Combined analysis of circulating β-endorphin with gene polymorphisms in OPRM1, CACNAD2 and ABCB1 reveals correlation with pain, opioid sensitivity and opioid-related side effects

Abstract

Background: Opioids are associated with wide inter-individual variability in the analgesic response and a narrow therapeutic index. This may be partly explained by the presence of single nucleotide polymorphisms (SNPs) in genes encoding molecular entities involved in opioid metabolism and receptor activation. This paper describes the investigation of SNPs in three genes that have a functional impact on the opioid response: OPRM1, which codes for the μ-opioid receptor; ABCB1 for the ATP-binding cassette B1 transporter enzyme; and the calcium channel complex subunit CACNA2D2. The genotyping was combined with an analysis of plasma levels of the opioid peptide β-endorphin in 80 well-defined patients with chronic low back pain scheduled for spinal fusion surgery, and with differential sensitivity to the opioid analgesic remifentanil. This patient group was compared with 56 healthy controls.

Results: The plasma β-endorphin levels were significantly higher in controls than in pain patients.A higher incidence of opioid-related side effects and sex differences was found in patients with the minor allele of the ABCB1 gene. Further, a correlation between increased opioid sensitivity and the major CACNA2D2 allele was confirmed. A tendency of a relationship between opioid sensitivity and the minor allele of OPRM1 was also found.

Conclusions: Although the sample cohort in this study was limited to 80 patients it appears that it was possible to observe significant correlations between polymorphism in relevant genes and various items related to pain sensitivity and opioid response. Of particular interest is the new finding of a correlation between increased opioid sensitivity and the major CACNA2D2 allele. These observations may open for improved strategies in the clinical treatment of chronic pain with opioids.

Figure 1

Genotype frequency of ABCB1. The genotype frequency of the ABCB1 SNP in chronic pain with different opioid sensitivity. For further details see Methods and Results.

Figure 2

β-endorphin levels and the ABCB1 SNP. Plasma levels of the opioid peptide β-endorphin in males and females with different alleles of the ABCB1 SNP. A tendency towards sex difference (p = 0.057) in the group carrying the minor TT allele is indicated. For further details see Methods and Results. Values are presented as mean ± SEM.

Figure 3

Scores of pain and other symptoms. Scores of pain and other symptoms for patients carrying the various ABCB1 alleles. For further details see Methods and Results.

Figure 4

Quality of Life and symptom scores. Quality of Life (QoL) and symptom scores in patients carrying the various alleles of the ABCB1 gene. For further details see Methods and Results.

Figure 5

The genotype frequency of CACNA2D2. The genotype frequency of the CACNA2D2 gene in chronic pain patients with different opioid sensitivity. For further details see Methods and Results.