Trazodone and Acetaminophen Interaction: What Patients and Clinicians Need to Know

Is there a direct interaction between trazodone and acetaminophen?

Acetaminophen is not listed in the trazodone tablet label's interaction table [1]. The current trazodone label covers trazodone hydrochloride tablets, indicated for major depressive disorder in adults; sleep use is off-label [1]. Its interaction table covers MAOIs, other serotonergic drugs, antiplatelet and anticoagulant drugs, strong CYP3A4 inhibitors, strong CYP3A4 inducers, digoxin and phenytoin, CNS depressants, and QT-prolonging drugs [1]. Not being on that table means only that the label does not name the combination.

Trazodone is a CYP3A4 substrate. Strong CYP3A4 inhibitors such as itraconazole, ketoconazole, clarithromycin and indinavir raise trazodone exposure and can increase adverse reactions, including arrhythmia; strong inducers such as rifampin, carbamazepine, phenytoin and St. John's wort lower exposure [1]. A crossover study in 10 healthy volunteers shows the size a CYP3A4 interaction can reach: low-dose ritonavir cut the oral clearance of a single 50 mg trazodone dose from 155 to 75 mL/min and lengthened half-life from 6.7 to 14.9 hours [3]. Acetaminophen is not among the label's strong CYP3A4 inhibitor or inducer examples [1].

What does the acetaminophen label warn about?

Acetaminophen is a pain reliever and fever reducer sold as Tylenol and as generic products, and it is an ingredient in many cold and flu products and in prescription opioid combinations such as Percocet and Norco [2]. OTC Tylenol labels print a liver warning: severe liver damage may occur if an adult takes more than 4,000 mg in 24 hours, takes it with other drugs containing acetaminophen, or has 3 or more alcoholic drinks every day while using the product [2]. The label also says to ask a doctor before use if you have liver disease [2].

The 4,000 mg figure is the ceiling stated in the liver warning, not the printed maximum on every product. Extra Strength 500 mg labels allow 6 caplets (3,000 mg) in 24 hours; Regular Strength 325 mg labels allow 10 tablets (3,250 mg); 8 HR Arthritis Pain 650 mg labels allow 6 caplets (3,900 mg) [2]. OTC acetaminophen has no boxed warning; the Drug Facts label uses a liver warning heading. Prescription intravenous acetaminophen and acetaminophen-opioid combination labels carry a boxed hepatotoxicity warning [2].

Liver harm is not only from intentional overdose. In a 662-patient US acute liver failure study at 22 centers, 275 cases (42%) were attributed to acetaminophen, and the median dose ingested was 24 g. Unintentional overdoses accounted for 48% of the acetaminophen cases; among those, 38% took two or more acetaminophen preparations and 63% used narcotic-containing products [4].

What about sedation and alcohol?

Trazodone causes drowsiness: in MDD outpatients it was reported by 41% of those on trazodone versus 20% on placebo [1]. The label says trazodone may enhance the effects of alcohol, barbiturates and other CNS depressants [1].

Alcohol appears on both sides. Acetaminophen labels warn about 3 or more alcoholic drinks every day because of liver-damage risk [2]. Two short randomized trials found no clinical liver injury at 4 g a day of acetaminophen: 102 patients given 1,000 mg four times daily for 2 days during alcohol detoxification had a day-4 mean AST of 38.0 U/L versus 37.5 U/L on placebo, and people drinking 1 to 3 drinks a day had a mean ALT rise of 8.7 IU/L after 10 days at 4 g daily without symptoms or predefined hepatotoxicity [5][6]. Neither trial covered long courses or heavy ongoing drinking.

What about serotonin syndrome?

Trazodone can cause serotonin syndrome on its own, and the risk rises with other serotonergic drugs [1]. The label names triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John's wort [1]. Acetaminophen does not appear on that list [1].