Drug Interactions between amitriptyline / perphenazine and propoxyphene

MONITOR CLOSELY: Concomitant use of propoxyphene and tricyclic and tetracyclic antidepressants (TCAs) may result in additive central nervous system (CNS) depressant effects. Misuse of propoxyphene, either alone or in combination with other CNS depressants, has been a major cause of drug-related deaths, particularly in patients with a history of emotional disturbances, suicidal ideation, or alcohol and drug abuse. In a large Canadian study, propoxyphene use was also associated with a 60% increased risk of hip fracture in the elderly, and the risk was further increased by concomitant use of psychotropic agents including antidepressants, presumably due to additive psychomotor impairment. Therefore, these drugs may constitute a dangerous combination in certain susceptible populations. Pharmacokinetically, propoxyphene is a CYP450 2D6 inhibitor and may increase the plasma concentrations of TCAs such as clomipramine, desipramine, doxepin, maprotiline, and nortriptyline that are primarily metabolized by the isoenzyme. In one case report, doxepin serum concentrations doubled in an 89-year-old patient following the addition of propoxyphene, resulting in lethargy. A retrospective study also found that the plasma concentration/dose ratio of nortriptyline was nearly 40% higher in patients treated concomitantly with propoxyphene than in patients treated with nortriptyline alone.

MANAGEMENT: Caution is advised if propoxyphene is prescribed with TCAs, particularly in the elderly and in patients with a history of emotional disturbances, suicidal ideation, or alcohol and drug abuse. Serum TCA levels should be monitored more closely following the addition or withdrawal of propoxyphene, and the TCA dosage adjusted as necessary. Patients should be warned not to exceed recommended dosages of either drug, to avoid alcohol, and to notify their physician if they experience symptoms of toxicity such as lethargy, excessive sedation, dizziness, syncope, seizures, and/or irregular heartbeat. In addition, they should avoid activities requiring mental alertness until they know how these agents affect them.

MONITOR CLOSELY: Concomitant use of propoxyphene and phenothiazines may result in additive central nervous system (CNS) depressant effects. Misuse of propoxyphene, either alone or in combination with other CNS depressants, has been a major cause of drug-related deaths, particularly in patients with a history of emotional disturbances, suicidal ideation, or alcohol and drug abuse. In a large Canadian study, propoxyphene use was also associated with a 60% increased risk of hip fracture in the elderly, and the risk was further increased by concomitant use of psychotropic agents including neuroleptics, presumably due to additive psychomotor impairment. Therefore, these drugs may constitute a dangerous combination in certain susceptible populations. Pharmacokinetically, propoxyphene may increase the plasma concentrations of phenothiazines by inhibiting their metabolism via CYP450 2D6. In addition to enhanced CNS depression, the possibility of increased adverse effects of phenothiazines such as tardive dyskinesia, hypotension, and prolongation of the QT interval should be considered. Many of these agents alone can and have produced these effects.

MANAGEMENT: Caution is advised if propoxyphene is prescribed with phenothiazines, particularly in the elderly and in patients with a history of emotional disturbances, suicidal ideation, or alcohol and drug abuse. Dosage reductions may be required. Patients should be warned not to exceed recommended dosages, to avoid alcohol, and to notify their physician if they experience symptoms of toxicity such as lethargy, excessive sedation, dizziness, syncope, seizures, and/or irregular heartbeat. In addition, they should avoid activities requiring mental alertness until they know how these agents affect them.

MONITOR: Coadministration of a phenothiazine with a tricyclic antidepressant (TCA) may result in elevated plasma concentrations of one or both drugs as well as additive adverse effects. Most phenothiazines and TCAs have been found to undergo metabolism by CYP450 2D6, thus competitive inhibition of the enzyme may occur when more than one of these agents are administered. Although these drugs have been used together clinically, the possibility of increased risk of serious adverse effects such as central nervous system depression, tardive dyskinesia, hypotension, and prolongation of the QT interval should be considered, as many of these agents alone can and have produced these effects. In addition, excessive anticholinergic effects may occur in combination use, which can result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of anticholinergic intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures.

MANAGEMENT: Concurrent use of phenothiazines and TCAs should be approached with caution, particularly in the elderly and those with underlying organic brain disease, who tend to be more sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be easily overlooked. Patients should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication (e.g., abdominal pain, fever, heat intolerance, blurred vision, confusion, hallucinations) or cardiovascular toxicity (e.g., dizziness, palpitations, arrhythmias, syncope). Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A dosage reduction in one or both drugs may be necessary if excessive adverse effects develop.