Treatment of codeine dependence with inhibitors of cytochrome P450 2D6.
Codeine is O-demethylated by cytochrome P450 2D6 (CYP2D6) to form the more potent drug morphine, accounting for much of codeine's analgesic and dependence-producing properties. Because morphine production can be decreased by inhibition of CYP2D6, the authors hypothesized that CYP2D6 inhibition could be used to treat codeine dependence. A randomized, double-blind, placebo-controlled trial was conducted. All patients received brief behavioral therapy. Two weeks of baseline monitoring were followed by 8 weeks of daily treatment with fluoxetine or quinidine (two potent CYP2D6 inhibitors) or placebo. Thirty patients were assessed (all white, age 40 + 12 years using 127 + 79 mg/day of codeine [mean + SD]), and 17 entered treatment. Eight patients remained in the study by treatment week 8. Quinidine > fluoxetine > placebo inhibited CYP2D6 as reflected in the change of the O-demethylation of dextromethorphan, a specific CYP2D6 probe. At treatment week 8, placebo, quinidine, and fluoxetine reduced mean daily codeine intake by 57%, 56%, and 51% of baseline intake respectively; there was no difference among treatment groups. In this small sample, CYP2D6 inhibitors did not appear to have a useful role in the treatment of codeine dependence.
Fernandes
Leona C
LC
Sunnybrook and Women's College Health Sciences Centre, Women's College Campus, Toronto, Ontario, Canada.
Kilicarslan
Tansel
T
Kaplan
Howard L
HL
Tyndale
Rachel F
RF
Sellers
Edward M
EM
Romach
Myroslava K
MK
D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid / Q000009:adverse effects*; D003061:Codeine / Q000009:adverse effects*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005473:Fluoxetine / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011802:Quinidine / Q000627:therapeutic use; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D019966:Substance-Related Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000523:psychology
D000701:Analgesics, Opioid; D003061:Codeine; D019389:Cytochrome P-450 CYP2D6; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D005473:Fluoxetine; D011802:Quinidine; D017367:Selective Serotonin Reuptake Inhibitors