Section 06 · Monograph

Tramadol

Reviewed Nov 2026FDA label

UltramOpioid + SNRI

Black Box Warning

Addiction, Abuse, and Misuse: exposes patients to risks of opioid addiction, abuse, and misuse, which can lead to overdose and death
Opioid Analgesic REMS: available only through a restricted program
Life-Threatening Respiratory Depression: risk is greatest during initiation or following a dose increase — monitor closely, especially during the first 24-72 hours
Accidental Ingestion: even one dose, especially by children, can result in fatal overdose
Neonatal Opioid Withdrawal Syndrome: prolonged use during pregnancy can result in a life-threatening withdrawal syndrome in the newborn
Contraindicated in children younger than 12 years and in patients younger than 18 years following tonsillectomy and/or adenoidectomy
CYP2D6 Ultra-Rapid Metabolizers: can lead to higher-than-expected serum levels of the active metabolite (M1) and increased/life-threatening respiratory depression risk
Interactions with Benzodiazepines or Other CNS Depressants: may result in profound sedation, respiratory depression, coma, and death

Management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate, in adultsFDA-labeled

Diabetic peripheral neuropathy and other neuropathic pain (adjunct, off-label)Off-label
Fibromyalgia-associated painOff-label

Centrally acting synthetic opioid analgesic with dual mechanism: a mu-opioid receptor agonist and an inhibitor of neuronal reuptake of both norepinephrine and serotonin
Tramadol itself has relatively weak mu-opioid affinity; its O-desmethyl metabolite (M1), formed via CYP2D6 metabolism, has substantially higher mu-opioid receptor affinity and contributes significantly to analgesia
Monoaminergic reuptake inhibition contributes an independent, non-opioid analgesic mechanism relevant to neuropathic pain, similar to SNRIs
Analgesia depends partly on CYP2D6-mediated conversion to M1, so genetic polymorphisms significantly affect both efficacy and toxicity risk

Opioid-naive adults: initiate 25 mg/day, titrate in 25 mg increments every 3 days as tolerated to reach 100 mg/day, then increase total daily dose by 50 mg every 3 days up to 200 mg/day
Usual dose 50-100 mg orally every 4-6 hours as needed for pain, not to exceed 400 mg/day
Geriatric patients >75 years: maximum 300 mg/day in divided doses
Extended-release formulations for opioid-tolerant patients requiring around-the-clock analgesia
Do not abruptly discontinue in physically dependent patients; taper gradually

Severe renal impairment (CrCl <30 mL/min): increase dosing interval to every 12 hours, maximum 200 mg/day

Significant respiratory depression
Acute or severe bronchial asthma in an unmonitored setting
Known or suspected gastrointestinal obstruction, including paralytic ileus
Hypersensitivity to tramadol or other opioids
Concurrent use of, or use within 14 days of discontinuing, an MAOI
Children younger than 12 years
Postoperative management following tonsillectomy and/or adenoidectomy in patients younger than 18 years

Benzodiazepines and other CNS depressants: profound sedation, respiratory depression, coma, death — boxed warning
MAOIs: contraindicated; risk of serotonin syndrome and seizures
Serotonergic drugs: increased risk of life-threatening serotonin syndrome
CYP2D6 inhibitors: increase parent tramadol and decrease active M1 metabolite, altering seizure/serotonin syndrome risk and analgesic effect
CYP3A4 inhibitors: increase tramadol exposure, increasing seizure and serotonin syndrome risk
CYP3A4 inducers (carbamazepine especially): decrease tramadol efficacy and increase seizure risk — not recommended
Mixed agonist/antagonist opioids: may reduce analgesic effect and/or precipitate withdrawal
Drugs that lower seizure threshold: additive risk of seizures

Dizziness/vertigo, nausea, constipation, headache, somnolence, vomiting, and pruritus (each ≥15% in trials)
Respiratory depression, which can be severe and fatal
Seizures, particularly at higher doses or with concomitant serotonergic/CYP-interacting drugs
Serotonin syndrome
Physical dependence, tolerance, and opioid use disorder with chronic use
Withdrawal symptoms on abrupt discontinuation
Hypotension, syncope
QT prolongation/torsade de pointes (rare)
Adrenal insufficiency with prolonged use

Respiratory rate, oxygen saturation, and sedation level, especially during initiation and after dose increases (first 24-72 hours)
Ongoing assessment for signs of addiction, abuse, or misuse, including periodic urine drug screening and PDMP review
Signs/symptoms of serotonin syndrome when combined with other serotonergic drugs
Seizure activity, particularly in at-risk patients
Signs of physical dependence/withdrawal if therapy is reduced or discontinued
Adrenal function with long-term use
Renal and hepatic function to guide dose adjustment
Blood pressure and cardiac status in at-risk patients

Prolonged use during pregnancy can cause neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated
Animal studies showed fetal toxicity at maternal exposures exceeding recommended human doses
Use during pregnancy only if benefits outweigh risks; not recommended for obstetrical pre/post-delivery analgesia due to neonatal respiratory depression risk
Breastfeeding not recommended during treatment; active metabolite M1 is more potent than parent drug and passes into breast milk
Mothers who are CYP2D6 ultra-rapid metabolizers can produce dangerously high M1 levels in breast milk, risking life-threatening respiratory depression in the breastfed infant