Genetics of methadone clearance

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Methadone ? long used to treat pain and addiction ? can be lethal if it lingers too long in the body. People metabolize the drug differently, and researchers have not completely understood how a person?s genetic makeup influences how slowly or rapidly methadone is cleared. But new research at Washington University School of Medicine in St. Louis has identified genetic subtypes in people that govern methadone clearance, findings that could help prevent some of the 5,000 methadone-related deaths that occur each year in the United States.

METHADONE IS A VERY GOOD TREATMENT FOR MULTIPLE FORMS OF PAIN, BUT IT CAN BE A DIFFICULT DRUG TO USE EFFECTIVELY. RESEARCHERS AT WASHINGTON UNIVERSITY SCHOOL OF MEDICINE IN ST. LOUIS SAY ONE REASON IS THAT PEOPLE CLEAR METHADONE FROM THEIR SYSTEMS AT VERY DIFFERENT RATES, SO SOME PEOPLE CAN END UP WITH TOO MUCH OF THE DRUG IN THEIR SYSTEMS, WHILE OTHERS DON?T GET ENOUGH. AND THEY SAY ONE REASON FOR THAT INVOLVES GENETIC DIFFERENCES BETWEEN PEOPLE. JIM DRYDEN REPORTS?

METHADONE IS A VERY WIDELY USED DRUG. WASHINGTON UNIVERSITY ANESTHESIOLOGIST EVAN KHARASCH SAYS MILLIONS OF PRESCRIPTIONS FOR METHADONE ARE WRITTEN EACH YEAR IN THE UNITED STATES. BUT HE SAYS THE DRUG ALSO CAN BE DEADLY.

(act):21o/c to patient

About 4 and a half million prescriptions for methadone are
written in this country every year. Unfortunately, about
5,000 people a year die from unintentional overdoses. The
challenge in using methadone is that there?s a lot of
variability from patient to patient.

KHARASCH AND HIS RESEARCH TEAM FOUND THAT DIFFERENT PEOPLE HAVE DIFFERENT VARIANTS OF A GENE THAT MAKES AN ENZYME IN THE LIVER THAT HELPS CLEAR METHADONE FROM THE SYSTEM. ONE OF THE GENE VARIANTS, CALLED THE STAR-6 VARIANT, LEADS TO SLOWER CLEARANCE OF THE DRUG. ANOTHER GENE VARIANT, CALLED STAR-4, CONTRIBUTES TO MORE RAPID CLEARANCE.

(act):13o/c same dose

We found that individuals who have the different genes for
this enzyme may metabolize methadone differently, even
though everybody gets the same dose.

KHARASCH SAYS BECAUSE PEOPLE WITH THE STAR-6 VERSION OF THE GENE CLEAR THE DRUG MORE SLOWLY, THEY CAN BE AT RISK.

(act):13o/c star-6 gene

And there?s some evidence from the literature that in
individuals who suffer accidental overdoses from methadone,
there is a higher representation of people who have the
star-6 gene.

ON THE OTHER HAND, PEOPLE WITH THE STAR-4 VARIANT OF THE GENE MAY NOT GET ADEQUATE PAIN RELIEF BECAUSE THEY CLEAR THE DRUG SO QUICKLY. AND KHARASCH SAYS IT?S TRICKY FOR DOCTORS BECAUSE IF A PATIENT COMES AND ASKS FOR MORE OR HIGHER DOSES OF THE DRUG, THAT CAN BE A WARNING SIGN THAT THE PATIENT MAY BE ABUSING THE DRUG.

(act):15o/c the difference

Because they have a particular genotype, such as the star-4
genotype, they may actually need higher doses of methadone.
And unless we genetically test, we can?t tell the difference.

SO KHARASCH SAYS IT MAY BE IMPORTANT TO DO GENETIC TESTING OF PEOPLE TAKING METHADONE, TO LEARN ABOUT THEIR GENES AND TO PREDICT HOW RAPIDLY AN INDIVIDUAL MAY CLEAR THE DRUG. THAT?S IMPORTANT FOR INDIVIDUAL PATIENTS, HE SAYS, AND THIS STUDY SHOWS THAT GENETICS ALSO MAY EXPLAIN RACIAL DIFFERENCES AMONG PEOPLE WHO TAKE METHADONE.

(act):30o/c is higher

African Americans had different methadone concentrations in
their blood, compared to Caucasians, even though everybody
received the same dose. Methadone metabolism and methadone
elimination were significantly lower in African Americans,
and part of the reason for this was that in African Americans,
the frequency of the star-6 allele, which is the poor-metabolizer
gene, is higher.

HE SAYS THE STAR-4 VERSION OF THE GENE ALSO IS LESS COMMON IN AFRICAN AMERICANS. KHARASCH AND HIS COLLEAGUES REPORT THEIR FINDINGS IN THE JOURNAL ANESTHESIOLOGY. I?M JIM DRYDEN…

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