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.

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.

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.

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: 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).

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

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.

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