Pain in adults severe enough to require an opioid analgesic (non-ocular; the only approved indication)
Titrate from 25 mg QD by 25 mg every 3 days to 100 mg per day (25 mg QID), then by 50 mg every 3 days to 200 mg per day (50 mg QID), then 50 to 100 mg every 4 to 6 hours as needed, maximum 400 mg per day; when rapid onset is required, 50 to 100 mg every 4 to 6 hours as needed from the start
Contraindications
Children younger than 12 years
Postoperative management in children younger than 18 years following tonsillectomy or adenoidectomy
Significant respiratory depression
Acute or severe bronchial asthma in an unmonitored setting or without resuscitative equipment
Known or suspected gastrointestinal obstruction, including paralytic ileus
Hypersensitivity to tramadol, any other component of the product, or opioids
Concurrent monoamine oxidase inhibitor use, or MAOI use within the last 14 days
Opioid agonist that also weakly inhibits norepinephrine and serotonin reuptake; most mu-receptor activity comes from the O-desmethyl metabolite M1, which in animal models is up to 6 times more potent as an analgesic and 200 times more potent at the mu receptor than the parent compound. Analgesia begins about one hour after a dose and peaks at two to three hours.
Warnings & Precautions
Boxed warning, addiction and abuse: Schedule IV opioid; addiction, abuse, and misuse can occur at recommended doses and can lead to overdose and death.
Boxed warning, respiratory depression: Serious, life-threatening, or fatal respiratory depression can occur, with the greatest risk during initiation and after a dose increase; monitor closely in the first 24 to 72 hours of therapy and after each increase.
Boxed warning, accidental ingestion: A single dose can be fatal, especially in a child.
Boxed warning, pediatric ultra-rapid metabolism: CYP2D6 ultra-rapid metabolizers generate high M1 levels and children have died of respiratory depression; contraindicated under 12 years and after tonsillectomy or adenoidectomy under 18 years, and avoid in adolescents 12 to 18 with hypoventilation risk factors such as obstructive sleep apnea, obesity, or severe pulmonary disease.
Boxed warning, neonatal withdrawal: Prolonged use in pregnancy causes neonatal opioid withdrawal syndrome, which is life-threatening if unrecognized.
Boxed warning, CYP450 interactions: Starting or stopping a CYP3A4 inducer, a 3A4 inhibitor, or a 2D6 inhibitor alters parent drug and M1 levels in complex ways, risking seizures, serotonin syndrome, opioid withdrawal, or fatal respiratory depression.
Boxed warning, CNS depressant co-use: Benzodiazepines, other CNS depressants, and alcohol can produce profound sedation, respiratory depression, coma, and death.
Boxed warning, opioid REMS: FDA requires a Risk Evaluation and Mitigation Strategy for opioid analgesics, including prescriber education and counseling with every prescription.
Serotonin syndrome: Can occur within the recommended dosage range, alone or with SSRIs, SNRIs, TCAs, triptans, cyclobenzaprine, linezolid, or intravenous methylene blue.
Common Side Effects
Ocular: Miosis and visual disturbance each at 1% to under 5%; mydriasis reported postmarketing; cataracts reported with causal relationship undetermined.
Common systemic: Cumulative incidence in chronic nonmalignant pain trials (N=427) at 7 days and at 90 days, dizziness or vertigo 26% and 33%, nausea 24% and 40%, constipation 24% and 46%, headache 18% and 32%, somnolence 16% and 25%, vomiting 9% and 17%, pruritus 8% and 11%.
Serious systemic: Respiratory depression, seizures, serotonin syndrome, anaphylaxis, Stevens-Johnson syndrome and toxic epidermal necrolysis, QT prolongation and torsade de pointes, hyponatremia with SIADH, hypoglycemia, adrenal insufficiency, androgen deficiency with chronic opioid use.
Pregnancy & Lactation
Pregnancy: Data in pregnant women are insufficient to inform birth defect or miscarriage risk; prolonged use causes neonatal opioid withdrawal syndrome, and neonatal seizures, fetal death, and stillbirth have been reported postmarketing. Not recommended during or immediately before labor.
Lactation: Breastfeeding not recommended. Drug and the more potent M1 metabolite are present in milk, and an ultra-rapid metabolizer mother can expose the infant to excess sedation and respiratory depression.
Pediatric Use
Safety and effectiveness not established; contraindicated under 12 years and for post-tonsillectomy or adenoidectomy pain under 18 years.
Seizures: Reported at recommended doses and more often above them, with added risk from SSRIs, TCAs, other opioids, MAOIs, neuroleptics, epilepsy, head trauma, or alcohol and drug withdrawal; naloxone given for overdose may raise seizure risk further.
Suicide risk: Not to be prescribed for suicidal or addiction-prone patients; consider a non-narcotic analgesic in suicidal or depressed patients.
Anaphylaxis: Serious and rarely fatal reactions occur, often after the first dose, along with angioedema, toxic epidermal necrolysis, and Stevens-Johnson syndrome; discontinue permanently and do not rechallenge with any formulation.
Acute angle closure: Mydriasis is a labeled postmarketing event, and bilateral angle-closure crisis has been reported in two single case reports, one after subcutaneous and one after oral tramadol; the oral case occurred in an anatomically predisposed eye (high hyperopia, short axial length), the subcutaneous case in a patient with an unremarkable ocular history.
Adrenal insufficiency: Reported with opioid use, more often after more than one month; confirm by testing, give physiologic corticosteroid replacement, and wean off the opioid.
Severe hypotension: Orthostatic hypotension and syncope can occur, more so with reduced blood volume or concurrent CNS depressants; avoid in circulatory shock.
Raised intracranial pressure: Reduced respiratory drive causes CO2 retention that can further raise intracranial pressure in patients with increased ICP or brain tumors; opioids may also obscure the clinical course after head injury, and use is to be avoided in impaired consciousness or coma.
Hyponatremia: Sodium below 135 mmol/L reported and often severe, most often in women over 65 and within the first week of therapy.
Hypoglycemia: Reported cases, some requiring hospitalization, mostly in patients with predisposing risk factors such as diabetes.
Abrupt discontinuation: Taper in a physically dependent patient; rapid discontinuation has produced withdrawal, uncontrolled pain, and suicide.
Available Forms
Mechanism of Action
Pregnancy & Lactation
Pediatric Use