Polypharmacy Challenged - Cost in Lives is Unknown

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Pharma

Doctors frequently prescribe more than one drug to patients to take contemporaneously, although interactions between drugs have hardly been tested. This practice - polypharmacy - is often deadly, studies indicate. Charles Sullivan, D.O. has challenged polypharmaceutical prescription at the New England Forensic Sciences Conference held in August 2003 at Colby College. Exact numbers of adverse events and loss of patient life are not known, but drug adverse events are one of the leading causes of death in western countries.

In the light of the adverse effects of drugs, recent comments about the supposed "threat to cancer care" of natural remedies such as garlic, cod liver oil and St. John's wort sound less than serious. Might the medical world be trying to divert attention from its own record of deaths and illness caused by their drugs?

After citing generic warnings "from pharmacists" against the natural remedies, Prof. Robert Souhami, of Cancer Research UK, states that "more work needs to be done to get a clearer picture about how complementary medicines react with conventional drugs". Hardly a basis for indicting safe and non-toxic traditional remedies, while cancer drugs of known high toxicity are routinely administered.

Here follows Charles Sullivan's paper on the morbidity and mortality associated with Polypharmacy:

Polypharmacy: What Cost in Morbidity and Mortality?©

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.)3 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". 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.
179 Main St Suite 403
Waterville, ME
(207)877-0950
(207)877-2441 FAX
(775)458-1135 FAX to email
path@doctorchuck.com

"Science progresses, funeral by funeral." - Max Planck

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

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

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

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

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Additional Refs:

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

Goodstein, D. 2000. How Science Works. In U.S. Federal Judiciary 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.

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.

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

Abstracts
  
David A. Flockhart, and Jose E. Tanus-Santos Implications of Cytochrome P450 Interactions When Prescribing Medication for Hypertension Archives of Internal Medicine 162: 405-412.

Kathryn A. Phillips, David L. Veenstra, Eyal Oren, Jane K. Lee, and Wolfgang Sadee Potential Role of Pharmacogenomics in Reducing Adverse Drug Reactions: A Systematic Review JAMA 286: 2270-2279.

Just Ebbesen, Ingebjørg Buajordet, Jan Erikssen, Odd Brørs, Thor Hilberg, Helge Svaar, and Leiv Sandvik Drug-Related Deaths in a Department of Internal Medicine - Archives of Internal Medicine 161: 2317-2323.

Jeffrey M. Rothschild, Frank A. Federico, Tejal K. Gandhi, Rainu Kaushal, Deborah H. Williams, and David W. Bates Analysis of Medication-Related Malpractice Claims: Causes, Preventability, and Costs - Archives of Internal Medicine 162: 2414-2420.

Mark T. Holdsworth, Richard E. Fichtl, Maryam Behta, Dennis W. Raisch, Elena Mendez-Rico, Alexa Adams, Melanie Greifer, Susan Bostwick, and Bruce M. Greenwald Incidence and Impact of Adverse Drug Events in Pediatric Inpatients - Arch Pediatr Adolesc Med 157: 60-65.

David N. Juurlink, Muhammad Mamdani, Alexander Kopp, Andreas Laupacis, and Donald A. Redelmeier Drug-Drug Interactions Among Elderly Patients Hospitalized for Drug Toxicity - JAMA 289: 1652-1658.

Jason Lazarou, Bruce H. Pomeranz, and Paul N. Corey Incidence of Adverse Drug Reactions in Hospitalized Patients: A Meta-analysis of Prospective Studies - JAMA 279: 1200-1205.

Karen E. Lasser, Paul D. Allen, Steffie J. Woolhandler, David U. Himmelstein, Sidney M. Wolfe, and David H. Bor Timing of New Black Box Warnings and Withdrawals for Prescription Medications - JAMA 287: 2215-2220.

Abstract 1 of 8
Implications of Cytochrome P450 Interactions When Prescribing Medication for Hypertension
David A. Flockhart, MD, PhD and Jose E. Tanus-Santos, MD, PhD

Arch Intern Med. 2002;162:405-412.
Many of the estimated 50 million Americans with high blood pressure receive medications for hypertension and for other conditions, placing them at risk for adverse drug interactions. The risk for hypertension and for adverse drug reactions is highest in the elderly, who have the greatest need for pharmacologic therapy. The most important class of drug interactions involves the cytochrome P450 microsomal enzyme system, which handles a variety of xenobiotic substances. A potential for interactions with these enzymes exists with calcium channel blockers, {beta}-adrenergic blocking agents, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers but not with diuretic antihypertensives, which are renally eliminated and more vulnerable to drug interactions that occur in the kidney. This article reviews the cytochrome P450 enzyme system, identifies drugs and foods that have been implicated in metabolic interactions with antihypertensive agents, and suggests measures for reducing the risk of adverse events when drugs are coadministered.

From the Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis. Dr Flockhart is now with the Department of Medicine, Indiana University School of Medicine, Wishard Hospital, Indianapolis.

Abstract 2 of 8
Potential Role of Pharmacogenomics in Reducing Adverse Drug Reactions - A Systematic Review
Kathryn A. Phillips, PhD, David L. Veenstra, PhD, PharmD, Eyal Oren, BA, Jane K. Lee, BA and Wolfgang Sadee, PhD

JAMA. 2001;286:2270-2279.
Context Adverse drug reactions are a significant cause of morbidity and mortality. Although many adverse drug reactions are considered nonpreventable, recent developments suggest these reactions may be avoided through individualization of drug therapies based on genetic information, an application known as pharmacogenomics.

Objective To evaluate the potential role of pharmacogenomics in reducing the incidence of adverse drug reactions.

Data Sources MEDLINE English-language only searches for adverse drug reaction studies published between January 1995 and June 2000 and review articles of variant alleles of drug-metabolizing enzymes published between January 1997 and August 2000. We also used online resources, texts, and expert opinion.

Study Selection Detailed inclusion criteria were used to select studies. We included 18 of 333 adverse drug reaction studies and 22 of 61 variant allele review articles.

Data Extraction All the investigators reviewed and coded articles using standardized abstracting forms.