Painkiller Side-Effects, Genes Play A Part

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Painkiller Side-Effects, Genes Play A Part

http://www.medicalnewstoday.com/medicalnews.php?newsid=35812

A study published in the January issue of the American

Gastroenterological Association (AGA) journal Gastroenterology found

a difference in how people responded to popular painkillers and that

up to 30 percent of this variability can be attributed to an

individual's genetic make-up. This variation can influence both how

useful the drugs are in affording relief from pain and inflammation,

and the number and severity of the adverse effects. This evaluation

is perhaps the most rigorous look at how people vary in their

response to drugs and was designed as part of a strategy to determine

genetic and other markers that might help predict response and safety

of these drugs, including susceptibility to cardiovascular

complications.

The study looked at people taking two popular painkillers--rofecoxib

(Vioxx, Merck) and celecoxib (Celebrex, Pfizer)--known as COX-2

inhibitors. During the past two years, evidence has emerged that COX-

2s confer a risk of heart attack and stroke, resulting in two of the

drugs in this class being withdrawn from the market and a black box

warning being issued for a third drug.

" The use of any drug involves a mix of benefits and risks. The

problems with COX-2 inhibitors were real, but involved less than 2

percent of patients who were taking them, " said Garret A. FitzGerald,

MD, study author from the University of Pennsylvania School of

Medicine. " Because we often underestimate just how much people differ

in their response to the same dose of the same drug, there is a need

to develop diagnostic methods to identify those patients at an

increased risk of cardiovascular events and explore this variability

in drug response to move toward an individualized approach in drug

development. "

Researchers at the University of Pennsylvania examined the

variability, both within and between subjects, in response to

celecoxib and rofecoxib, in a randomized, double-blind, placebo

controlled study. Screening, enrollment and follow-up of healthy

study volunteers was performed between January 2002 and January 2004.

The study was conducted on 50 healthy volunteers between the ages of

21 and 43 years old who received a single dose of placebo, celecoxib

and rofecoxib in random order. This was done to allow researchers a

direct comparison of the responses to the drugs within the same

subjects. Five of the patients went through the entire protocol five

times to assess variability within individuals.

According to study authors, different factors in the environment

result in a variety of responses from an individual who is dosed with

the same drug at different times. This effect is seen even when as

many variables as possible are standardized or controlled for.

Approximately 30 percent of the variability found in patients was

attributable to differences between individuals, suggesting the

contribution of genetics to a variety of biomarkers of drug response.

The study also illustrates that even healthy individuals without a

recognized risk of disease respond quite differently to the drugs.

Previous studies have shown that rofecoxib and celecoxib result in a

small number of the people who were apparently at a low-risk of

cardiovascular disease initially, proceeding to increase that risk to

the point that culminates in heart attack and stroke following

prolonged use of these drugs. According to researchers, exploiting

this variability could permit management of the cardiovascular risk

of COX-2 inhibitors, while preserving their efficacy for patients

most likely to benefit from them and determining how these drugs

might be administered to people initially at low risk for

cardiovascular disease.

" Typically when a drug causes hazardous side effects, the reaction is

to suggest that people reduce the dosage they are taking. However,

this has often been followed by withdrawal of the drug from the

market when the problems are not eliminated, " said FitzGerald. " These

findings highlight that while a lower dose may reduce the likelihood

of problems on average, it will not eliminate them on an individual

level because there is such a marked variability in how each person

reacts to these drugs based on their genetic make-up. "

Study authors are hopeful that this work will provide an impetus for

the development of a science-based approach to risk management.

Exploitation of variability in response can lead to tests which

identify patients most likely to benefit or suffer from harmful side

effects caused by these drugs. " This study provides a starting point

for the development of diagnostics that allow the medical and

research communities to conserve benefits while managing the risks of

COX-2 inhibitors, " said FitzGerald.

This study was supported by grants from the National Heart, Lung and

Blood Institute, the National Center for Research Resources, the

American Heart Association, the Wellcome Trust and Orchid

Biosciences. Genotyping was performed at the Genomics Institute of

Novartis Foundation.