Pharmacogenomic variability and anaesthesia.

The concept of 'personalized medicine' in which a knowledge of genetic factors guides prescribing tailored to the individual is popularly considered to be an inevitable consequence of completion of the International Human Genome Project. We should not forget, however, that a personal or family history of one of several uncommon pharmacogenetic conditions has influenced the use of the implicated drug(s) during anaesthesia for the past 50 yr. Although this has been important for those affected, pharmacogenomics heralds the prospect of an individual's genetic profile informing every prescription. Progress has been rapid in some areas, notably cancer chemotherapy where response to treatment can be predicted on the basis of the genetic profile of the tumour cells. The situation is different for most currently available drugs, including those used by anaesthetists, where genetic variability to drug response is presumed to be the result of a complex interaction of multiple factors. We review the nature and investigation of pharmacogenomic variability and contrast the progress made with research into opioid variability with the more limited literature concerning i.v. and inhalation anaesthetics.

[1]  P. Coriat,et al.  Relationships between Measurement of Pain Using Visual Analog Score and Morphine Requirements during Postoperative Intravenous Morphine Titration , 2003, Anesthesiology.

[2]  Stefan Platzer,et al.  COMT Val108/158Met genotype affects the mu-opioid receptor system in the human brain: Evidence from ligand-binding, G-protein activation and preproenkephalin mRNA expression , 2005, NeuroImage.

[3]  A. Concejero,et al.  Association of mu-opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty. , 2006, Acta anaesthesiologica Scandinavica.

[4]  V. Rollason,et al.  Pharmacogenetics of analgesics: toward the individualization of prescription. , 2008, Pharmacogenomics.

[5]  V. Ruiz-Velasco,et al.  Modulation of Ca2+ channels by heterologously expressed wild-type and mutant human micro-opioid receptors (hMORs) containing the A118G single-nucleotide polymorphism. , 2007, Journal of neurophysiology.

[6]  R. Dionne,et al.  Genetic polymorphisms in monoamine neurotransmitter systems show only weak association with acute post-surgical pain in humans , 2006, Molecular pain.

[7]  L. Arendt-Nielsen,et al.  The Analgesic Effect of Tramadol After Intravenous Injection in Healthy Volunteers in Relation to CYP2D6 , 2006, Anesthesia and analgesia.

[8]  S. Scherer,et al.  Localization of the gene encoding the alpha 2/delta-subunits of the L-type voltage-dependent calcium channel to chromosome 7q and analysis of the segregation of flanking markers in malignant hyperthermia susceptible families. , 1994, Human molecular genetics.

[9]  Marc Beaussier,et al.  Environmental and genetic factors associated with morphine response in the postoperative period , 2006, Clinical pharmacology and therapeutics.

[10]  K. Jurkat-Rott,et al.  Recent advances in the diagnosis of malignant hyperthermia susceptibility: How confident can we be of genetic testing? , 2003, European Journal of Human Genetics.

[11]  G. Loyd,et al.  Anesthetic Requirement Is Increased in Redheads , 2004, Anesthesiology.

[12]  B. Jawan,et al.  Human Opioid Receptor A118G Polymorphism Affects Intravenous Patient-controlled Analgesia Morphine Consumption after Total Abdominal Hysterectomy , 2006, Anesthesiology.

[13]  M. Eichelbaum,et al.  Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation , 1998, Pain.

[14]  J. Lötsch,et al.  The polymorphism A118G of the human mu-opioid receptor gene decreases the pupil constrictory effect of morphine-6-glucuronide but not that of morphine. , 2002, Pharmacogenetics.

[15]  P. Morgan,et al.  Understanding anesthesia: making genetic sense of the absence of senses. , 2002, Human molecular genetics.

[16]  K. Dahlen,et al.  ABCB1 genetic variability and methadone dosage requirements in opioid‐dependent individuals , 2006, Clinical pharmacology and therapeutics.

[17]  Andrew A Somogyi,et al.  Pharmacogenetics of Opioids , 2007, Clinical pharmacology and therapeutics.

[18]  I. Sora,et al.  Analgesic requirements after major abdominal surgery are associated with OPRM1 gene polymorphism genotype and haplotype. , 2008, Pharmacogenomics.

[19]  I. Sora,et al.  How individual sensitivity to opiates can be predicted by gene analyses. , 2005, Trends in pharmacological sciences.

[20]  J. Lötsch,et al.  The μ-opioid receptor gene polymorphism 118A>G depletes alfentanil-induced analgesia and protects against respiratory depression in homozygous carriers , 2006 .

[21]  Vree Tb,et al.  Codeine analgesia is due to codeine-6-glucuronide, not morphine. , 2000 .

[22]  Y. Sato,et al.  Genetic background differences between FVB and C57BL/6 mice affect hypnotic susceptibility to pentobarbital, ketamine and nitrous oxide, but not isoflurane , 2006, Acta anaesthesiologica Scandinavica.

[23]  J. Blouin,et al.  Genetic variability of the μ-opioid receptor influences intrathecal fentanyl analgesia requirements in laboring women , 2008, PAIN.

[24]  S. Joel,et al.  Clinical response to morphine in cancer patients and genetic variation in candidate genes , 2005, The Pharmacogenomics Journal.

[25]  L. Arendt-Nielsen,et al.  Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects , 1996, European Journal of Clinical Pharmacology.

[26]  A. Urwyler,et al.  Guidelines for molecular genetic detection of susceptibility to malignant hyperthermia. , 2001, British journal of anaesthesia.

[27]  M. Preisig,et al.  Cytochrome P450 2D6 Genotype and Methadone Steady-State Concentrations , 2001, Journal of clinical psychopharmacology.

[28]  E. Kharasch,et al.  Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: Role of circulating active metabolites , 2006, Clinical pharmacology and therapeutics.

[29]  Nashville Tennessee,et al.  Polymorphisms in Human Organic Anion-transporting Polypeptide 1A2 (OATP1A2) , 2005, Journal of Biological Chemistry.

[30]  S. Kaasa,et al.  The 118 A > G polymorphism in the human µ‐opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease , 2004, Acta anaesthesiologica Scandinavica.

[31]  S. Sindrup,et al.  Codeine in post-operative pain Study of the influence of sparteine phenotype and serum concentrations of morphine and morphine-6-glucuronide , 1998, European Journal of Clinical Pharmacology.

[32]  Elissa J. Chesler,et al.  The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[33]  A. Molven,et al.  Polymorphisms in CYP2D6 duplication-negative individuals with the ultrarapid metabolizer phenotype: a role for the CYP2D6*35 allele in ultrarapid metabolism? , 2001, Pharmacogenetics.

[34]  E. Eger,et al.  Naturally occurring variability in anesthetic potency among inbred mouse strains. , 2000, Anesthesia and analgesia.

[35]  M. Mittlböck,et al.  Influence of Methylenetetrahydrofolate Reductase Gene Polymorphisms on Homocysteine Concentrations after Nitrous Oxide Anesthesia , 2008, Anesthesiology.

[36]  P. Dayer,et al.  Impact of environmental and genetic factors on codeine analgesia , 2004, European Journal of Clinical Pharmacology.

[37]  C. Alm,et al.  Codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation. , 1989, British journal of clinical pharmacology.

[38]  A. Winnie,et al.  The Subclavian Perivascular Technique of Brachial Plexus Anesthesia , 1964, Anesthesiology.

[39]  A. Somogyi,et al.  Disposition andmetabolism ofcodeine after single andchronic doses inonepoorandseven extensive metabolisers , 1991 .

[40]  M. Miaskaoski Patient Controlled Analgesia (PCA) , 2006 .

[41]  A. Hoeft,et al.  Concentrations of Tramadol and O‐desmethyltramadol Enantiomers in Different CYP2D6 Genotypes , 2007, Clinical pharmacology and therapeutics.

[42]  B. Sweeney Pharmacogenomics and anaesthesia: explaining the variability in response to opiates. , 2007, European journal of anaesthesiology.

[43]  Hui Zhang,et al.  Effect of the CYP2D6*10 C188T polymorphism on postoperative tramadol analgesia in a Chinese population , 2006, European Journal of Clinical Pharmacology.

[44]  Timothy B. Stockwell,et al.  The Sequence of the Human Genome , 2001, Science.

[45]  J A Tischfield,et al.  Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[46]  W. Chou,et al.  Association of μ‐opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty , 2006 .

[47]  J Kirchheiner,et al.  Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication , 2007, The Pharmacogenomics Journal.

[48]  A. Olckers,et al.  Evidence for the localization of a malignant hyperthermia susceptibility locus (MHS2) to human chromosome 17q. , 1992, Genomics.

[49]  K. Hogan,et al.  Adverse effect of nitrous oxide in a child with 5,10-methylenetetrahydrofolate reductase deficiency. , 2003, The New England journal of medicine.

[50]  W. Kalow,et al.  On distribution and inheritance of atypical forms of human serum cholinesterase, as indicated by dibucaine numbers. , 1957, Canadian journal of biochemistry and physiology.

[51]  Mouse Chromosome 7 Harbors a Quantitative Trait Locus for Isoflurane Minimum Alveolar Concentration , 2007, Anesthesia and analgesia.

[52]  J. Lötsch,et al.  Modulation of the central nervous effects of levomethadone by genetic polymorphisms potentially affecting its metabolism, distribution, and drug action , 2006, Clinical pharmacology and therapeutics.

[53]  Zhaohui S. Qin,et al.  A second generation human haplotype map of over 3.1 million SNPs , 2007, Nature.

[54]  J. Lötsch Basic genetic statistics are necessary in studies of functional associations in anesthesiology. , 2007, Anesthesiology.

[55]  C. van Broeckhoven,et al.  A genome wide search for susceptibility loci in three European malignant hyperthermia pedigrees. , 1997, Human molecular genetics.

[56]  A. Somogyi,et al.  Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers. , 1991, British journal of clinical pharmacology.

[57]  K. Jurkat-Rott,et al.  Several interacting genes influence the malignant hyperthermia phenotype , 2003, Human Genetics.

[58]  Karamarie Fecho,et al.  Catechol-O-methyltransferase inhibition increases pain sensitivity through activation of both beta2- and beta3-adrenergic receptors. , 2007, Pain.

[59]  Nagele P Pharmacogenetics of Nitrous Oxide , 2008 .

[60]  A. Hoeft,et al.  Impact of CYP2D6 genotype on postoperative tramadol analgesia , 2003, Pain.

[61]  E. Mascha,et al.  Association of Ethnicity with the Minimum Alveolar Concentration of Sevoflurane , 2007, Anesthesiology.

[62]  D. Shields,et al.  An investigation of potential genetic determinants of propofol requirements and recovery from anaesthesia , 2007, European journal of anaesthesiology.

[63]  R. Robinson,et al.  Mutations in RYR1 in malignant hyperthermia and central core disease , 2006, Human mutation.

[64]  W. Kalow Pharmacogenetics and Anesthesia , 1964, Anesthesiology.

[65]  W. Willis,et al.  Protein phosphatase 2A regulates central sensitization in the spinal cord of rats following intradermal injection of capsaicin , 2006, Molecular pain.

[66]  A. Rane,et al.  Patient-controlled analgesia (PCA) with codeine for postoperative pain relief in ten extensive metabolisers and one poor metaboliser of dextromethorphan. , 1995, British journal of clinical pharmacology.

[67]  L. Arendt-Nielsen,et al.  The hypoalgesic effect of tramadol in relation to CYP2D6 * , 1996, Clinical pharmacology and therapeutics.

[68]  H. Muir,et al.  Reversible nitrous oxide myelopathy and a polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase. , 2006, British journal of anaesthesia.

[69]  P. Dayer,et al.  Contribution of monoaminergic modulation to the analgesic effect of tramadol. , 1996, British journal of clinical pharmacology.

[70]  Iversen Ll Neurotransmitters and CNS disease. Introduction. , 1982 .

[71]  R. Howard,et al.  Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability. , 2002, British journal of anaesthesia.

[72]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.

[73]  B. Mets,et al.  A Genetic Association Study of the Functional A118G Polymorphism of the Human &mgr;-Opioid Receptor Gene in Patients with Acute and Chronic Pain , 2006, Anesthesia and analgesia.

[74]  M. Ingelman-Sundberg,et al.  Duplication, multiduplication, and amplification of genes encoding drug-metabolizing enzymes: evolutionary, toxicological, and clinical pharmacological aspects. , 1999, Drug metabolism reviews.

[75]  U. Hofmann,et al.  Evidence for morphine‐independent central nervous opioid effects after administration of codeine: Contribution of other codeine metabolites , 2006, Clinical pharmacology and therapeutics.

[76]  P Stieglitz,et al.  Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. , 1997, American journal of human genetics.

[77]  R. Fillingim,et al.  Melanocortin-1 receptor gene variants affect pain and μ-opioid analgesia in mice and humans , 2005, Journal of Medical Genetics.

[78]  D. Clayton,et al.  Genetic association studies , 2005, The Lancet.

[79]  Ulrich M. Zanger,et al.  Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry , 2003, Naunyn-Schmiedeberg's Archives of Pharmacology.

[80]  G. Wolf,et al.  Influence of the Concentration Effect on the Uptake of Anesthetic Mixtures: The Second Gas Effect , 1964, Anesthesiology.

[81]  T. Vree,et al.  CODEINE ANALGESIA IS DUE TO CODEINE‐6‐GLUCURONIDE, NOT MORPHINE , 2000, International journal of clinical practice.

[82]  U. Hofmann,et al.  Pharmacokinetic modelling of morphine, morphine-3-glucuronide and morphine-6-glucuronide in plasma and cerebrospinal fluid of neurosurgical patients after short-term infusion of morphine. , 2002, British journal of clinical pharmacology.

[83]  J. Miners,et al.  Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance. , 2000, Pharmacogenetics.

[84]  R. Gainetdinov,et al.  Enhanced morphine analgesia in mice lacking beta-arrestin 2. , 1999, Science.

[85]  M. Yahr,et al.  Catechol‐O‐methyltransferase inhibition increases striatal L‐dopa and dopamine , 1992, Neurology.

[86]  J. Payen,et al.  Presence of Two Different Genetic Traits in Malignant Hyperthermia Families: Implication for Genetic Analysis, Diagnosis, and Incidence of Malignant Hyperthermia Susceptibility , 2002, Anesthesiology.

[87]  A. Somogyi,et al.  POLYMORPHIC O-DEMETHYLATION OF CODEINE , 1988, The Lancet.

[88]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[89]  R. Robinson,et al.  Multiple interacting gene products may influence susceptibility to malignant hyperthermia , 2000, Annals of human genetics.

[90]  E. Bruera,et al.  Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene , 2007, PAIN.

[91]  S. Kaasa,et al.  The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients , 2005, Pain.

[92]  I. Sora,et al.  The mu opiate receptor as a candidate gene for pain: polymorphisms, variations in expression, nociception, and opiate responses. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[93]  Joshua A. Bueller,et al.  COMT val158met Genotype Affects µ-Opioid Neurotransmitter Responses to a Pain Stressor , 2003, Science.