“Do no harm” is the first rule of medicine, yet 106,000 Americans die each year from properly prescribed and correctly taken medications.1 In some cases, the cause of death is known and can be attributed to a drug-drug interaction. The likelihood of death or hospitalization is directly proportional to the number of medications a patient is taking, even after controlling for underlying diseases.2
In psychiatry, it is not unusual for us to prescribe more than one psychotropic agent to manage a patient’s symptoms:
- Patients with affective and psychotic disorders are commonly prescribed combinations of antipsychotics, mood stabilizers, antidepressants (often from more than one class), anxiolytics, antihistamines, and anticholinergics.
- Patients with posttraumatic stress disorder may take selective serotonin reuptake inhibitors, buspirone, trazodone, antipsychotics, mood stabilizers, benzodiazepines, beta blockers, and opiates.
- Multiple-drug regimens are used in treating other medical and psychiatric disorders, including chronic pain, fibromyalgia, chronic fatigue syndrome, sleep disorders, and epilepsy.
The greater the number of drugs used, the greater the likelihood that adverse events are emerging and are being treated, sometimes while being mistaken for patient psychopathology. As a prescriber, you are in a unique position to recognize and prevent interactions that can occur when patients are treated with two or more medications. This article defines polypharmacy, describes its consequences, prevalence, and risk factors, and offers an eight-step strategy with two mnemonics to help you avoid adverse events when prescribing multiple-drug regimens.
POLYPHARMACY: MANY DRUGS, MANY DEFINITIONS
Poly, from the Greek word polus (many, much) and pharmacy, from the Greek word pharmakon (drug, poison) literally means many drugs or, alternatively, much poison.3 The word polypharmacy first appeared in the medical literature in 1959 in the New England Journal of Medicine4 and in the psychiatric literature in 1969 in an article citing its incidence at a state mental hospital.5
Many definitions have been used to describe and define polypharmacy, both qualitatively and quantitatively. Monotherapy is drug treatment with one drug. Sometimes treatment with two drugs is referred to as co-pharmacy, while treatment with three or more drugs is referred to as polypharmacy.Minor polypharmacy refers to treatment with two to four drugs, while major polypharmacyrefers to treatment with five or more drugs.6
What is polypharmacy?
Many definitions have been used to describe polypharmacy (Box 1).3-6 The most common definition is the use of five or more drugs at the same time in the same patient.7 Although polypharmacy often has a pejorative connotation, using five or more drugs may be therapeutic or contratherapeutic.
Therapeutic polypharmacy occurs, for example, when expert panels or researchers in carefully controlled clinical trials recommend using multiple medications to treat specific diseases. For example, the five-drug combination of isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine is therapeutic in initial tuberculosis treatment. More is better in this case because four antibiotics are needed to prevent the development of multiple drug-resistant Mycobacterium tuberculosis, and adding pyridoxine prevents isoniazid-induced neurotoxicity. This example illustrates two prescribing principles:
- using multiple drugs can help achieve an intended therapeutic goal
- adding one drug can prevent a known side effect of another drug.
Another example is the therapeutic management of congestive heart failure, in which five drug classes—an angiotensin-converting enzyme (ACE) inhibitor, a diuretic, a digitalis glycoside, a beta blocker, and an aldosterone antagonist—are used in various combinations. All play a role in improving cardiac function and reducing morbidity and mortality.
Using combination drug therapy can also generate cost benefits, such as by adding a drug to delay or inhibit the metabolism of an expensive principal drug. For example, adding diltiazem—a cytochrome P450 (CYP) 3A4 inhibitor—to cyclosporine—which is metabolized by CYP 3A4 enzymes—reduces the dosage of cyclosporine needed to achieve a desired serum level, thereby reducing the cost of this drug. (Some have abandoned this strategy because of cyclosporine’s narrow therapeutic index.)
Contratherapeutic polypharmacy occurs when a patient taking multiple drugs experiences an unexpected or unintended adverse outcome.
Settings for polypharmacy
Polypharmacy occurs in five principal prescribing situations:
- treatment of symptoms
- treatment of multiple illnesses
- treatment of phasic illnesses, such as many affective, anxiety, seizure, and neurodegenerative disorders
- preventing or treating adverse effects of other drugs
- attempting to accelerate the onset of action or augment the effects of a preceding drug.
As described above, diseases such as tuberculosis and congestive heart failure, with well-understood causes and pathophysiologies, are often treated with multiple therapeutic drug combinations. However, the causes of many psychiatric disorders and syndromes are less well-understood, which makes prescribing drug combinations more difficult. It may be that treating less well-understood diseases is a risk factor for contratherapeutic polypharmacy.