Polypharmacy: What Cost in Morbidity and Mortality?

A paper by Dr. Charles Sullivan, presented by the author at the 2003 New England Forensic Sciences Conference at Colby College: It is common practice in Medicine to put patients on combinations of drugs. The vast majority of these combinations of drugs (especially where 3 or more drugs are involved) have never been studied at all, let alone in double-blind trials ( with the exception of Oncology/AIDS treatment, where the toxicity of the drugs demands study); yet it is frequent practice to prescribe these multiple-drug combinations.

It is well accepted in pharmacology that it is scientifically impossible to accurately predict the side effects or clinical effects of a combination of drugs without studying that particular combination of drugs in test subjects. Knowledge of the pharmacologic profiles of the individual drugs in question does not in any way assure accurate prediction of the side effects of combinations of those drugs, especially when they have different mechanisms of action, which is very common because polypharmacy is most often prescribed to patients with “multiple illnesses”. More than 100,000 patients in this country die from identified adverse drug reactions (perhaps the 4th to 6th leading cause of death in the U.S.)[1] The number who die as a consequence of polypharmacy is, to my knowledge, unknown.

The argument that the prescribing of drugs is the “Art” of Medicine is not valid in defending polypharmacy, because drugs are developed (indications, dose and administration, etc.) and approved through a “scientific” process (double-blind, placebo-controlled studies). The fact that the medicines are often prescribed for “different conditions” is irrelevant (especially to the patient’s physiology). The idea that ” we are doing the best we can “, a frequent defense of Polypharmacy, does not in any way uphold a scientific argument in favor of it. (We are, indeed, trying the best we can, with tools which do not improve at the rate we would wish!) The fact that “there is a limit to how much research can be done” in no way makes the research unnecessary in order to predict the side effects of specific combinations of drugs.

It has been said in the past that less than 30% of medical practice was backed by controlled studies.[2,3] Has this changed? How do we know? Are we looking closely enough at our way of practicing Medicine? Can the use of unstudied polypharmacy really be considered evidence-based, “scientific” Medicine? Can the Pathology community help initiate meaningful debate regarding this subject at a level that will produce more widespread awareness?

Charles Sullivan, D.O.

“Science progresses, funeral by funeral.” – Max Planck

1. Incidence of Adverse Drug Reactions in Hospitalized Patients. JAMA. 1998;279:1200-1205

2. Office of Technology Assessment: Assessing the efficacy and safety of medical technologies. U.S. Government Printing Office, Washington, 1978

3. Smith R: Where is the wisdom? The poverty of medical evidence. BMJ 1991;303:798

4. “…only about 15% of medical interventions are supported by solid scientific evidence; in other words, eighty-five percent are not.” Smith, R (editor of British Medical Journal). The ethics of ignorance. Journal of Medical Ethics. 1992;18:117

Additional References

Daubert v. Merrel Dow Pharmaceuticals 509 U.S. 579 (1993), 509, 579.

Goodstein, D. 2000. How Science Works. In U.S. Federal Judiciar Reference Manual on Evidence, pp. 66-72.

Horrobin, D.F. 1990. The philosophical basis of peer review and the suppression of innovation. J. Am. Med. Assoc. 263:1438-1441.

Horrobin, D.F. 1996. Peer review of grant applications: A harbinger for mediocrity in clinical research? Lancet 348:1293-1295.

Horrobin, D.F. 1981-1982. Peer review: Is the good the enemy of the best? J. Res. Commun. Stud. 3:327-334.

Horrobin, D.F. 2000. Innovation in the pharmaceutical industry. J. R. Soc. Med. 93:341-345.

Rothwell, P.M. and Martyn, C.N. 2000. Reproducibility of peer review in clinical neuroscience: Is agreement between reviewers any greater than would be expected by chance alone? Brain 123:1964-1969.