 compared what happened in the year after a first prescription. Deaths were substantially more common on tramadol than on any of four anti-inflammatories, and no different from codeine.
What was measured
All-cause mortality per 1,000 person-years within one year of initial prescription, tramadol against four NSAIDs and against codeine, in 88,902 propensity-matched patients
Effect estimate
No reviewed effect estimate exists for this record.
Limits
This entry records a failure.
From the source
The sequential propensity-score-matched cohort study used United Kingdom general practice records from the Health Improvement Network, covering individuals aged at least 50 with osteoarthritis diagnosed between January 2000 and December 2015, followed to December 2016. Initial prescriptions were tramadol (n=44,451), naproxen (12,397), diclofenac (6,512), celecoxib (5,674), etoricoxib (2,946) or codeine (16,922); after matching, 88,902 patients were analysed, mean age 70.1 years, 61.2% women. Over one year of follow-up, 278 deaths occurred in the tramadol cohort (23.5 per 1,000 person-years) against 164 in the naproxen cohort (13.8 per 1,000) — a rate difference of 9.7 deaths per 1,000 person-years (95% CI 6.3 to 13.2) and a hazard ratio of 1.71 (1.41 to 2.07). Against diclofenac the hazard ratio was 1.88 (1.51 to 2.35), against celecoxib 1.70 (1.33 to 2.17) and against etoricoxib 2.04 (1.37 to 3.03). Against codeine there was no significant difference: 32.2 against 34.6 per 1,000 person-years, hazard ratio 0.94 (0.83 to 1.05). The authors state plainly that these findings may be susceptible to confounding by indication and that further research is needed to determine whether the association is causal — tramadol may be prescribed preferentially to frailer patients in whom NSAIDs are avoided. The codeine comparison is the part that is hardest to explain away, because it holds the opioid indication roughly constant.
Written into the record, not signed off as a reviewed claim
The same tablet is a different opioid dose in different people, and children have died of it
In plain words
Tramadol barely binds the opioid receptor. The liver turns some of it into a metabolite that binds about two hundred times more tightly, and how much you make depends on an enzyme that varies enormously between people. Children who convert unusually fast have died.
What was measured
Relative mu-opioid binding potency of M1 against tramadol, and the labelled paediatric contraindications arising from CYP2D6 ultra-rapid metabolism
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Section 12.1 states that opioid activity is due to both low-affinity binding of the parent compound and higher-affinity binding of the O-desmethyl metabolite M1 to mu-opioid receptors, and that in animal models M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in mu-opioid binding, with the relative contribution of each depending on their plasma concentrations. M1 is formed by CYP2D6, which has poor, intermediate, extensive and ultra-rapid metaboliser phenotypes; an ultra-rapid metaboliser converts a standard dose into a much larger effective opioid dose. The boxed warning records the consequence: life-threatening respiratory depression and death have occurred in children who received tramadol, some following tonsillectomy or adenoidectomy, with at least one documented case of CYP2D6 ultra-rapid metabolism. Tramadol is now contraindicated in children younger than 12 and in anyone younger than 18 following tonsillectomy or adenoidectomy, and is to be avoided in adolescents 12 to 18 with other risk factors. The boxed warning also notes that the effects of CYP3A4 inducers, CYP3A4 inhibitors and CYP2D6 inhibitors on tramadol are complex and require careful consideration of the effects on both parent drug and metabolite.
Source
Tramadol hydrochloride extended-release tablets United States prescribing information, boxed warning and section 12.1 (openFDA drug label endpoint, ANDA 201384)
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
The second mechanism causes seizures within the recommended dose range
In plain words
Tramadol’s block of noradrenaline and serotonin reuptake was sold as the feature that made it gentler than a pure opioid. It is also the source of two risks no other opioid carries in the same way: seizures and serotonin syndrome. The label says the seizure risk is present at recommended doses.
What was measured
Labelled seizure and serotonin syndrome risk, dose relationship and interacting drug classes
Effect estimate
No reviewed effect estimate exists for this record.
Limits
This entry records a failure.
From the source
Section 5.10 states that the increased risk of seizures is present within the recommended dosage range, and that risk rises with higher than recommended doses and with concomitant SSRIs, SNRIs, anorectics, tricyclic antidepressants and other tricyclic compounds, other opioids, MAO inhibitors, neuroleptics and other drugs that reduce seizure threshold, and in patients with epilepsy or at risk of seizures. Section 5.9 states that serotonin syndrome, a potentially life-threatening condition, could result from concomitant serotonergic drug administration, with discontinuation directed if it is suspected. Section 5.11 directs that tramadol not be used in suicidal or addiction-prone patients, and be used with caution in those taking tranquillisers or antidepressants or who abuse alcohol. The mechanistic point is that these are not incidental: section 12.1 states that tramadol inhibits reuptake of noradrenaline and serotonin in vitro and that these mechanisms may contribute independently to the overall analgesic profile. The half of the drug that was presented as the safety feature is the half that produces its two most distinctive harms — and the patients most likely to be co-prescribed an SSRI or a tricyclic are chronic pain patients, which is the population the drug is aimed at.
Source
Tramadol hydrochloride extended-release tablets United States prescribing information, sections 5.9, 5.10, 5.11 and 12.1 (openFDA drug label endpoint, ANDA 201384)
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
"Weak opioid" is a description of receptor affinity, not of what the drug does
In plain words
Tramadol is called a weak opioid because tramadol itself binds the receptor weakly. That is true of the molecule you swallow and not of the metabolite your liver makes, and the label’s full boxed warning is the same one carried by any other opioid.
What was measured
That tramadol is categorically safer than other opioids because the parent molecule binds the mu receptor weakly — an inference from the prodrug’s affinity that the metabolite, the boxed warning and the scheduling decision all contradict
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
The boxed warning covers addiction, abuse and misuse leading to overdose and death; serious, life-threatening or fatal respiratory depression, especially on initiation or dose increase; fatal overdose from accidental ingestion of even one extended-release dose, especially by a child; profound sedation, respiratory depression, coma and death from concomitant benzodiazepines, other central nervous system depressants or alcohol; neonatal opioid withdrawal syndrome after prolonged use in pregnancy, which may be life-threatening if not recognised and treated; and an Opioid Analgesic Risk Evaluation and Mitigation Strategy education programme. None of that is qualified by the word weak. The affinity statement is real — the parent compound binds the mu receptor with low affinity — and it describes the prodrug rather than the active species. The label’s own arithmetic, that M1 binds about 200 times more tightly, is the correction. The clinical consequence of the misreading was nineteen unscheduled years, guideline positions recommending tramadol as a first-line option in knee osteoarthritis, and the mortality signal that followed.
Source
Tramadol hydrochloride extended-release tablets United States prescribing information, boxed warning and section 12.1 (openFDA drug label endpoint, ANDA 201384); Zeng C et al., JAMA 2019;321:969-982, which opens by noting the guideline recommendations it set out to test
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
How many documents were read
98 documents were read for this substance.
RNAWiki source record
58 of them state the same bioavailability, and they agree.
RNAWiki source record
Where else this substance is registered
FDA substance identifier (UNII)
9N7R477WCK
CAS registry number
27203-92-5
PubChem compound
33741
RxNorm concept
10689
Checks this page had to pass
✓ Passed
Identity resolved
no open identity hold
✓ Passed
No unresolved merge across substance families
no quarantine open
✓ Passed
Every public sentence names a source
The opening statement carries the origin: Written into the record, not signed off.
✗ Not passed
Trial roles classified for highlighted evidence
No registered study is classified as testing this substance.
✓ Passed
No internal keys in reader text
enforced by the copy-contract test over the rendered page
✓ Passed
Safety mode resolved
Suppression classes recorded: S5, S6.
✓ Passed
Canonical metadata present
slug and display name present
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
54 approved applications cover products containing this substance. The earliest was NDA020281, approved 19950303 to JANSSEN PHARMS.
This order is fixed in code and does not count clicks or time on the page.
What is not here
3 questions this page could not answer
These sections were prepared and left out because there was nothing to put in them. They are listed rather than hidden, so the gaps in this record are visible.
What it may clash with — found nothing in the sources checked.
Other ways to the same goal — found nothing in the sources checked.
What changed on this page — found nothing in the sources checked.
The record as stored
The full record, for auditing
Everything above is built from what is below. This layer keeps the technical vocabulary, record identifiers and every stored row, so a reader who wants to check the page can.
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.
An opioid prodrug whose activity depends on a liver enzyme that varies enormously between people — the M1 metabolite binds the mu receptor about 200 times more tightly than tramadol itself — sold unscheduled in the United States for nineteen years before being placed in schedule IV, producing a 4% absolute improvement in osteoarthritis pain in pooled randomised trials and a 71% higher one-year all-cause mortality than naproxen in 88,902 propensity-matched patients.
Recorded evidence blocks (12)
Q2
What did Tramadol's largest trial (1561 people) and its longest (8.4 years) measure?
1561 people in Tramadol's largest registered study, 8.4 years in its longest registered window, measuring The primary outcome is the change from baseline to Week 12 in the WOMAC OA Index pain and physical function subscale scores and the patient global assessment of disease activity. ClinicalTrials.gov · 2026-09-01
69 phase4, 49 na, 47 phase3, 35 phase2, 26 phase1, 7 na or unstated, 2 early phase1; NCT01263652; 2019-06-01. Last human test completed 2026, NCT06860100.
Interpretation These counts include studies where Tramadol was a comparison treatment, a background treatment or an exposure in an observational study, and the longest window may be a planned end date. Trial roles have not yet been classified for this record.
Show the evidence
phase4
69
na
49
phase3
47
phase2
35
phase1
26
na or unstated
7
2 more recorded rows
early phase1
2
Last recorded human testNCT06860100
2026-07-01
recorded 2026-09-01 · last checked 2026-09-04
Q3
From mouse to human: where has Tramadol shown healthspan?
The primary outcome is the change from baseline to Week 12 in the WOMAC OA Index pain and physical function subscale scores and the patient global assessment… — the recorded outcome words.
Show the evidence
mouse
mechanism-only
humanNCT00325858
healthspan; The primary outcome is the change from baseline to Week 12 in the WOMAC OA Index pain and physical function subscale scores and the patient global assessment of disease activity.; 222
recorded 2026-09-01 · last checked 2026-09-04
Q4
14 of Tramadol's trials stopped: safety, futility/efficacy, accrual/recruitment, other?
safety (1), futility/efficacy (1), accrual/recruitment (5) and other (7): Tramadol's stop wording, clustered. ClinicalTrials.gov · 2026-09-01
"Not enough data to analyze the results."; 14 of 222 registered studies
Show the evidence
Trial
NCT00505531
terminated; "Not enough data to analyze the results."
terminated; "This study was terminated because of recruitment difficulties."
NCT01263652
withdrawn; "inability to complete recruitment as planned"
NCT02076893
terminated; "Interim analysis results indicated need to recruit beyond scope of budget."
NCT02094807
withdrawn; "Slow inclusion rate. Awaiting results from NCT02132416."
8 further recorded trials
NCT02722603
terminated; "The study was early terminated due to insufficient recruitment"
NCT03255330
withdrawn; "no participant enrolled"
NCT03586934
withdrawn; "Difficult to enroll patients for the study"
NCT03678792
withdrawn; "Infeasible to conduct at this time."
NCT04593329
withdrawn; "Strategy review"
NCT04766996
terminated; "Loss of surgery team member deemed the study procedures impossible to achieve, and no replacement could be found in a timely manner to complete trial as initially planned."
NCT04939987
withdrawn; "PI left institution and study was not transferred to new PI"
NCT05125978
withdrawn; "Strategy review"
recorded 2026-09-01 · last checked 2026-09-04
Q5
Human studies of Tramadol used Tramadol Hydrochloride 50mg — over how long?
Tramadol's half-life is approximately 7.9 hours (tramadol); 8.8 hours (M1 metabolite) — which schedules were studied?
approximately 7.9 hours (tramadol); 8.8 hours (M1 metabolite), the half-life Tramadol's label states. openfda-label · e5005d9e-91cb-4ff8-bcf2-b5ee70cf4f3f · 2026-08-27
bioavailability approximately 85 to 90% (relative to immediate-release tablets) %.
Show the evidence
half life
approximately 7.9 hours (tramadol); 8.8 hours (M1 metabolite) hours; The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 after administration of tramadol hydrochloride extended-release tablets are approximately 7.9 and 8.8 hours, respectively.
bioavailability
approximately 85 to 90% (relative to immediate-release tablets) %; In healthy subjects, the bioavailability of a tramadol hydrochloride extended-release tablet 200 mg administered once daily relative to a 50 mg immediate-release (IR) tablet administered every six hours was approximately 85 to 90%.
metabolism
Elimination Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys.
recorded 2026-08-27 · last checked 2026-09-04
Q7
Which of 10 reduction of the thoracotomy pain recorded by vas, adverse events and analgesic efficacy did Tramadol's trials measure?
10 reduction of the thoracotomy pain recorded by vas, adverse events and analgesic efficacy lead 40 outcome terms across Tramadol's trials. ClinicalTrials.gov · 2026-09-01
Interpretation nausea, sedation, discrimination effects assessed by operant responses, discrimination effects assessed by distribution, discrimination effects assessed by discrete choice and vas pain scoring follow.
Show the evidence
physiological effects
1
physiologic measures
1
satisfaction
1
nausea
1
sedation
1
discrimination effects assessed by operant responses
1
14 more recorded rows
discrimination effects assessed by distribution
1
discrimination effects assessed by discrete choice
1
vas pain scoring
1
requiring rescue medication
1
pressure pain threshold area under the curve
1
cmax
1
concentration of o desmethyltramadol
1
analgesic efficacy
1
who tolerate qutenza treatment
1
clinician administered ptsd scale
1
clinical global impression improvement
1
adverse events
1
pain assessed by visual analogue scale
1
swiss spinal stenosis questionnaire
1
recorded 2026-09-01 · last checked 2026-09-04
Q8
Which of Tramadol's 20 ongoing trials reports first?
The Sum of Pain Intensity Differences through 24 hours; Differences across drugs in Withdrawal relief assessed by Pain and Craving Index (PCI).; latest 2029-09-01
Show the evidence
Trial
NCT03774836
"Tramadol Versus Placebo and Morphine in the Management of Post-Operative Pain Abdominoplasty"; n 360; "The Sum of Pain Intensity Differences through 24 hours"; 2019-06-30
NCT05463367
"Project 1 Aim 2, Adaptations of the Brain in Chronic Pain With Opioid Exposure"; n 60; "Differences across drugs in Withdrawal relief assessed by Pain and Craving Index (PCI)."; 2025-06-01
NCT05488847
"Opioid-Free Pain Protocol After Shoulder Arthroplasty"; n 83; "Pain Levels"; 2026-09-01
NCT05657704
"Utility of CYP2D6 Genotyping to Improve the Efficacy and Safety of Tramadol"; n 300; "Efficacy: analgesic effect (Pain assessment) 4 hours after treatment"; 2026-08-31
NCT06232577
"5x-Multiplier vs 3-Tier Model for Discharge Opioid Prescriptions After Intra-abdominal Cancer Surgery: A Randomized Clinical Trial"; n 170; "Safety and adverse events (AEs)"; 2027-05-31
NCT06237231
"Efficacy and Safety of DIT112 in the Treatment of Moderate to Severe Pain After Dental Surgery for the Extraction of Impacted Third Molars"; n 252; "Total pain relief within four (04) hours after the first PSI administration, assessed using the area under the curve of pain interruption scores (TOTPAR0-4h)."; 2027-04-10
14 further recorded trials
NCT06373978
"NonNarcotic Pain Control in Percutaneous Needle Tenotomy of Elbow"; n 92; "Number of pills taken"; 2027-06-30
NCT06612996
"Intravenous Tramadol and Magnesium Sulphate for Prevention of Shivering"; n 180; "Shivering score"; 2025-01-10
NCT06722742
"Use of Iv Tramadol and Ketamine for Prevention of Post Spinal Anesthesia Shivering"; n 250; "Shivering"; 2025-01-30
NCT06728033
"Fascia Iliaca Compartment Block and Tramadol for Analgesia in Hip Fracture"; n 240; "Resting numerical rating scale (NRS) pain scores preoperatively"; 2027-12-31
NCT06742554
"Comparative Efficacy of Buprenorphine Transdermal Patch Versus Tramadol in Postoperative Analgesia for Shoulder Arthroscopy"; n 70; "Postoperative pain score"; 2025-04-30
NCT07064993
"Effects of Intraarticular Tramadol and Tramadol-Dexamethasone on Postoperative Pain After Knee Arthroscopy"; n 135; "Postoperative pain intensity - Area Under the Curve (VAS AUC 0-24 hours)"; 2027-04-30
NCT07066111
"The Effect of Bupivacaine Liposome Preemptive Analgesia on Postoperative Pain and Delirium in Elderly Patients Undergoing Hip Fracture Surgery"; n 40; "POD incidence"; 2026-12-30
NCT07110051
"Nalbuphine Versus Tramadol on Post Operative Analgesia in Abdominal Surgery on Pediatric Cancer Patient"; n 128; "time to first rescue analgesia"; 2025-10-15
NCT07264309
"Combined Intravenous Tramadol and Paracetamol Versus Intramuscular Pethidine for Pain Relief During the First Stage of Labor. Compare the Efficacy and Adverse Effects"; n 140; "The effect on pain relief"; 2027-12
NCT07346872
"EXORA Block vs Epidural Analgesia in Gynecological Surgery"; n 60; "NRS"; 2026-10-01
NCT07440069
"Analgesic Efficacy and Obstetric Effects of Tramadol, Paracetamol and Placebo in Active Labor"; n 300; "Duration of Active Labor"; 2026-09-30
NCT07606638
"Effectiveness of Opioid vs Pregabalin Plus Naproxen Sodium in Pain Management of Oral Cancer Patients"; n 98; "Mean Change in Visual Analog Scale Pain Score From Baseline to Day 7"; 2026-07-30
NCT07779473
"Tapentadol vs Tramadol in Arthroscopic Rotator Cuff Repair"; n 64; "Post-operative pain"; 2029-09-01
NCT07787702
"Comparison of Low-Dose Intravenous Ketamine and Tramadol for Prevention of Post-Spinal Anaesthesia Shivering in Orthopedic Surgical Patients"; n 106; "Incidence of post-spinal anesthesia shivering"; 2027-02-21
recorded 2026-09-01 · last checked 2026-09-04
Q9
Which 107 trials of Tramadol posted no result?
Posted no result
107 of 107 completed trials
Registrations
NCT00348010, NCT00347724, NCT00347685, NCT00325858, NCT00142896 and NCT00361686, and 101 more
Completion dates
oldest 2001-07; newest 2024-07-26
Show the evidence
Trial
NCT00348010
2001-07
NCT00347724
2001-11
NCT00347685
2003-02
NCT00325858
2003-12
NCT00142896
2005-12
NCT00361686
2007-01
14 further recorded trials
NCT02329561
2007-02
NCT00510666
2007-05
NCT00301210
2007-11
NCT00487175
2008-03
NCT00713726
2008-07
NCT00692263
2008-08
NCT00310908
2009-02
NCT00743587
2009-03
NCT00426647
2009-08
NCT02436980
2009-12
NCT01178203
2010-08
NCT01800682
2011-09
NCT01526525
2012-02
NCT00560443
2012-04
Q10
At the median, Tramadol's trials enrolled 90 people — anything larger?
Median enrolment
90
Largest enrolment
1561
Registered trials counted
221
Q11
Tramadol and CYP2D6, CYP3A4 and CYP2B6: shared by which compounds?
CYP2D6, CYP3A4 and CYP2B6 appear in Tramadol's recorded interaction sentences, 13 in all. openfda-label+europepmc · 2026-08-30
Interpretation pharmacokinetics
Show the evidence
CYP2B6pharmacokinetics
The major metabolic pathways appear to be N- (mediated by CYP3A4 and CYP2B6) and O- (mediated by CYP2D6) demethylation and glucuronidation or sulfation in the liver.
CYP2D6
pharmacokinetics
The major metabolic pathways appear to be N- (mediated by CYP3A4 and CYP2B6) and O- (mediated by CYP2D6) demethylation and glucuronidation or sulfation in the liver.
pharmacokinetics
Poor / Extensive Metabolizers, CYP2D6 The formation of the active metabolite, M1, is mediated by CYP2D6, a polymorphic enzyme.
pharmacokinetics
Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450 metabolizing enzyme system.
pharmacokinetics
Quinidine Tramadol is metabolized to active metabolite M1 by CYP2D6.
pharmacokinetics
Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition and polymorphism, which may affect the therapeutic response [see Drug Interactions (7) ] .
pharmacokinetics
CYP2D6 Inhibitors In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol.
2 more recorded rows
CYP2D6pharmacokinetics
Coadministration of quinidine, a selective inhibitor of CYP2D6, with tramadol ER resulted in a 50-60% increase in tramadol exposure and a 50-60% decrease in M1 exposure.
CYP2D6pharmacokinetics
To evaluate the effect of tramadol, a CYP2D6 substrate on quinidine, an in vitro drug interaction study in human liver microsomes was conducted.
CYP3A4
pharmacokinetics
The major metabolic pathways appear to be N- (mediated by CYP3A4 and CYP2B6) and O- (mediated by CYP2D6) demethylation and glucuronidation or sulfation in the liver.
pharmacokinetics
CYP3A4 Inhibitors and Inducers Since tramadol is also metabolized by CYP3A4, administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or CYP3A4 inducers, such as rifampin and St. John's Wort, with CONZIP may affect the metabolism of tramadol leading to altered tramadol exposure [see Warnings and Precautions (5.1 , 5.7) , Drug Interactions (7) ] .
pharmacokinetics
Carbamazepine Carbamazepine, a CYP3A4 inducer, increases tramadol metabolism.
pharmacokinetics
Drug Interaction Studies Potential for Tramadol to Affect Other Drugs In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when tramadol is administered concomitantly at therapeutic doses.
recorded 2026-08-30 · last checked 2026-09-04
Q12
Was Tramadol studied with fasting and exercise?
fasting and exercise are named in Tramadol's label sentences: "The relative bioavailability study employed a randomized, single-dose, two-period, two-sequence crossover design (n = 14) comparing DW-1021 with co-administration of Pelubi CR (pelubiprofen 45 mg) and Zytram CR (tramadol hydrochloride 75 mg, equivalent to 65.9 mg tramadol base) under fasting…" openfda-label+europepmc · 2026-08-30
2 recorded statements; fasting, exercise
Show the evidence
fasting
The relative bioavailability study employed a randomized, single-dose, two-period, two-sequence crossover design (n = 14) comparing DW-1021 with co-administration of Pelubi CR (pelubiprofen 45 mg) and Zytram CR (tramadol hydrochloride 75 mg, equivalent to 65.9 mg tramadol base) under fasting conditions.
exercise
In a randomized, double-blind crossover format, we administered rofecoxib (50 mg, daily), tramadol (50 mg, 3 times per day), and a placebo (orally for 3 days), starting immediately after exercise.
recorded 2026-08-30 · last checked 2026-09-04
Q13
What is recorded about Tramadol and AMPK?
"To investigate whether ezetimibe attenuates naloxone-precipitated tramadol withdrawal in mice through modulation of the AMPK/TFEB pathway." — where Tramadol and AMPK appear together. Europe PMC · pathway abstract search · 2026-04-07
"To investigate whether ezetimibe attenuates naloxone-precipitated tramadol withdrawal in mice through modulation of the AMPK/TFEB pathway."
PMID 41944914
"Ezetimibe ameliorates tramadol-withdrawal-induced neurobehavioral and molecular alterations, most likely via AMPK-mediated activation of TFEB and enhancement of autophagy, highlighting its therapeutic potential in opioid withdrawal."
autophagy
PMID 41944914
"Ezetimibe ameliorates tramadol-withdrawal-induced neurobehavioral and molecular alterations, most likely via AMPK-mediated activation of TFEB and enhancement of autophagy, highlighting its therapeutic potential in opioid withdrawal."
PMID 41526224
"Concurrently, tramadol triggers endoplasmic reticulum (ER) stress and activates the p-eIF2α/ATF4/CHOP signaling axis, leading to the generation of reactive oxygen species, impaired autophagy, mitochondrial dysfunction, including mitochondrial membrane depolarization and the decline of ATP production, cytoplasmic vacuolization, and lipid droplet accumulation which is characteristics of…"
mTORPMID 37051630
"TMZ inhibited tramadol-induced neurotoxicity by modulating the PI3K/Akt/mTOR signaling pathways and its downstream inflammatory, apoptosis, and autophagy-related cascades."
autophagyPMID 37051630
"TMZ inhibited tramadol-induced neurotoxicity by modulating the PI3K/Akt/mTOR signaling pathways and its downstream inflammatory, apoptosis, and autophagy-related cascades."
mTOR
PMID 34319855
"The aim of this study was to compare the in vitro cytotoxic effect of tramadol and M1 metabolite in HepG2 cell line, the underlying mechanism, and PI3K/AKT/mTOR as potential target.2."
PMID 29317054
"On the other hand, tramadol that is a very well tolerated opioid analgesic has been revealed to inhibit mTOR upstream controllers through interaction with specific types of muscarinic, serotonergic, nicotinic and NMDA receptors, although it seems to induce the opposite effect via µ-opioid receptor."
AMPK
"The invention relates to a composition that includes a first agent selected including an agent that possesses anti-inflammatory activity or acetaminophen, phenacetin, tramadol and the like a second agent selected from the group consisting of an oxidative phosphorylation inhibitor, an ionophore, and an adenosine 5-monophosphate-activated Protein kinase (AMPK) activator a third agent that possesses…"
recorded 2026-04-07 · last checked 2026-09-04
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