Polypharmacy – Is It Evidence-Based?




In another common scenario, the patient gets drug A which causes a side effect. He is given drug B to counteract that side effect. Drug B causes a side effect of its own, so he’s given drug C to counteract that one. If drug A is needed to save life or limb, such an approach may be justified; but sometimes the doctor doesn’t recognize that the symptoms are drug side effects and he ends up just chasing his tail.

Any effective drug can have side effects. When patients are on multiple drugs, the risk of reactions and drug interactions increases.

We try to practice evidence-based medicine, but there may not be any evidence for a specific combination of drugs. We have evidence that drugs A, B, C, D and E are each safe, but we don’t have evidence from controlled studies to show that drugs A, B, C, D, and E can safely be used together.

I recently received an inquiry about polypharmacy. The writer stated that 100,000 people die from adverse drug reactions every year and we don’t know how many die from polypharmacy. He repeated a commonly cited estimate that only 30% of medical practice is evidence-based. He asked whether the use of unstudied polypharmacy can really be considered evidence-based, “scientific” medicine.

That’s an excellent question. The answer is yes and no.

It is certainly true that patients are often put on a number of different drugs that have not been specifically tested in combination. It would be nice if every possible combination could be properly tested, but that simply isn’t possible. There are too many combinations and permutations. I’m no statistician, but I’m pretty sure the number of studies needed would far exceed the number of people in the world.

The statistics for adverse drug reactions are misleading. A drug that kills 5 people might also have saved 500 people. Some drugs are prescribed as risky “last resort” treatments for patients who would have died without any treatment. Sometimes drugs with potential interactions are prescribed together because there is no better alternative. Nevertheless, it’s a reasonable guess that polypharmacy does considerable harm. By one estimate, it may be responsible for up to 28% of hospital admissions. How can we avoid that harm when we don’t have comprehensive studies? How can we practice evidence-based medicine when there’s no evidence?

The Wikipedia article on polypharmacy makes a distinction between “thoughtful” and “thoughtless” polypharmacy. We know a lot about drug interactions and can try to avoid them. We know that the more medications, the greater risk of side effects. On the other hand, sometimes we deliberately use multiple medications so that the dose of each can be reduced and the risk of side effects minimized. Multiple drugs are commonly used for infectious diseases like TB and AIDS to reduce the development of drug resistant strains. The different drugs in these regimens have different mechanisms of action so they are less likely to have additive toxicities. Combinations of that sort usually have been adequately tested.

When patients see more than one doctor or fill their prescriptions at more than one pharmacy, thoughtful polypharmacy may be sabotaged. And patients may be to blame for unforeseen or foreseeable interactions when they take over-the-counter medications, herbal medicines, or dietary supplements without the knowledge of their doctors.

Ideally, you would have to test every combination of prescription drugs with every combination of OTCs, herbs, and dietary supplements. Not to speak of combining them with different foods. Grapefruit juice is a notorious offender: it affects drug metabolism by blocking the enzyme CYP3A4. Once we know what it does, do we really need to separately test grapefruit with every drug that is metabolized by that pathway?

The medical literature recommends frequent re-assessment to see if a patient really needs to continue all the drugs he’s on, and it recommends asking the patient to put all his meds and dietary supplements in a paper bag and bring them to each appointment – the “brown bag” review. Guidelines have been published for reducing polypharmacy, for instance this CME article with nine key questions for the provider to ask.

The claim that only 30% of medical practice is evidence-based is misleading. There are some things we can never study with RCTs. You couldn’t ethically do a study of appendicitis with a “no-treatment” arm. You couldn’t ethically compare cancer surgery to placebo surgery. You couldn’t try a placebo instead of casting a fracture. RCTs are the gold standard, but they’re not the only standard. Sometimes we have no recourse but to accept a less perfect kind of evidence.

There are some things we may never know. Does a single chest x-ray increase the risk of cancer? If there is a risk it is very small; the risk from natural background radiation is much greater. Factors like living at different altitudes and living in brick vs. wood houses cause wide variations in individual radiation exposure that would mask any effect from a single x-ray.

Medicine is not an exact science like physics, and the nature of clinical trials means that even in the best of cases we must use common sense to apply imperfect knowledge to a unique individual.

I think there is widespread awareness of the polypharmacy problem, and “thoughtful” polypharmacy IS evidence-based. It’s based on knowledge of the individual drugs, their mechanisms of action and their known interactions. What’s really promising is our increasing knowledge of the genome: we will eventually be able to predict which patients will respond to which drug and which combinations of drugs will be more dangerous for one individual than for another. Calling for RCTs to study every possible combination of drugs in the general population would not be a good use of scarce research money even if it were possible. If certain drugs are frequently prescribed in combination, then those combinations would warrant study, especially if adverse reactions are reported.

Even when we don’t have good evidence for specific combinations of pills, we do have evidence to guide us. We have evidence about the mechanism of action and metabolism of individual drugs, and we can use that evidence to predict some drug interactions. We can do the “brown bag” review and look for evidence that the patient still needs each drug. When a patient develops a new symptom we can review the known side effects for each of his meds to check for a possible drug reaction.

We don’t have all the facts, but we can apply all the knowledge we do have. We can follow general principles like “keep the number of drugs to a minimum.” We can avoid thoughtless polypharmacy – and most good clinicians do. Science-based medicine doesn’t mean requiring an impossible standard of perfection; it means using all the evidence we do have and using common sense to apply it to clinical decisions.


