Acute pain severe enough to require an opioid analgesic (non-ocular; the only approved indication)
2 tablets (tramadol hydrochloride 37.5 mg with acetaminophen 325 mg) every 4 to 6 hours as needed, maximum 8 tablets per day, for five days or less; creatinine clearance under 30 mL/min, maximum 2 tablets every 12 hours
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
Previous hypersensitivity to tramadol, acetaminophen, any other component of the product, or opioids
Concurrent monoamine oxidase inhibitor use, or MAOI use within the last 14 days
Available Forms
Tablets: tramadol hydrochloride 37.5 mg with acetaminophen 325 mg
Mechanism of Action
Combination of tramadol, a mu-opioid agonist that also weakly inhibits norepinephrine and serotonin reuptake, with acetaminophen, a non-opioid non-salicylate analgesic whose analgesic site is undetermined and thought to be primarily central. Most opioid activity comes from the O-desmethyl metabolite M1, which binds mu receptors with higher affinity than the parent compound.
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 cause fatal overdose, especially in a child.
Boxed warning, hepatotoxicity: The acetaminophen component has caused acute liver failure, transplant, and death, most often above 4,000 mg per day and often when a second product containing it is taken as well.
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, CNS depressant co-use: Benzodiazepines, other CNS depressants, and alcohol can produce profound sedation, respiratory depression, coma, and death.
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, opioid REMS: FDA requires a Risk Evaluation and Mitigation Strategy for opioid analgesics, including prescriber education and counseling with every prescription.
Common Side Effects
Ocular: Abnormal vision under 1% in clinical trials; miosis and mydriasis reported postmarketing.
Common systemic: Over five days of use (N=142), constipation 6%, somnolence 6%, sweating increased 4%, diarrhea 3%, nausea 3%, anorexia 3%, dizziness 3%, dry mouth 2%, insomnia 2%, pruritus 2%.
Serious systemic: Respiratory depression, seizures, serotonin syndrome, anaphylaxis, acute liver failure, 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.
Serotonin syndrome: Can occur within the recommended dosage range, alone or with SSRIs, SNRIs, TCAs, triptans, cyclobenzaprine, linezolid, or intravenous methylene blue.
Seizures: Reported at recommended doses and more often above them, with added risk from SSRIs, SNRIs, 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; discontinue permanently and do not rechallenge with any formulation.
Serious skin reactions: Rare acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, which can be fatal; stop at the first rash.
Acute angle closure: Mydriasis is a labeled postmarketing event, and two published single case reports describe bilateral angle-closure crisis, the oral case in an anatomically predisposed eye (high hyperopia, short axial length) and the subcutaneous case in a patient with an unremarkable ocular history; both involved tramadol given alone, not this combination.
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