Genetic variation and response to morphine in cancer patients: catechol-O-methyltransferase and multidrug resistance-1 gene polymorphisms are associated with central side effects.
BACKGROUND
Pain is a common symptom for patients with cancer, and opioids are the treatment of choice for moderate or severe cancer-related pain. Central side effects, such as drowsiness, confusion, and hallucinations, can limit the use of opioids in clinical practice.


METHODS
The authors prospectively recruited 228 cancer patients who received morphine. Clinical data, including pain and side-effect scores, were correlated with genotype data.


RESULTS
Genetic variation in the multidrug resistance-1 gene (MDR-1) was associated with moderate or severe drowsiness and confusion or hallucinations. Patients who carried the common guanosine (G) allele at position 2677 in exon 26 were less likely to experience drowsiness and confusion or hallucinations than patients who carried the variant thymidine or adenosine alleles, which code for alternate amino-acid substitutions (chi-square statistic, 13.3; P=.0003). In addition, genetic variation in the catechol-O-methyltansferase (COMT) enzyme was associated independently with these central side effects. Single nucleotide polymorphisms (SNPs) in intron 1 were associated significantly with central side effects; the most significant was at position -4873G (chi-square statistic, 9.1; P=.003). SNPs in intron 1, defined as haplotype, were present in 10.4% of the population and were associated significantly with central side effects (chi-square statistic, 7.7; P=.005). Genotype data did not correlate with morphine dose or serum morphine or metabolite concentrations in this study.


CONCLUSIONS
COMT and MDR-1 genotypes were correlated with morphine-related central side effects. The authors believe that this work adds significantly to the current understanding of genetic variants that may influence an individual's response to opioids.
Ross
Joy R
JR
St. Joseph's Hospice, and Department of Clinical Genomics, Imperial College, London, United Kingdom. j.ross@stjh.org.uk
Riley
Julia
J
Taegetmeyer
Annie B
AB
Sato
Hiroe
H
Gretton
Sophy
S
du Bois
Roland M
RM
Welsh
Kenneth I
KI
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000483:Alleles; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000627:therapeutic use*; D009294:Narcotics / Q000627:therapeutic use*; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D010146:Pain / Q000139:chemically induced*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012894:Sleep Stages / Q000187:drug effects*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009294:Narcotics; D012333:RNA, Messenger; D009020:Morphine; D002394:Catechol O-Methyltransferase