Abstract
Opioid analgesics form an important component of the management of acute and chronic pain in patients with sickle cell disease (SCD). Chronic opioid use, sometimes associated with dependence and addiction in a subset of patients, may pose difficult management problems. This adds to the sometime antagonistic relationship that can develop between providers and patients with SCD. Pain management can become a sociological and psychological issue in the management of SCD. The Mu opioid receptor (OPRM-1) is the primary site of action of endogenous opioid peptides (enkephalins and endorphins) and of opioid analgesics, such as morphine, methadone, fentanyl, heroin, and related compounds. Rapid activation of the mu receptor results in a euphoric effect, conferring the reinforcing or rewarding effects of opioids and thus contributing to the development of addiction. It has been known that there is variation between individuals in sensitivity to opioids suggesting potential variation in the receptor protein and the gene. Some recent data have shown that polymorphisms in the OPRM-1 gene affect pain threshold and tolerance as well as opioid requirements for optimal pain control. In an effort to unravel the complex issues surrounding pain frequency, pain tolerance, opioid usage, and opioid addiction in this patient population, we conducted a study of our adult sickle cell patients for the frequency of the two common cSNPs and another SNP in the IVSII (G691C) of the OPRM-1 gene. DNA samples from randomly selected patients were used in this study. The OPRM-1 gene was PCR amplified and subjected to cycle sequencing on an ABI Prism automated sequencer. The results showed that of the 97 adult SCD patients screened for the C17T polymorphism (GenBank accession #AY292291 and 292290), 67 (69.7%) had the wild type (CC), 28 (29.1%) were heterozygous (CT), and 11 (11.4%) were homozygous (TT) for the SNP. This represents an allele frequency for the T of 0.26. Of the 39 sequenced samples for the A1189G, all (100%) showed the wild type (AA). These results closely resemble those reported by Bond et al (PNAS, 95;9608,1998) for the frequency of the two cSNPs in the African-American population (allele frequency of 0.21 for the C17T and 0.016 for the A118G). Of the 16 samples screened for IVS II G691C polymorphism (GenBank accession #AY299483), 6 (37.5%) had the wild type (GG), 9 (56.3%) were heterozygous (GC), and 1 (6.2%) was homozygous (CC). Our results among SCD patients show a high frequency of C17T polymorphism in the OPRM-1 gene. Detailed studies in higher numbers of SCD patients and clinical correlations with pain frequency and threshold, opioid usage, opioid abuse and drug seeking behavior will be undertaken. It is expected that these studies will clarify the role of OPRM-1 polymorphisms as a genetic modifier associated with pain frequency, with tolerance as well as opioid use and abuse.
Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects
