The ABCB1, rs9282564, AG and TT Genotypes and the COMT, rs4680, AA Genotype are Less Frequent in Deceased Patients with Opioid Addiction than in Living Patients with Opioid Addiction

Abstract

Sudden death due to acute intoxication occurs frequently in patients with opioid addiction (OA). To examine whether certain genotypes were associated with this, we examined the frequencies of 29 SNPs located in candidate genes related to opioid pharmacology: ABCB1, OPRM1, UGT2B7, CYP3A5, CYP2B6, CYP2C19, CYP2D6, COMT, KCNJ6 and SCN9A in 274 deceased patients with OA (DOA), 309 living patients with OA (LOA) and in 394 healthy volunteers (HV). The main hypothesis of the study was that subjects homozygous for the variant 3435T in ABCB1 (rs1045642) occur more frequently in DOA than in LOA and HV because morphine and methadone more readily cross the blood barrier in these subjects due to a lower efflux transporter activity of the ABCB1 (p-glycoprotein) transporter. Our results did not support this hypothesis, because no statistically significant difference (p = 0.506) in the frequency of the TT genotype of rs1045642 was observed between the DOA, LOA and HV cohorts. However, for another ABCB1 variant, rs9282564, we found that the frequencies of the AG and TT genotypes were 13, 21 and 25% in DOA, LOA and HV, respectively, and after correcting for age, sex and multiple testing, the differences between DOA and LOA were statistically significantly different (p = 0.027). The COMT rs4680 AA genotype frequencies were 25%, 35% and 31% in DOA, LOA and HV, respectively, and the difference between DOA and LOA was also statistically significant (p = 0.0028). In conclusion, this study generated two hypotheses suggesting possible associations of a reduced risk of death and carrying, respectively, the ABCB1 rs9282564 AG and TT genotypes and the COMT rs4680 AA genotype among patients with OA. These findings should be confirmed in independent cohorts, and if a causal relationship between these variants and fatal poisoning in OA is confirmed, then it may be possible at least in theory to personalize prevention of sudden death in this patient group.

Pharmacogenetics and prediction of adverse events in prescription opioid use disorder patients

“…22 In relation to AEs, some evidence exists relating to COMT genotype and the appearance of pruritus (1947-GG genotype: 2.9 times more, P < 0.05) 22 and with acute intoxication in patients with opioid addiction (472-AA genotype). 32 These results were not replicated in our study, although we observed in the baseline visit that skin redness was more frequent in COMT-GG patients.…”

Genetic Influences of OPRM1,OPRD1 and COMT on Morphine Analgesia in a Multi‐Modal, Multi‐Tissue Human Experimental Pain Model

“…Comparably, findings were seen in cancer patients where patients with the Val/Val (GG) genotype needed more morphine [9]. Moreover, in a study in deceased patients with opioid addiction, a lower frequency of the AA genotype was found compared with living patients with opioid addictions [22]. Thus, it was speculated that in carriers of the G allele, a relatively higher dose is required to achieve the stimulating effect [22].…”

The Role of Genetic Polymorphisms in Chronic Pain Patients

“…A pharmacogenetic study conducted by Christoffersen et.al examined whether certain genotypes are associated with sudden death due to opioid addiction. They found no statistically significant differences in the frequency of the TT genotype of rs1045642 in ABCB1 between the deceased opioid addiction (DOA) population of patients, living patients with active opioid addiction (LOA) getting opioid replacement therapy and healthy volunteers [ 69 ]. However, a statistically lower frequency of AG and TT in the ATP-binding cassette sub-family B member 1 ( ABCB1 ) rs9282564 in DOA compared to LOA was found when adjusted for age and sex, and lower COMT rs4680 AA genotype frequency in DOA (25%), compared to LOA (35%), and healthy volunteers (31%), suggesting lower risk of death in patients with opioid addiction [ 69 ].…”

“…They found no statistically significant differences in the frequency of the TT genotype of rs1045642 in ABCB1 between the deceased opioid addiction (DOA) population of patients, living patients with active opioid addiction (LOA) getting opioid replacement therapy and healthy volunteers [ 69 ]. However, a statistically lower frequency of AG and TT in the ATP-binding cassette sub-family B member 1 ( ABCB1 ) rs9282564 in DOA compared to LOA was found when adjusted for age and sex, and lower COMT rs4680 AA genotype frequency in DOA (25%), compared to LOA (35%), and healthy volunteers (31%), suggesting lower risk of death in patients with opioid addiction [ 69 ]. Further research is required before establishing a causal relationship between these genetic variants, and if findings can be replicated, the personalized treatment through pharmacogenetic testing can help find high-risk individuals, prevent sudden death and help resolve the consequences of the opioid epidemic.…”