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Does the A118G polymorphism at the mu-opioid receptor gene protect against morphine-6-glucuronide toxicity?
Jörn Lötsch1, Michael Zimmermann, Jutta Darimont
1pharmazentrum-frankfurt, Department of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt, Germany. j.loetsch@em.uni-franfurt.de
Background:
Some, but not all, patients with renal dysfunction suffer from side effects after morphine administration because of accumulation of the active metabolite morphine-6-glucuronide (M6G). The current study aims to identify genetic causes that put patients at risk for, or protect them from, opioid side effects related to high plasma M6G. Candidate genetic causes are the single nucleotide polymorphism (SNP) A118G of the mu-opioid-receptor gene (OPRM1), which has recently been identified to result in decreased potency of M6G, and mutations in the MDR1-gene coding P-glycoprotein, of which morphine and M6G might be a substrate.
Methods:
Two men, aged 87 and 65 yr, with renal failure (creatinine clearance of 6 and 9 ml/min) received 30 mg/day oral morphine for pain treatment. Both patients had sufficient analgesia from morphine. However, while one patient tolerated morphine well despite high plasma M6G of 1735 nM, in the patient with M6G plasma concentrations of 941 nM it caused severe sleepiness and drowsiness. Patients were genotyped for known SNPs of the OPRM1 and MDR1 genes.
Results:
The patient who tolerated morphine well despite high plasma M6G was a homozygous carrier of the mutated G118 allele of the mu-opioid-receptor gene, which has been previously related to decreased M6G potency. In contrast, the patient who suffered from side effects was "wild-type" for this mutation. No other differences were found between the OPRM1 and MDR1 genes.
Conclusions:
The authors hypothesize that the A118G single nucleotide polymorphism of the mu-opioid-receptor is among the protective factors against M6G-related opioid toxicity. The observation encourages the search for pharmacogenetic reasons that cause interindividual variability of the clinical effects of morphine.
Insights
The A118G single nucleotide polymorphism in the mu-opioid-receptor gene may protect against morphine side effects in patients with renal dysfunction. This genetic factor influences morphine-6-glucuronide (M6G) toxicity.
Area of Science:
- Pharmacogenetics
- Clinical Pharmacology
- Renal Medicine
Background:
- Patients with renal dysfunction may experience morphine side effects due to accumulation of morphine-6-glucuronide (M6G).
- Genetic factors may influence individual susceptibility to M6G-related opioid toxicity.
- The study investigated the role of OPRM1 and MDR1 gene variants.
Observation:
- Two patients with renal failure received oral morphine for pain management.
- One patient tolerated high M6G plasma levels without side effects, while the other experienced severe drowsiness at lower M6G levels.
- Genetic analysis was performed on both patients.
Findings:
- The patient tolerating morphine well was homozygous for the G118 allele of the OPRM1 gene (A118G SNP).
- This specific OPRM1 genotype has been linked to decreased M6G potency.
- The patient experiencing side effects was wild-type for this SNP.
Implications:
- The A118G OPRM1 polymorphism may act as a protective factor against M6G-related opioid toxicity.
- This finding highlights the importance of pharmacogenetics in understanding inter-individual variability in morphine response.
- Further research into genetic determinants of morphine toxicity is warranted.