¹pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany

Correspondence: Dr J Lötsch, pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, Frankfurt am Main 60590, Germany. E-mail: j.loetsch@em.uni-frankfurt.de

Received 28 June 2005; Revised 17 October 2005; Accepted 26 October 2005; Published online 17 January 2006.

Abstract

Polymorphisms in the -opioid receptor gene (OPRM1) are primary candidate sources of clinical variability in opioid therapy. Apart from the 118A>G single nucleotide polymorphism, nothing is known about the role of OPRM1 mutations in opioid therapy. The influence of the OPRM1 mutations on opioid pharmacodynamics was assessed in pooled data from 31 healthy volunteers obtained in previous studies with available plasma concentrations and pupil diameters after intravenous administration of morphine or morphine-6-glucuronide (M6G). A total of 24 candidate ORPM1 mutations were screened for and those found at an allelic frequency of at least 5% in the 31 subjects were analyzed for functional consequences, using population pharmacokinetic–pharmacodynamic modeling of the miotic effects of the opioids as a reliable and sensitive surrogate parameter of the central nervous opioid effects. Polymorphisms at an allelic frequency of 5% (n=310) were 118A>G in exon 1 (11.5%), the IVS2-31G>A (8.9%) and IVS2-691C>G (44.5%) SNPs in intron 2. The 118A>G SNP significantly increased the values of EC₅₀ by a factor of more than 2 (non-mutated: EC_50,morphine=30 nmol/l, EC_50,M6G=750 nmol/l, 118G carriers: EC_50,morphine=66 nmol/l, EC_50,M6G=1650 nmol/l), whereas the IVS2-691C>G SNP had no effect. Based on morphine and M6G, the present analysis encourages focusing on the 118A>G SNP when investigating the role of OPRM1 mutations for the activity of opioid analgesics. Other OPRM1 mutations are probably less important either owing to low allelic frequency or due to poor indications for functional consequences. This applies to opioid potency in the context of opioid therapy but not to pain processing or substance addiction, in which opioid receptors are involved but other or additional OPRM1 mutations may be important.