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.
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.
Authors: Maria Meringolo; Valentina Brusadin; Maria T De Luca; Christian Montanari; Christian L Montanari; Letizia Antonilli; Paolo Nencini; Aldo Badiani Journal: Psychopharmacology (Berl) Date: 2011-10-21 Impact factor: 4.530
Authors: Kenneth Blum; Edward J Modestino; Marjorie Gondre-Lewis; Edwin J Chapman; Jennifer Neary; David Siwicki; David Baron; Mary Hauser; David E Smith; Alphonse Kenison Roy; Panayotis K Thanos; Bruce Steinberg; Thomas McLaughlin; Lyle Fried; Debmalya Barh; Georgia A Dunston; Rajendra D Badgaiyan Journal: Int J Genom Data Min Date: 2018-01-15
Authors: Amanda L-C Chen; Thomas J H Chen; Roger L Waite; Jeffrey Reinking; Howard L Tung; Patrick Rhoades; B William Downs; Eric Braverman; Dasha Braverman; Mallory Kerner; Seth H Blum; Nicholas DiNubile; David Smith; Marlene Oscar-Berman; Thomas J Prihoda; John B Floyd; David O'Brien; H H Liu; Kenneth Blum Journal: Med Hypotheses Date: 2008-10-31 Impact factor: 1.538