The 118 A > G polymorphism in the human mu-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease.
BACKGROUND
Dispositions for genes encoding opioid receptors may explain some variability in morphine efficacy. Experimental studies show that morphine and morphine-6-glucuronide are less effective in individuals carrying variant alleles caused by the 118 A > G polymorphism in the mu-opioid receptor gene (OPRM1). The purpose of the study was to investigate whether this and other genetic polymorphisms in OPRM1 influence the efficacy of morphine in cancer pain patients.


METHODS
We screened 207 cancer pain patients on oral morphine treatment for four frequent OPRM1 gene polymorphisms. The polymorphisms were the -172 G > T polymorphism in the 5'untranslated region of exon 1, the 118 A > G polymorphism in exon 1, and the IVS2 + 31 G > A and IVS2 + 691 G > C polymorphisms, both in intron 2. Ninety-nine patients with adequately controlled pain were included in an analysis comparing morphine doses and serum concentrations of morphine and morphine metabolites in the different genotypes for the OPRM1 polymorphisms.


RESULTS
No differences related to the -172 G > T, the IVS2 + 31 G > A and the IVS2 + 691 G > C polymorphisms were observed. Patients homozygous for the variant G allele of the 118 A > G polymorphism (n = 4) needed more morphine to achieve pain control, compared to heterozygous (n = 17) and homozygous wild-type (n = 78) individuals. This difference was not explained by other factors such as duration of morphine treatment, performance status, time since diagnosis, time until death, or adverse symptoms.


CONCLUSIONS
Patients homozygous for the 118 G allele of the mu-opioid receptor need higher morphine doses to achieve pain control. Thus, genetic variation at the gene encoding the mu-opioid receptor contributes to variability in patients' responses to morphine.
Klepstad
P
P
Institute of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway. pal.klepstad@medisin.ntnu.no
Rakvåg
T T
TT
Kaasa
S
S
Holthe
M
M
Dale
O
O
Borchgrevink
P C
PC
Baar
C
C
Vikan
T
T
Krokan
H E
HE
Skorpen
F
F
D000368:Aged; D000483:Alleles; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D009022:Morphine Derivatives / Q000097:blood; D009369:Neoplasms / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D010147:Pain Measurement / Q000187:drug effects; D010148:Intractable Pain / Q000188:drug therapy* / Q000235:genetics*; D011110:Polymorphism, Genetic; D011788:Quality of Life; D017450:Receptors, Opioid, mu / Q000235:genetics* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000701:Analgesics, Opioid; D009022:Morphine Derivatives; C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; C035349:morphine-6-glucuronide; D009020:Morphine; C018108:morphine-3-glucuronide