• 1
    UNODC. 2008 World drug report. United nations office on drugs and crime 2008.
  • 2
    Doran CM, Shanahan M, Mattick RP, Ali R, White J, Bell J. Buprenorphine versus methadone maintenance: a cost-effectiveness analysis. Drug Alcohol Depend 2003; 71: 292302.
  • 3
    Rosenblum A, Joseph H, Fong C, Kipnis S, Cleland C, Portenoy RK. Prevalence and characteristics of chronic pain among chemically dependent patients in methadone maintenance and residential treatment facilities. JAMA 2003; 289: 23708.
  • 4
    Huxtable CA, Roberts LJ, Somogyi AA, Macintyre PE. Acute pain management in opioid-tolerant patients: a growing challenge. Anaesth Intensive Care 2011; 39: 80423.
  • 5
    Hay JL, White JM, Bochner F, Somogyi AA, Semple TJ, Rounsefell B. Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients. J Pain 2009; 10: 31622.
  • 6
    Doverty M, Somogyi AA, White JM, Bochner F, Beare CH, Menelaou A, Ling W. Methadone maintenance patients are cross-tolerant to the antinociceptive effects of morphine. Pain 2001; 93: 15563.
  • 7
    Alford DP, Compton P, Samet JH. Acute pain management for patients receiving maintenance methadone or buprenorphine therapy. Ann Intern Med 2006; 144: 12734.
  • 8
    Gillen C, Haurand M, Kobelt DJ, Wnendt S. Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor. Naunyn Schmiedebergs Arch Pharmacol 2000; 362: 11621.
  • 9
    Paar WD, Frankus P, Dengler HJ. The metabolism of tramadol by human liver microsomes. Clin Investig 1992; 70: 70810.
  • 10
    Subrahmanyam V, Renwick AB, Walters DG, Young PJ, Price RJ, Tonelli AP, Lake BG. Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos 2001; 29: 114655.
  • 11
    Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet 2004; 43: 879923.
  • 12
    Coller JK, Christrup LL, Somogyi AA. Role of active metabolites in the use of opioids. Eur J Clin Pharmacol 2009; 65: 12139.
  • 13
    Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL. Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. J Pharmacol Exp Ther 1992; 260: 27585.
  • 14
    Driessen B, Reimann W, Glertz H. Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro. Br J Pharmacol 1993; 108: 80611.
  • 15
    Poulsen L, Arendt-Nielsen L, Brøsen K, Sindrup S. The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 1996; 60: 63644.
  • 16
    Slanar O, Nobilis M, Kvetina J, Idle J, Perlik F. CYP2D6 polymorphism, tramadol pharmacokinetics and pupillary response. Eur J Clin Pharmacol 2006; 62: 756.
  • 17
    Levo A, Koski A, Ojanpera I, Vuori E, Sajantila A. Post-mortem SNP analysis of CYP2D6 gene reveals correlation between genotype and opioid drug (tramadol) metabolite ratios in blood. Forensic Sci Int 2003; 135: 915.
  • 18
    Enggaard TP, Poulsen L, Arendt-Nielsen L, Brosen K, Ossig J, Sindrup SH. The analgesic effect of tramadol after intravenous injection in healthy volunteers in relation to CYP2D6. Anesth Analg 2006; 102: 14650.
  • 19
    Stamer UM, Musshoff F, Kobilay M, Madea B, Hoeft A, Stuber F. Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin Pharmacol Ther 2007; 82: 417.
  • 20
    Wu D, Otton SV, Sproule BA, Busto U, Inaba T, Kalow W, Sellers EM. Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone. Br J Clin Pharmacol 1993; 35: 304.
  • 21
    Shiran MR, Chowdry J, Rostami-Hodjegan A, Ellis SW, Lennard MS, Iqbal MZ, Lagundoye O, Seivewright N, Tucker GT. A discordance between cytochrome P450 2D6 genotype and phenotype in patients undergoing methadone maintenance treatment. Br J Clin Pharmacol 2003; 56: 2204.
  • 22
    Gelston EA, Coller JK, Lopatko OV, James HM, Schmidt H, White JM, Somogyi AA. Methadone inhibits CYP2D6 and UGT2B7/2B4 in vivo: a study using codeine in methadone and buprenorphine maintained subjects. Br J Clin Pharmacol 2011. DOI: 10.1111/j.1365-2125.2011.04145.x. Epub Nov 17.
  • 23
    Laugesen S, Enggaard TP, Pedersen RS, Sindrup SH, Brosen K. Paroxetine, a cytochrome P450 2D6 inhibitor, diminishes the stereoselective O-demethylation and reduces the hypoalgesic effect of tramadol. Clin Pharmacol Ther 2005; 77: 31223.
  • 24
    Zhang W, Ramamoorthy Y, Tyndale RF, Sellers EM. Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes P450 in vitro. Drug Metab Dispos 2003; 31: 76872.
  • 25
    Ciraulo DA, Hitzemann RJ, Somoza E, Knapp CM, Rotrosen J, Sarid-Segal O, Ciraulo AM, Greenblatt DJ, Chiang CN. Pharmacokinetics and pharmacodynamics of multiple sublingual buprenorphine tablets in dose-escalation trials. J Clin Pharmacol 2006; 46: 17992.
  • 26
    James HM, Coller JK, Gillis D, Bahnisch J, Sallustio BC, Somogyi AA. A new simple diagnostic assay for the identification of the major CYP2D6 genotypes by DNA sequencing analysis. Int J Clin Pharmacol Ther 2004; 42: 71923.
  • 27
    Paar WD, Frankus P, Dengler HJ. High-performance liquid chromatographic assay for the simultaneous determination of tramadol and its metabolites in microsomal fractions of human liver. J Chromatogr B Biomed Sci Appl 1996; 686: 2217.
  • 28
    Foster DJ, Morton E, Murtder T, Somogyi A. Stereoselective quantification of methadone and a d(6)-labeled isotopomer using high performance liquid chromatography-atmospheric pressure chemical ionization mass-spectrometry: application to a pharmacokinetic study in a methadone maintained subject. Ther Drug Monit 2006; 28: 55967.
  • 29
    Jensen ML, Foster D, Upton R, Grant C, Martinez A, Somogyi A. Comparison of cerebral pharmacokinetics of buprenorphine and norbuprenorphine in an in vivo sheep model. Xenobiotica 2007; 37: 44157.
  • 30
    Newcombe RG. Confidence intervals for an effect size measure based on the Mann-Whitney statistic. Part 1: general issues and tail-area-based methods. Stat Med 2006; 25: 54357.
  • 31
    Newcombe RG. Confidence intervals for an effect size measure based on the Mann-Whitney statistic. Part 2: asymptotic methods and evaluation. Stat Med 2006; 25: 55973.
  • 32
    Zhang L, Zhang Y, Zhao P, Huang SM. Predicting drug-drug interactions: an FDA perspective. AAPS J 2009; 11: 3006.
  • 33
    Paar WD, Poche S, Gerloff J, Dengler HJ. Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol. Eur J Clin Pharmacol 1997; 53: 2359.
  • 34
    Pedersen RS, Damkier P, Brøsen K. Tramadol as a new probe for cytochrome P450 2D6 phenotyping: a population study. Clin Pharmacol Ther 2005; 77: 45867.
  • 35
    Stamer UM, Lehnen K, Hothker F, Bayerer B, Wolf S, Hoeft A, Stuber F. Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain 2003; 105: 2318.
  • 36
    Carroll CP, Walsh SL, Bigelow GE, Strain EC, Preston KL. Assessment of agonist and antagonist effects of tramadol in opioid-dependent humans. Exp Clin Psychopharmacol 2006; 14: 10920.