GENETICALLY DEFICIENT CYP2D6 METABOLISM PROVIDES PROTECTION AGAINST ORAL OPIATE DEPENDENCE

Oral opiates (e.g. codeine, oxycodone, and hydrocodone) are metabolize d by cytochrome CYP2D6 to metabolites of increased activity (e.g. morp hine, oxymorphone and hydromorphone), CYP2D6 is genetically polymorphi c, 4-10% of Caucasians lack CYP2D6 activity (poor metabolizers) due to inheritance of two non-functional alleles. We tested whether the fail ure to activate oral opiates was a protection factor in opiate depende nce by genotyping (CYP2D63 and CYP2D6*4 defective mutant alleles) cau casians who met or didn't meet DSM criteria for oral opiate dependence , In opiate (+/- smoking) dependent subjects rye found no poor metabol izers, In contrast, the poor metabolizer frequency in never-dependent control and multi-drug dependent comparison groups was 4% and 6.5%, re spectively, This under-representation of poor metabolizers (Fisher's e xact test, p less than or equal to 0.05) in people dependent on oral o piates suggests that the CYP2D6 defective genotype is a pharmacogeneti c protection factor for oral opiate dependence (estimated odds ratio > 7), This is the first investigation and demonstration of differences i n genetically determined P450 metabolism influencing risk for substanc e dependence and we suggest that these differences may influence the r isk for dependence of other substrate drugs, and may occur with other genetically variable P450s.