Influence of genetic variants of opioid-related genes on opioid-induced adverse effects in patients with lung cancer

Abstract

Despite the dramatic advancement of cancer chemotherapy and immunotherapy, the insufficient progress has been made in basic or translational research on personalization of opioid therapy. Predicting the effectiveness of opioid analgesic therapy and the risk of adverse effects prior to therapy are expected to enable safer and more appropriate opioid therapy for cancer patients. In this study, we compared the incidence of opioid-induced adverse effects between patients with different variants of the genes related to responsiveness to opioid analgesics.Participants were 88 patients with lung cancer who provided general consent for exome sequencing and were treated with morphine or oxycodone at Shizuoka Cancer Center Hospital between April 2014 and August 2018. Incidence rates for 6 adverse effects of opioid therapy (somnolence, nausea, constipation, delirium, urinary retention, and pruritus) were determined and the influence of single nucleotide polymorphisms in coding regions of the opioid m receptor 1 (OPRM1) (rs1799971), opioid d receptor 1 (rs2234918), opioid k receptor 1 (rs1051660), catechol-O-methyltransferase (COMT) (rs4680), dopamine receptor D2 (rs6275), adenosine triphosphate binding cassette B1 (rs1045642), G-protein regulated inward rectifier potassium channel 2 (rs2070995), and fatty acid amide hydrolase (rs324420) genes on those adverse effects were analyzed.Analysis of OPRM1 gene variant status (Asn133Asp A > G) showed that G/G homozygotes were at significantly lower risk of somnolence compared with A allele carriers (0% vs 28.4%; Fisher exact test, P = .005; OR, 0; 95% CI, 0-0.6), and analysis of COMT gene variant status (Val158Met, G > A) showed that G/G homozygotes were at significantly higher risk of somnolence compared with A allele carriers (35.0% vs 10.4%; Fisher exact test, P = .008; OR, 4.5; 95% CI, 1.4-18.1). No relationship between variant status and adverse effects was found for the other genes.These findings demonstrate that OPRM1 and COMT gene variants influence the risk of somnolence as an adverse effect of opioid analgesic therapy.

Single nucleotide polymorphisms as predictors of treatment efficacy and adverse effects of morphine in palliative medicine — a literature review

“…Reports regarding the protective effect of carriers of SNP rs1799971 A118G with the G allele support the results of a study that indicates a significantly lower risk of somnolence as an adverse effect of morphine treatment in G/G homozygous patients compared to carriers of the A allele (0% vs. 28.4%, p = 0.005) [25]. The fact that patients are more susceptible to the sedative effects of opioids, especially morphine in carriers of A118G OPRM1 SNP with the A allele, may be considered as a potential marker of high-risk groups for this adverse effect, given that Hajj et al [13] found an association between the presence of lower levels of cognitive function in carriers of A118G SNP A/G and A/A, and thus the use of opioids may result in cognitive and sedative impairment in this group, and consequently deterioration of QoL of palliative care patients [13].…”

“…This SNP was an independent factor in the occurrence of adverse effects [31]. Tanaka et al [25] investigated the two most common SNPs associated with individual variability in response to morphine, namely OPRM1 A118G and COMT Val158Met, and their potential association with opioid-induced adverse effects. As with the OPRM1 A118G SNP, the polymorphism studied in COMT was also found to be a statistically significant risk factor for opioid-induced somnolence [25].…”

Pharmacogenetic landscape of pain management variants among Mediterranean populations

“…The increasing noradrenaline concentration may have also an effect on the analgesic effects ( Valomon et al, 2014 ). A clinical study of cancer pain in Asian patients found that GG carriers require a greater intravenous morphine dosage than AA carriers ( Tanaka et al, 2021 ), with the lack of drug preventing or lowering opioid-induced somnolence ( Cargnin et al, 2014 ). We showed significant MAF differences of rs4633 (C>T) between The MED, AMR and EAS populations.…”

Progress, Challenges, and Prospects of Research on the Effect of Gene Polymorphisms on Adverse Reactions to Opioids

“…This indicates that the demand for opioid analgesia is different among individuals, which is likely to lead to huge differences in individual adverse reactions to opioids. In recent years, studies have increasingly begun to focus on the correlation between SNP and adverse reactions to opioids [11], expecting to find a new way to clinically predict the occurrence or severity of adverse reactions in patients. Most of these pioneering studies are animal experiments or single-center, small-sample clinical studies, and the results of these studies are sometimes ambiguous or even conflicting due to the excessive factors influencing the adverse reactions to opioids.…”