Background: Many children with painful sickle cell crises take prescription opioid pain medications, such as codeine. Drug efficacy depends on metabolic activation by a specific cytochrome P450 enzyme, CYP2D6. CYP2D6 exhibits clinically relevant genetic polymorphism with poor and intermediate metabolizers having marked and somewhat reduced CYP2D6 activity, respectively, resulting in decreased production of active opioid. We hypothesize that a higher proportion of children with sickle cell disease who fail outpatient therapy with opioids will have a reduced functioning allele compared to norms for the African American population. We further posited that the proportion of children with reduced functioning alleles would be higher among children with more severe disease, defined by a history of hydroxyurea therapy.

Methods: Children with sickle cell disease (4–18 years) who presented to the emergency department with a painful crisis unresponsive to oral CYP2D6-dependent opioid therapy were eligible. Those taking other CYP2D6 substrates were excluded. Blood was drawn for CYP2D6 genotyping, with allelic determination performed by DNA PCR amplification followed by single base extention. The main outcome measure was the proportion of children who possessed at least one of the alleles previously associated with reduced function (CYP2D6 *4, *5, *6, *10, *17 and *40). This proportion was compared to previously published norms for the African American population. A chi-square test was then used to examine whether a difference existed between sample children classified as mild or severe based on hydroxyurea status.

Results: Seventy-six children were enrolled of which 47 (62%) had HgbSS, 17 (22%) had HgbSC, 8 (11%) had HgbSβ+ and 4 (5%) had HgbSβ°. Twenty-seven of the children were classified as severe based on hydroxyurea usage. Overall, 45 (58%) of the 76 children had at least one reduced functioning allele. This proportion was similar to the African American population norms previously described. When analyzed by severity, a significantly greater proportion of severe children (21/27; 78%) possessed at least one reduced functioning allele compared to children with mild disease (24/49; 49%); p=0.014. A subanalysis of children with HgbSS revealed about half of the children (22/47) to be on hydroxyurea. Among HgbSS patients, patients treated with hydroxyurea were more likely to have a reduced functioning allele (18/22; 82%) compared to patients not treated with hydroxyurea [12/25 (48%); p = 0.016].

Conclusions: Children with sickle cell disease severe enough to warrant hydroxyurea therapy who present to the emergency department for pain crisis are more likely to possess a CYP2D6 allele with reduced function. This variation in allelic frequency would be expected to result in poorer pain control, which may lead to increased care seeking for pain crises and thus be a factor in health care provider decisions to use hydroxyurea. Screening for genetic polymorphisms or the use of non-CYP2D6 dependent pain medications should be considered in this patient group.

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