Acetaminophen and Tramadol

Pronunciation

(a seet a MIN oh fen & TRA ma dole)

U.S. Brand Names

Ultracet™

Synonyms

APAP and Tramadol; Tramadol Hydrochloride and Acetaminophen

Generic Available

Use

Short-term (

5 days) management of acute pain

Use - Dental

Treatment of postoperative pain (

5 days)

Pregnancy Risk Factor

Pregnancy Implications

Tramadol has been shown to cross the placenta. Postmarketing reports following tramadol use during pregnancy include neonatal seizures, withdrawal syndrome, fetal death and stillbirth. Not recommended for use during labor and delivery.

Lactation

Tramadol: Enters breast milk/contraindicated

Contraindications

Hypersensitivity to acetaminophen, tramadol, opioids, or any component of the formulation; opioid-dependent patients; acute intoxication with ethanol, hypnotics, narcotics, centrally-acting analgesics, opioids, or psychotropic drugs; hepatic dysfunction

Warnings/Precautions

Should be used only with extreme caution in patients receiving MAO inhibitors. Use with caution and reduce dosage when administering to patients receiving other CNS depressants. Seizures may occur when taken within the recommended dosage; risk is increased in patients receiving serotonin reuptake inhibitors (SSRIs or anorectics), tricyclic antidepressants, other cyclic compounds (including cyclobenzaprine, promethazine), neuroleptics, MAO inhibitors, or drugs which may lower seizure threshold. Patients with a history of seizures, or with a risk of seizures (head trauma, metabolic disorders, CNS infection, or malignancy, or during alcohol/drug withdrawal) are also at increased risk. Do not use with ethanol or other acetaminophen- or tramadol-containing products.

Limit acetaminophen to <4 g/day. May cause severe hepatic toxicity in acute overdose; in addition, chronic daily dosing in adults has resulted in liver damage in some patients. Use with caution in patients with alcoholic liver disease; consuming 3 alcoholic drinks/day may increase the risk of liver damage. Use caution in patients with known G6PD deficiency.

Elderly patients and patients with chronic respiratory disorders may be at greater risk of adverse events. Use with caution in patients with increased intracranial pressure or head injury. Use tramadol with caution and reduce dosage in patients with renal dysfunction and in patients with myxedema, hypothyroidism, or hypoadrenalism. Tolerance or drug dependence may result from extended use (withdrawal symptoms have been reported); abrupt discontinuation should be avoided. Tapering of dose at the time of discontinuation limits the risk of withdrawal symptoms. Safety and efficacy in pediatric patients have not been established.

Adverse Reactions

1% to 10%:

Central nervous system: Somnolence (6%), dizziness (3%), insomnia (2%), anxiety, confusion, euphoria, fatigue, headache, nervousness, tremor

Dermatologic: Pruritus (2%), rash

Endocrine & metabolic: Hot flashes

Gastrointestinal: Constipation (6%), anorexia (3%), diarrhea (3%), nausea (3%), dry mouth (2%), abdominal pain, dyspepsia, flatulence, vomiting

Genitourinary: Prostatic disorder (2%)

Neuromuscular & skeletal: Weakness

Miscellaneous: Diaphoresis increased (4%)

<1%: Abnormal thinking, abnormal vision, albuminuria, amnesia, anemia, arrhythmia, ataxia, chest pain, convulsions, depersonalization, drug abuse, dysphagia, dyspnea, emotional lability, hallucination, hyper-/hypotension, hypertonia, impotence, liver function abnormalities, melena, micturition disorder, migraine, muscle contractions (involuntary), oliguria, palpitation, paresthesia, paroniria, rigors, stupor, syncope, tachycardia, tinnitus, tongue edema, urinary retention, weight loss, vertigo

Postmarketing and/or case reports: Agitation, allergic reactions, anaphylactoid reactions, anaphylaxis, cognitive dysfunction, coma, depression, diaphoresis, difficulty concentrating, fever, gastrointestinal bleeding, hepatitis, hyper-reflexia, mental status change, myocardial ischemia, orthostatic hypotension, liver failure, pulmonary edema, seizure, serotonin syndrome, shivering, Stevens-Johnson syndrome, suicidal tendency, toxic epidermal necrolysis, urticaria, vasodilation

A withdrawal syndrome may occur with abrupt discontinuation; includes anxiety, diarrhea, hallucinations (rare), nausea, pain, piloerection, rigors, sweating, and tremor. Uncommon discontinuation symptoms may include severe anxiety, panic attacks, or paresthesia.

Overdosage/Toxicology

Symptoms of overdose include signs and symptoms from both acetaminophen and tramadol toxicity. Treatment should be symptom-directed and supportive.

Acetaminophen: Symptoms of overdose include hepatic necrosis, transient azotemia, renal tubular necrosis with acute toxicity, anemia, and GI disturbances with chronic toxicity. Treatment consists of acetylcysteine 140 mg/kg orally (loading), followed by 70 mg/kg every 4 hours for 17 doses; therapy should be initiated based upon laboratory analysis suggesting a high probability of hepatotoxic potential. Activated charcoal is very effective at binding acetaminophen. Intravenous acetylcysteine should be reserved for patients unable to take oral forms.

Tramadol: CNS and respiratory depression, coma, seizure, cardiac arrest and death. Naloxone may be helpful, but may also increase risk of seizures.

Drug Interactions

Acetaminophen: Substrate (minor) of CYP1A2, 2A6, 2C8/9, 2D6, 2E1, 3A4; Inhibits CYP3A4 (weak)

Tramadol: Substrate of CYP2D6 (major), 3A4 (minor)

Amphetamines: May increase the risk of seizures with tramadol.

Anesthetic agents: May increase risk of CNS and respiratory depression; use together with caution and in reduced dosage.

Barbiturates: Barbiturates may increase the hepatotoxic effects of acetaminophen; in addition, acetaminophen levels may be lowered.

Carbamazepine: Carbamazepine decreases half-life of tramadol by 33% to 50%; also have increase risk of seizures; in addition, carbamazepine may increase the hepatotoxic effects and lower serum levels of acetaminophen; concomitant use is not recommended.

CYP2D6 inhibitors: May decrease the effects of tramadol. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

Digoxin: Rare reports of digoxin toxicity with concomitant tramadol use.

Hydantoin anticonvulsants: Phenytoin may increase the hepatotoxic effects of acetaminophen; in addition, acetaminophen levels may be lowered.

MAO inhibitors: May increase the risk of seizures. Use extreme caution.

Naloxone: May increase the risk of seizures (if administered in tramadol overdose).

Neuroleptic agents: May increase the risk of tramadol-associated seizures and may have additive CNS depressant effects.

Narcotics: May increase risk of CNS and respiratory depression; use together with caution and in reduced dosage.

Opioids: May increase the risk of seizures, and may have additive CNS depressant effects. Use together with caution and in reduced dosage.

Phenothiazines: May increase risk of CNS and respiratory depression; use together with caution and in reduced dosage.

Rifampin: Rifampin may increase the clearance of acetaminophen.

Quinidine: May increase the tramadol serum concentrations by inhibiting CYP metabolism.

SSRIs: May increase the risk of seizures with tramadol by inhibiting CYP metabolism (citalopram, fluoxetine, paroxetine, sertraline).

Sulfinpyrazone: Sulfinpyrazone may increase the hepatotoxic effects of acetaminophen; in addition, acetaminophen levels may be lowered.

Tricyclic antidepressants: May increase the risk of seizures.

Warfarin: Acetaminophen and tramadol may lead to an elevation of prothrombin times; monitor.

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (increased liver toxicity with concomitant use).

Food: May delay time to peak plasma levels, however, the extent of absorption is not affected.

Herb/Nutraceutical:

Acetaminophen: Avoid St John's wort (may decrease acetaminophen levels).

Tramadol: Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).

Stability

Store at controlled room temperature of 25°C (77°F).

Mechanism of Action

Based on acetaminophen component: Inhibits the synthesis of prostaglandins in the central nervous system and peripherally blocks pain impulse generation; produces antipyresis from inhibition of hypothalamic heat-regulating center

Based on tramadol component: Binds to -opiate receptors in the CNS causing inhibition of ascending pain pathways, altering the perception of and response to pain; also inhibits the reuptake of norepinephrine and serotonin, which also modifies the ascending pain pathway

Pharmacodynamics/Kinetics

See individual agents.

Dosage

Oral: Adults: Acute pain: Two tablets every 4-6 hours as needed for pain relief (maximum: 8 tablets/day); treatment should not exceed 5 days

Dosage adjustment in renal impairment: Clcr<30 mL/minute: Maximum of 2 tablets every 12 hours; treatment should not exceed 5 days

Dosage adjustment in hepatic impairment: Use is not recommended.

Monitoring Parameters

Pain relief, respiratory rate, blood pressure, and pulse; signs of tolerance or abuse

Dietary Considerations

May be taken with or without food. Avoid use of ethanol and ethanol-containing products.

Patient Education

See individual agents. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Should not be used during pregnancy. Do not breast-feed.

Nursing Implications

Driving or operating machinery should be avoided until the effect of drug wears off. Cravings should be reported to physician immediately.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia and changes in salivation (normal salivary flow resumes upon discontinuation).

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause sedation, dizziness, insomnia, anxiety, confusion, or euphoria; monitor with concurrent psychotropic use

Mental Health: Effects on Psychiatric Treatment

Contraindicated with acute intoxication of psychotropic drugs. Use with extreme caution with MAOIs. Seizure risk is increased with SSRIs, TCAs, antipsychotics, and MAOIs. Carbamazepine may decrease the half-life of tramadol (concurrent use is not recommended). Fluoxetine and paroxetine may increase tramadol serum concentrations.

Dosage Forms

Tablet: Acetaminophen 325 mg and tramadol hydrochloride 37.5 mg

References

Mokhlesi B, Leikin JB, Murray P, et al, "Adult Toxicology in Critical Care: Part II: Specific Poisonings," Chest , 2003, 123(3):897-922.

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