The mu-opioid receptor gene polymorphism 118A>G depletes alfentanil-induced analgesia and protects against respiratory depression in homozygous carriers
To investigate whether OPRM1 118A>G polymorphism affects analgesic and respiratory depressive effects of alfentanil and assess its role for the therapeutic range of alfentanil. In an open-label, single-occasion design, 10 non-carriers, four heterozygous and six homozygous carriers of the variant...
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| Vydané v: | Pharmacogenetics and genomics Ročník 16; číslo 9; s. 625 |
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| Hlavní autori: | , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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01.09.2006
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| ISSN: | 1744-6872 |
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| Abstract | To investigate whether OPRM1 118A>G polymorphism affects analgesic and respiratory depressive effects of alfentanil and assess its role for the therapeutic range of alfentanil.
In an open-label, single-occasion design, 10 non-carriers, four heterozygous and six homozygous carriers of the variant OPRM1 118G allele received a computerized infusion of alfentanil to achieve target effect-site concentrations of 0, 33.33, 66.67 and 100 ng/ml. At each concentration level, analgesia was assessed by means of electrically and chemically induced pain, and respiratory depression was quantified by hypercapnic challenge and breathing frequency.
The relationship between the percent change of tolerance to electrical stimuli and measured alfentanil concentrations, described by power models, was flatter in carriers of the 118G variant allele than in non-carriers, indicating decreased opioid analgesia (P<0.05). For chemically induced pain, a flatter analgesia versus concentration relationship was found only for homozygous carriers of the 118G allele (P<0.05). The relationship between the percent changes in respiratory parameters was significantly flatter (P<0.01) only in homozygous carriers as compared to heterozygous carriers and non-carriers of the 118G allele. Higher alfentanil concentrations were needed in homozygous carriers as compared to wild-type subjects (2-4 times) to produce the same degree of analgesia, whereas 10-12 times higher alfentanil concentrations were needed to produce the same degree of respiratory depression.
OPRM1 118A>G polymorphism affects both analgesic and respiratory depressive effects of alfentanil. However, while the analgesic effects are already partly decreased in heterozygous carriers, depending on the pain model, the respiratory depressive effects are decreased in homozygous carriers of the variant 118G allele. The therapeutic range of alfentanil was only broadened in homozygous carriers. |
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| AbstractList | To investigate whether OPRM1 118A>G polymorphism affects analgesic and respiratory depressive effects of alfentanil and assess its role for the therapeutic range of alfentanil.
In an open-label, single-occasion design, 10 non-carriers, four heterozygous and six homozygous carriers of the variant OPRM1 118G allele received a computerized infusion of alfentanil to achieve target effect-site concentrations of 0, 33.33, 66.67 and 100 ng/ml. At each concentration level, analgesia was assessed by means of electrically and chemically induced pain, and respiratory depression was quantified by hypercapnic challenge and breathing frequency.
The relationship between the percent change of tolerance to electrical stimuli and measured alfentanil concentrations, described by power models, was flatter in carriers of the 118G variant allele than in non-carriers, indicating decreased opioid analgesia (P<0.05). For chemically induced pain, a flatter analgesia versus concentration relationship was found only for homozygous carriers of the 118G allele (P<0.05). The relationship between the percent changes in respiratory parameters was significantly flatter (P<0.01) only in homozygous carriers as compared to heterozygous carriers and non-carriers of the 118G allele. Higher alfentanil concentrations were needed in homozygous carriers as compared to wild-type subjects (2-4 times) to produce the same degree of analgesia, whereas 10-12 times higher alfentanil concentrations were needed to produce the same degree of respiratory depression.
OPRM1 118A>G polymorphism affects both analgesic and respiratory depressive effects of alfentanil. However, while the analgesic effects are already partly decreased in heterozygous carriers, depending on the pain model, the respiratory depressive effects are decreased in homozygous carriers of the variant 118G allele. The therapeutic range of alfentanil was only broadened in homozygous carriers. To investigate whether OPRM1 118A>G polymorphism affects analgesic and respiratory depressive effects of alfentanil and assess its role for the therapeutic range of alfentanil.AIMTo investigate whether OPRM1 118A>G polymorphism affects analgesic and respiratory depressive effects of alfentanil and assess its role for the therapeutic range of alfentanil.In an open-label, single-occasion design, 10 non-carriers, four heterozygous and six homozygous carriers of the variant OPRM1 118G allele received a computerized infusion of alfentanil to achieve target effect-site concentrations of 0, 33.33, 66.67 and 100 ng/ml. At each concentration level, analgesia was assessed by means of electrically and chemically induced pain, and respiratory depression was quantified by hypercapnic challenge and breathing frequency.METHODSIn an open-label, single-occasion design, 10 non-carriers, four heterozygous and six homozygous carriers of the variant OPRM1 118G allele received a computerized infusion of alfentanil to achieve target effect-site concentrations of 0, 33.33, 66.67 and 100 ng/ml. At each concentration level, analgesia was assessed by means of electrically and chemically induced pain, and respiratory depression was quantified by hypercapnic challenge and breathing frequency.The relationship between the percent change of tolerance to electrical stimuli and measured alfentanil concentrations, described by power models, was flatter in carriers of the 118G variant allele than in non-carriers, indicating decreased opioid analgesia (P<0.05). For chemically induced pain, a flatter analgesia versus concentration relationship was found only for homozygous carriers of the 118G allele (P<0.05). The relationship between the percent changes in respiratory parameters was significantly flatter (P<0.01) only in homozygous carriers as compared to heterozygous carriers and non-carriers of the 118G allele. Higher alfentanil concentrations were needed in homozygous carriers as compared to wild-type subjects (2-4 times) to produce the same degree of analgesia, whereas 10-12 times higher alfentanil concentrations were needed to produce the same degree of respiratory depression.RESULTSThe relationship between the percent change of tolerance to electrical stimuli and measured alfentanil concentrations, described by power models, was flatter in carriers of the 118G variant allele than in non-carriers, indicating decreased opioid analgesia (P<0.05). For chemically induced pain, a flatter analgesia versus concentration relationship was found only for homozygous carriers of the 118G allele (P<0.05). The relationship between the percent changes in respiratory parameters was significantly flatter (P<0.01) only in homozygous carriers as compared to heterozygous carriers and non-carriers of the 118G allele. Higher alfentanil concentrations were needed in homozygous carriers as compared to wild-type subjects (2-4 times) to produce the same degree of analgesia, whereas 10-12 times higher alfentanil concentrations were needed to produce the same degree of respiratory depression.OPRM1 118A>G polymorphism affects both analgesic and respiratory depressive effects of alfentanil. However, while the analgesic effects are already partly decreased in heterozygous carriers, depending on the pain model, the respiratory depressive effects are decreased in homozygous carriers of the variant 118G allele. The therapeutic range of alfentanil was only broadened in homozygous carriers.CONCLUSIONOPRM1 118A>G polymorphism affects both analgesic and respiratory depressive effects of alfentanil. However, while the analgesic effects are already partly decreased in heterozygous carriers, depending on the pain model, the respiratory depressive effects are decreased in homozygous carriers of the variant 118G allele. The therapeutic range of alfentanil was only broadened in homozygous carriers. |
| Author | Geisslinger, Gerd Schneider, Andreas Lötsch, Jörn Schmidt, Ronald Oertel, Bruno G |
| Author_xml | – sequence: 1 givenname: Bruno G surname: Oertel fullname: Oertel, Bruno G organization: pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany – sequence: 2 givenname: Ronald surname: Schmidt fullname: Schmidt, Ronald – sequence: 3 givenname: Andreas surname: Schneider fullname: Schneider, Andreas – sequence: 4 givenname: Gerd surname: Geisslinger fullname: Geisslinger, Gerd – sequence: 5 givenname: Jörn surname: Lötsch fullname: Lötsch, Jörn |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/16906017$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | Adult Alfentanil - administration & dosage Alfentanil - blood Alfentanil - pharmacology Analgesia - methods Analgesics - pharmacology Carbon Dioxide - adverse effects Dose-Response Relationship, Drug Electric Stimulation - adverse effects Female Forced Expiratory Volume Genotype Heterozygote Homozygote Humans Infusion Pumps Male Pain - chemically induced Pain - drug therapy Polymorphism, Genetic - physiology Receptors, Opioid, mu - genetics Respiration - drug effects Respiratory Insufficiency - chemically induced Respiratory Insufficiency - genetics Treatment Outcome |
| Title | The mu-opioid receptor gene polymorphism 118A>G depletes alfentanil-induced analgesia and protects against respiratory depression in homozygous carriers |
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