Clinical Pharmacokinetics

, Volume 41, Issue 14, pp 1153–1193 | Cite as

Interindividual Variability of the Clinical Pharmacokinetics of Methadone

Implications for the Treatment of Opioid Dependence
  • Chin B. EapEmail author
  • Thierry Buclin
  • Pierre Baumann
Review Articles Special Populations


Methadone is widely used for the treatment of opioid dependence. Although in most countries the drug is administered as a racemic mixture of (R)- and (S)-methadone, (R)-methadone accounts for most, if not all, of the opioid effects. Methadone can be detected in the blood 15–45 minutes after oral administration, with peak plasma concentration at 2.5–4 hours. Methadone has a mean bioavailability of around 75% (range 36–100%). Methadone is highly bound to plasma proteins, in particular to α1-acid glycoprotein. Its mean free fraction is around 13%, with a 4-fold interindividual variation. Its volume of distribution is about 4 L/kg (range 2–13 L/kg). The elimination of methadone is mediated by biotransformation, followed by renal and faecal excretion. Total body clearance is about 0.095 L/min, with wide interindividual variation (range 0.02–2 L/min). Plasma concentrations of methadone decrease in a biexponential manner, with a mean value of around 22 hours (range 5–130 hours) for elimination half-life. For the active (R)-enantiomer, mean values of around 40 hours have been determined.

Cytochrome P450 (CYP) 3A4 and to a lesser extent 2D6 are probably the main isoforms involved in methadone metabolism. Rifampicin (rifampin), phenobarbital, phenytoin, carbamazepine, nevirapine, and efavirenz decrease methadone blood concentrations, probably by induction of CYP3A4 activity, which can result in severe withdrawal symptoms. Inhibitors of CYP3A4, such as fluconazole, and of CYP2D6, such as paroxetine, increase methadone blood concentrations. There is an up to 17-fold interindividual variation of methadone blood concentration for a given dosage, and interindividual variability of CYP enzymes accounts for a large part of this variation.

Since methadone probably also displays large interindividual variability in its pharmacodynamics, methadone treatment must be individually adapted to each patient. Because of the high morbidity and mortality associated with opioid dependence, it is of major importance that methadone is used at an effective dosage in maintenance treatment: at least 60 mg/day, but typically 80–100 mg/day. Recent studies also show that a subset of patients might benefit from methadone dosages larger than 100 mg/day, many of them because of high clearance.

In clinical management, medical evaluation of objective signs and subjective symptoms is sufficient for dosage titration in most patients. However, therapeutic drug monitoring can be useful in particular situations. In the case of non-response trough plasma concentrations of 400 μg/L for (R, S)-methadone or 250 μg/L for (R)-methadone might be used as target values.


Therapeutic Drug Monitoring Withdrawal Symptom Methadone Dosage Human Liver Microsome Methadone Maintenance Treatment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Studies from our group (Prilly-Lausanne) mentioned in the present paper were supported in part by the Swiss Federal Office of Public Health, grant numbers 8045 and 316.97.0629, and by a grant from the Sandoz Foundation. We gratefully acknowledge the editorial assistance of Mrs C. Bertschi, and the bibliographic help of Mrs M. Gobin, Mrs E. Ponce and Mrs J. Rosselet. We greatly thank Stewart B. Leavitt, PhD, Glenview, IL, USA, Marc Shinderman, MD, Chicago, IL, USA, Jason M. White, PhD, Adelaide, Australia, Fernand Mathot, PhD, Liège, Belgium, and Andrew Byrne, MD, Redfern, NSW, Australia for their review and their helpful comments during the preparation of this paper.


  1. 1.
    Bertschy G. Methadone maintenance treatment: an update. Eur Arch Psychiatry Clin Neurosci 1995; 245: 114–24PubMedGoogle Scholar
  2. 2.
    Farrell M, Ward J, Mattick R, et al. Methadone maintenance treatment in opiate dependence: a review. BMJ 1994; 309: 997–1001PubMedGoogle Scholar
  3. 3.
    O’Connor PG, Fiellin DA. Pharmacologic treatment of heroin-dependent patients. Ann Intern Med 2000; 133: 40–54PubMedGoogle Scholar
  4. 4.
    Zaric GS, Barnett PG, Brandeau ML, et al. HIV transmission and the cost-effectiveness of methadone maintenance. Am J Public Health 2000; 90: 1100–11PubMedGoogle Scholar
  5. 5.
    Dole VP, Nyswander ME. Rehabilitation of heroin addicts after blockade with methadone. N Y State J Med 1966; 66: 2011–7PubMedGoogle Scholar
  6. 6.
    Dole VP. Implications of methadone maintenance for theories of narcotic addiction. JAMA 1988; 260: 80–4Google Scholar
  7. 7.
    Dole VP, Nyswander M. A medical treatment for diacetylmorphine (heroin) addiction: a clinical trial with methadone hydrochloride. JAMA 1965; 193: 80–4Google Scholar
  8. 8.
    Johnson RE, Chutuape MA, Strain EC, et al. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med 2000; 343: 1290–7PubMedGoogle Scholar
  9. 9.
    Rhoades HM, Creson D, Elk R, et al. Retention, HIV risk, and illicit drug use during treatment: methadone dose and visit frequency. Am J Public Health 1998; 88: 34–9PubMedGoogle Scholar
  10. 10.
    Preston KL, Umbricht A, Epstein DH, et al. Methadone dose increase and abstinence reinforcement for treatment of continued heroin use during methadone maintenance. Arch Gen Psychiatry 2000; 57: 395–404PubMedGoogle Scholar
  11. 11.
    Strain EC, Bigelow GE, Liebson IA, et al. Moderate- vs highdose methadone in the treatment of opioid dependence: a randomized trial. JAMA 1999; 281: 1000–5PubMedGoogle Scholar
  12. 12.
    Ling W, Wesson DR, Charuvastra C, et al. A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence. Arch Gen Psychiatry 1996; 53: 401–7PubMedGoogle Scholar
  13. 13.
    Schottenfeld RS, Pakes JR, Oliveto A, et al. Buprenorphine vs methadone maintenance treatment for concurrent opioid dependence and cocaine abuse. Arch Gen Psychiatry 1997; 54: 713–20PubMedGoogle Scholar
  14. 14.
    Caplehorn JRM, Bell J. Methadone dosage and retention of patients in maintenance treatment. Med J Aust 1991; 154: 195–9PubMedGoogle Scholar
  15. 15.
    Payte JT, Khuri ET. Principles of methadone dose determinations. In: US Department of Health and Human Services, editor. State methadone treatment guidelines. Rockville (MD): Rockwall, 1993: 101–24Google Scholar
  16. 16.
    D’Aunno T, Vaughn TE. Variations in methadone treatment practices: results from a national study. JAMA 1992; 267: 253–8PubMedGoogle Scholar
  17. 17.
    Byrne AJ. Ten patients prescribed high dose methadone maintenance in general practice [letter]. Med J Aust 1996; 165: 239PubMedGoogle Scholar
  18. 18.
    Maremmani I, Canoniero S, Pacini M, et al. Methadone dose and retention in treatment of heroin addicts with bipolar I disorder comorbidity. Preliminary results. Heroin Addict Relat Clin Probl 2000; 2: 39–46Google Scholar
  19. 19.
    Byrne A. Use of serum levels for optimising doses in methadone maintenance treatment. J Main Addict 1998; 1: 13–4Google Scholar
  20. 20.
    Maxwell S, Shinderman M. Optimizing response to methadone maintenance treatment: use of higher dose methadone. J Psychoactive Drugs 1999; 31: 95–102PubMedGoogle Scholar
  21. 21.
    Säwe J. High-dose morphine and methadone in cancer patients: clinical pharmacokinetic considerations of oral treatment. Clin Pharmacokinet 1986; 11: 87–106PubMedGoogle Scholar
  22. 22.
    Ward J, Bell J, Mattick RP, et al. Methadone maintenance therapy for opioid dependence. CNS Drugs 1996; 6: 440–9Google Scholar
  23. 23.
    Eap CB, Dégion JJ, Baumann P. Pharmacokinetics and pharmacogenetics of methadone: clinical relevance. Heroin Addict Relat Clin Probl 1999; 1: 19–34Google Scholar
  24. 24.
    Garrido MJ, Trocóniz IF. Methadone: a review of its pharmacokinetic/pharmacodynamic properties. J Pharmacol Toxicol Methods 1999; 42: 61–6PubMedGoogle Scholar
  25. 25.
    Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science 1973; 179: 1011–4PubMedGoogle Scholar
  26. 26.
    Kristensen K, Christensen CB, Christrup LL, et al. The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci 1995; 56: 45–50Google Scholar
  27. 27.
    Scott CC, Robbins EB, Chen KK. Pharmacological comparison of the optical isomers of methadone. J Pharmacol Exp Ther 1948; 92: 282–6Google Scholar
  28. 28.
    Isbell H, Eisenman AJ. The addiction liability of some drugs of the methadone series. J Pharmacol Exp Ther 1948; 93: 305–13PubMedGoogle Scholar
  29. 29.
    Olsen GD, Wendel HA, Livermore JD, et al. Clinical effects and pharmacokinetics of racemic methadone and its optical isomers. Clin Pharmacol Ther 1977; 21: 147–57PubMedGoogle Scholar
  30. 30.
    Fraser HF, Isbell H. Human pharmacology and addictiveness of certain dextroisomers of synthetic analgesics. Bull Narc 1962; 14: 25–35Google Scholar
  31. 31.
    Judson BA, Horns WH, Goldstein A, et al. Side effects of levomethadone and racemic methadone in a maintenance program. Clin Pharmacol Ther 1976; 20: 445–9PubMedGoogle Scholar
  32. 32.
    Scherbaum N, Finkbeiner T, Leifert K, et al. The efficacy of l-methadone and racemic methadone in substitution treatment for opiate addicts: a double-blind comparison. Pharmacopsychiatry 1996; 29: 212–5PubMedGoogle Scholar
  33. 33.
    De Vos JW, Ufkes JG, Kaplan CD, et al. L-methadone and D,L-methadone in methadone maintenance treatment: a comparison of therapeutic effectiveness and plasma concentrations. Eur Addict Res 1998; 4: 134–41PubMedGoogle Scholar
  34. 34.
    Gorman AL, Elliott KJ, Inturrisi CE, et al. The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neurosci Lett 1997; 223: 5–8PubMedGoogle Scholar
  35. 35.
    Ebert B, Andersen S, Krogsgaard-Larsen P, et al. Ketobemidone, methadone and pethidine are non-competitive N-methyl-D-aspartate (NMDA) antagonists in the rat cortex and spinal cord. Neurosci Lett 1995; 187: 165–8PubMedGoogle Scholar
  36. 36.
    Shimoyama N, Shimoyama M, Elliot KJ, et al. d-Methadone is antinociceptive in the rat formalin test. J Pharmacol Exp Ther 1997; 283: 648–52PubMedGoogle Scholar
  37. 37.
    Codd EE, Shank RP, Schupsky JJ, et al. Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther 1995; 274: 1263–70PubMedGoogle Scholar
  38. 38.
    Beck O, Boreus LO, Lafolie P, et al. Chiral analysis of methadone in plasma by high-performance liquid chromatography. J Chromatogr B Biomed Appl 1991; 570: 198–202Google Scholar
  39. 39.
    Foster DJR, Somogyi AA, Dyer KR, et al. Steady-state pharmacokinetics of (R)- and (S)-methadone in methadone maintenance patients. Br J Clin Pharmacol 2000; 50: 427–40PubMedGoogle Scholar
  40. 40.
    Eap CB, Bertschy G, Powell K, et al. Fluvoxamine and fluoxetine do not interact in the same way with the metabolism of the enantiomers of methadone. J Clin Psychopharmacol 1997; 17: 113–7PubMedGoogle Scholar
  41. 41.
    Kristensen K, Angelo HR. Stereospecific gas chromatographic method for determination of methadone in serum. Chirality 1992; 4: 263–7PubMedGoogle Scholar
  42. 42.
    Pham-Huy C, Chikhi-Chorfi N, Galons H, et al. Enantioselective high-performance liquid chromatography determination of methadone enantiomers and its major metabolite in human biological fluids using a new derivatized cyclodextrin-bonded phase. J Chromatogr B Biomed Appl 1997; 700: 155–63Google Scholar
  43. 43.
    Rudaz S, Veuthey JL. Stereoselective determination of methadone in serum by HPLC following solid-phase extraction on disk. J Pharm Biomed Anal 1996; 14: 1271–9PubMedGoogle Scholar
  44. 44.
    Eap CB, Finkbeiner T, Gastpar M, et al. Replacement of (R)-methadone by a double dose of (R, S)-methadone in addicts: interindividual variability of the (R)/(S) ratios and evidence of adaptive changes in methadone pharmacokinetics. Eur J Clin Pharmacol 1996; 50: 385–9PubMedGoogle Scholar
  45. 45.
    Hiltunen AJ, Beck O, Hjemdahl P, et al. Rated well-being in relation to plasma concentrations of l- and d-methadone in satisfied and dissatisfied patients on methadone maintenance treatment. Psychopharmacology (Berl) 1999; 143: 385–93Google Scholar
  46. 46.
    Nilsson M-I, Widerlov E, Meresaar U, et al. Effect of urinary pH on the disposition of methadone in man. Eur J Clin Pharmacol 1982; 22: 337–42PubMedGoogle Scholar
  47. 47.
    Meresaar U, Nilsson MI, Holmstrand J, et al. Single dose pharmacokinetics and bioavailability of methadone in man studied with a stable isotope method. Eur J Clin Pharmacol 1981; 20: 473–8PubMedGoogle Scholar
  48. 48.
    Wolff K, Hay AW, Raistrick D, et al. Steady-state pharmacokinetics of methadone in opioid addicts. Eur J Clin Pharmacol 1993; 44: 189–94PubMedGoogle Scholar
  49. 49.
    Nilsson M-I, Anggard E, Holmstrand J, et al. Pharmacokinetics of methadone during maintenance treatment: adaptive changes during the induction phase. Eur J Clin Pharmacol 1982; 22: 343–9PubMedGoogle Scholar
  50. 50.
    Wolff K, Rostami-Hodjegan A, Shires S, et al. The pharmacokinetics of methadone in healthy subjects and opiate users. Br J Clin Pharmacol 1997; 44: 325–34PubMedGoogle Scholar
  51. 51.
    Inturrisi CE, Colburn WA, Kaiko RF, et al. Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain. Clin Pharmacol Ther 1987; 41: 392–401PubMedGoogle Scholar
  52. 52.
    Nilsson MI, Gronbladh L, Widerlov E, et al. Pharmacokinetics of methadone in methadone maintenance treatment: characterization of therapeutic failures. Eur J Clin Pharmacol 1983; 25: 497–501PubMedGoogle Scholar
  53. 53.
    Kristensen K, Blemmer T, Angelo HR, et al. Stereoselective pharmacokinetics of methadone in chronic pain patients. Ther Drug Monit 1996; 18: 221–7PubMedGoogle Scholar
  54. 54.
    De Vos JW, Geerlings PJ, van den Brink W, et al. Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts. Eur J Clin Pharmacol 1995; 48: 361–6PubMedGoogle Scholar
  55. 55.
    Gourlay GK, Wilson PR, Glynn CJ, et al. Pharmacodynamics and pharmacokinetics of methadone during the perioperative period. Anesthesiology 1982; 57: 458–67PubMedGoogle Scholar
  56. 56.
    Boulton DW, Arnaud P, DeVane CL, et al. Pharmacokinetics and pharmacodynamics of methadone enantiomers after a single oral dose of racemate. Clin Pharmacol Ther 2001; 70: 48–57PubMedGoogle Scholar
  57. 57.
    Inturrisi CE, Verebely K. The levels of methadone in the plasma in methadone maintenance. Clin Pharmacol Ther 1972; 13: 633–7PubMedGoogle Scholar
  58. 58.
    Verebely K, Volavka J, Mule S, et al. Methadone in man: pharmacokinetic and excretion studies in acute and chronic treatment. Clin Pharmacol Ther 1975; 18: 180–90PubMedGoogle Scholar
  59. 59.
    Plummer JL, Gourlay GK, Cherry DA, et al. Estimation of methadone clearance: application in the management of cancer pain. Pain 1988; 33: 313–22PubMedGoogle Scholar
  60. 60.
    Inturrisi CE, Verebely K. Disposition of methadone in man after a single oral dose. Clin Pharmacol Ther 1972; 13: 923–30PubMedGoogle Scholar
  61. 61.
    Kreek MJ, Hachey DL, Klein PD, et al. Stereoselective disposition of methadone in man. Life Sci 1979; 24: 925–32PubMedGoogle Scholar
  62. 62.
    Nakamura K, Hachey DL, Kreek MJ, et al. Quantitation of methadone enantiomers in humans using stable isotope-labeled (2H3)- and (2H8)methadone. J Pharm Sci 1982; 71: 40–3PubMedGoogle Scholar
  63. 63.
    Gourlay GK, Cherry DA, Cousins MJ, et al. A comparative study of the efficacy and pharmacokinetics of oral methadone and morphine in the treatment of severe pain in patients with Cancer. Pain 1986; 25: 297–312PubMedGoogle Scholar
  64. 64.
    Bellward GD, Warren PM, Howald W, et al. Methadone maintenance: effect of urinary pH on renal clearance in chronic high and low doses. Clin Pharmacol Ther 1977; 22: 92–9PubMedGoogle Scholar
  65. 65.
    Gourevitch MN, Hartel D, Tenore P, et al. Three oral formulations of methadone: a clinical and pharmacodynamic comparison. J Subst Abuse Treat 1999; 17: 237–41PubMedGoogle Scholar
  66. 66.
    Oda Y, Kharasch ED. Metabolism of methadone and levo-alpha-acetylmethadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4): potential contribution of intestinal metabolism to presysternic clearance and bioactivation. J Pharmacol Exp Ther 2001; 298: 1021–32PubMedGoogle Scholar
  67. 67.
    Callaghan R, Riordan JR. Synthetic and natural opiates interact with P-glycoprotein in multidrug-resistant cells. J Biol Chem 1993; 268: 16059–64PubMedGoogle Scholar
  68. 68.
    Bouër R, Barthe L, Philibert C, et al. The roles of P-glycoprotein and intracellular metabolism in the intestinal absorption of methadone: in vitro studies using the rat everted intestinal sac. Fundam Clin Pharmacol 1999; 13: 494–500PubMedGoogle Scholar
  69. 69.
    Thompson SJ, Koszdin K, Bernards CM, et al. Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology 2000; 92: 1392–9PubMedGoogle Scholar
  70. 70.
    Olsen GD. Methadone binding to human plasma proteins. Clin Pharmacol Ther 1973; 14: 338–43PubMedGoogle Scholar
  71. 71.
    Tocque B, Pontikis R, Nam NH, et al. Morphine and methadone binding to human serum proteins. J Pharm Pharmacol 1980; 32: 729–31PubMedGoogle Scholar
  72. 72.
    Olsen JD. Methadone binding to human plasma albumin. Science 1972; 176: 525–6PubMedGoogle Scholar
  73. 73.
    Romach MK, Piafsky KM, Abel JG, et al. Methadone binding to orosomucoid (alpha1-acid glycoprotein): determinant of free fraction in plasma. Clin Pharmacol Ther 1981; 29: 211–7PubMedGoogle Scholar
  74. 74.
    Eap CB, Cuendet C, Baumann P. Binding of d-, l-, and dl-methadone, and dl-methadone to proteins in plasma of healthy volunteers: role of the variants of alpha1-acid glycoprotein. Clin Pharmacol Ther 1990; 47: 338–46PubMedGoogle Scholar
  75. 75.
    Kremer JM, Wilting J, Janssen LH, et al. Drug binding to human alpha1-acid glycoprotein in health and disease. Pharmacol Rev 1988; 40: 1–47PubMedGoogle Scholar
  76. 76.
    Garrido MJ, Aguirre C, Troconiz IF, et al. Alpha1-acid glycoprotein (AAG) and serum protein binding of methadone in heroin addicts with abstinence syndrome. Int J Clin Pharmacol Ther 2000; 38: 35–40PubMedGoogle Scholar
  77. 77.
    Abramson FP. Methadone plasma protein binding: alterations in cancer and displacement from alpha1-acid glycoprotein. Clin Pharmacol Ther 1982; 32: 652–8PubMedGoogle Scholar
  78. 78.
    Wilkins JN, Ashofteh A, Setoda D, et al. Ultrafiltration using the amicon MPS-1 for assessing methadone plasma protein binding. Ther Drug Monit 1997; 19: 83–7PubMedGoogle Scholar
  79. 79.
    Garrido MJ, Jiminez R, Gomez E, et al. Influence of plasmaprotein binding on analgesic effect of methadone in rats with spontaneous withdrawal. J Pharm Pharmacol 1996; 48: 281–4PubMedGoogle Scholar
  80. 80.
    Garrido MJ, Valle M, Calvo R, et al. Altered plasma and brain disposition and pharmacodynamics of methadone in abstinent rats. J Pharmacol Exp Ther 1999; 288: 179–87PubMedGoogle Scholar
  81. 81.
    Gomez E, Martinez-Jorda R, Suarez E, et al. Altered methadone analgesia due to changes in plasma protein binding: role of the route of administration. Gen Pharmacol 1995; 26: 1273–6PubMedGoogle Scholar
  82. 82.
    Tomei L, Eap CB, Baumann P, et al. Use of transgenic mice for the characterization of human alpha1-acid glycoprotein (or-osomucoid) variants. Hum Genet 1989; 84: 89–91PubMedGoogle Scholar
  83. 83.
    Eap CB, Cuendet C, Baumann P. Orosomucoid (alpha1-acid glycoprotein) phenotyping by use of immobilized pH gradients with 8 M urea and immunoblotting. Hum Genet 1988; 80: 183–5PubMedGoogle Scholar
  84. 84.
    Hervé F, Duche JC, d’Athis P, et al. Binding of disopyramide, methadone, dipyridamole, chlorpromazine, lignocaine and progesterone to the two main genetic variants of human alpha1-acid glycoprotein: evidence for drug-binding difference between the variants and for the presence of two separate drug-binding sites on the alpha1-acid glycoprotein. Pharmacogenetics 1996; 6: 403–15PubMedGoogle Scholar
  85. 85.
    Jolliet-Riant P, Boukef MF, Duche JC, et al. The genetic variant a of human alpha1-acid glycoprotein limits the blood to brain transfer of drugs it binds. Life Sci 1999; 62: 219–26Google Scholar
  86. 86.
    Kreek MJ, Oratz M, Rothschild MA, et al. Hepatic extraction of long- and short-acting narcotics in the isolated perfused rabbit liver. Gastroenterology 1978; 75: 88–94PubMedGoogle Scholar
  87. 87.
    Rostami-Hodjegan A, Wolff K, Hay AW, et al. Population pharmacokinetics of methadone in opiate users: characterization of time-dependent changes. Br J Clin Pharmacol 1999; 48: 43–52PubMedGoogle Scholar
  88. 88.
    Änggàrd E, Gunne LM, Homstrand J, et al. Disposition of methadone in methadone maintenance. Clin Pharmacol Ther 1975; 17: 258–66PubMedGoogle Scholar
  89. 89.
    Sullivan HR, Due SL. Urinary metabolites of dl-methadone in maintenance subjects. J Med Chem 1973; 16: 909–13PubMedGoogle Scholar
  90. 90.
    Kreek MJ, Bencsath FA, Field FH, et al. Effects of liver disease on urinary excretion of methadone and metabolites in maintenance patients: quantitation by direct probe chemical ionization mass spectrometry. Biomed Mass Spectrom 1980; 7: 385–95PubMedGoogle Scholar
  91. 91.
    Kreek MJ, Bencsath FA, Fanizza A, et al. Effects of liver disease on fecal excretion of methadone and its unconjugated metabolites in maintenance patients: quantitation by direct probe chemical ionization mass spectrometry. Biomed Mass Spectrom 1983; 10: 544–9PubMedGoogle Scholar
  92. 92.
    Nilsson MI, Meresaar U, Änggard E. Clinical pharmacokinetics of methadone. Acta Anaesthesiol Scand 1982; 74: 66–9Google Scholar
  93. 93.
    Wolff K, Rostami-Hodjegan A, Hay AW, et al. Population-based pharmacokinetic approach for methadone monitoring of opiate addicts: potential clinical utility. Addiction 2000; 95: 1771–83PubMedGoogle Scholar
  94. 94.
    Lucas ACS, Bermejo AM, Tabernero MJ, et al. Influence of concomitant drugs on methadone elimination half-life in patients under a maintenance treatment. Addict Biol 2001; 6: 171–6PubMedGoogle Scholar
  95. 95.
    Pinzani V, Faucherre V, Peyriere H, et al. Methadone withdrawal symptoms with nevirapine and efavirenz. Ann Pharmacother 2000; 34: 405–7PubMedGoogle Scholar
  96. 96.
    Otero MJ, Fuertes A, Sanchez R, et al. Nevirapine-induced withdrawal symptoms in HIV patients on methadone maintenance programme: an alert. AIDS 1999; 13: 1004–5PubMedGoogle Scholar
  97. 97.
    Altice FL, Friedland GH, Cooney EL, et al. Nevirapine induced opiate withdrawal among injection drug users with HIV infection receiving methadone. AIDS 1999; 13: 957–62PubMedGoogle Scholar
  98. 98.
    Kreek MJ, Schecter AJ, Gutjahr CL, et al. Methadone use in patients with chronic renal disease. Drug Alcohol Depend 1980; 5: 197–205PubMedGoogle Scholar
  99. 99.
    Eap CB, Bourquin M, Martin J, et al. Plasma concentrations of the enantiomers of methadone and therapeutic response in methadone maintenance treatment. Drug Alcohol Depend 2000; 61: 47–54PubMedGoogle Scholar
  100. 100.
    Davies G, Kingswood C, Street M, et al. Pharmacokinetics of opioids in renal dysfunction. Clin Pharmacokinet 1996; 31: 410–22PubMedGoogle Scholar
  101. 101.
    Furlan V, Hafi A, Dessalles MC, et al. Methadone is poorly removed by haemodialysis. Nephrol Dial Transplant 1999; 14: 254–5PubMedGoogle Scholar
  102. 102.
    Novick DM, Kreek MJ, Arns PA, et al. Effect of severe alcoholic liver disease on the disposition of methadone in maintenance patients. Alcohol Clin Exp Res 1985; 9: 349–54PubMedGoogle Scholar
  103. 103.
    Novick DM, Kreek MJ, Fanizza AM, et al. Methadone disposition in patients with chronic liver disease. Clin Pharmacol Ther 1981; 30: 353–62PubMedGoogle Scholar
  104. 104.
    Okruhlica L, Klempova D. Hepatitis C infected patients and higher doses of methadone. Heroin Addict Relat Clin Probl 2000; 2: 57–8Google Scholar
  105. 105.
    Maxwell S, Shinderman M, Miner A, et al. Correlation between Hepatitis C serostatus and methadone dose requirement in 1163 methadone-maintained patients. Heroin Add & Rel Clin Prob 2002; 4(2): 5–10Google Scholar
  106. 106.
    Preston KL, Griffiths RR, Stitzer ML, et al. Diazepam and methadone interactions in methadone maintenance. Clin Pharmacol Ther 1984; 36: 534–41PubMedGoogle Scholar
  107. 107.
    Preston KL, Griffiths RR, Cone EJ, et al. Diazepam and methadone blood levels following concurrent administration of diazepam and methadone. Drug Alcohol Depend 1986; 18: 195–202PubMedGoogle Scholar
  108. 108.
    Pond SM, Tong TG, Benowitz NL, et al. Lack of effect of diazepam on methadone metabolism in methadone-maintained addicts. Clin Pharmacol Ther 1982; 31: 139–43PubMedGoogle Scholar
  109. 109.
    Borg L, Kreek MJ. Clinical problems associated with interactions between methadone pharmacotherapy and medications used in the treatment of HIV-1-positive and AIDS patients. Curr Opin Psychiatry 1995; 8: 199–202Google Scholar
  110. 110.
    Liu S-J, Wang RIH. Case report of barbiturate-induced enhancement of methadone metabolism and withdrawal syndrome. Am J Psychiatry 1984; 141: 1287–8PubMedGoogle Scholar
  111. 111.
    Finelli PF. Phenytoin and methadone tolerance [letter]. N Engl J Med 1976; 294: 227PubMedGoogle Scholar
  112. 112.
    Tong TG, Pond SM, Kreek MJ, et al. Phenytoin-induced methadone withdrawal. Ann Intern Med 1981; 94: 349–51PubMedGoogle Scholar
  113. 113.
    Heelon MW, Meade LB. Methadone withdrawal when starting an antiretroviral regimen including nevirapine. Pharmacotherapy 1999; 19: 471–2PubMedGoogle Scholar
  114. 114.
    Marzolini C, Troillet N, Telenti A, et al. Efavirenz decreases methadone blood concentrations. AIDS 2000; 14: 1291–2PubMedGoogle Scholar
  115. 115.
    Clarke SM, Mulcahy FM, Tjia J, et al. The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz. Br J Clin Pharmacol 2001; 51: 213–7PubMedGoogle Scholar
  116. 116.
    Bart PA, Rizzardi PG, Gallant S, et al. Methadone blood concentrations are decreased by the administration of abacavir plus amprenavir. Ther Drug Monit 2001; 23: 553–5PubMedGoogle Scholar
  117. 117.
    Beauverie P, Taburet AM, Dessalles MC, et al. Therapeutic drug monitoring of methadone in HIV-infected patients receiving protease inhibitors. AIDS 1998; 12: 2510–1PubMedGoogle Scholar
  118. 118.
    Hsu A, Granneman GR, Carothers L, et al. Ritonavir does not increase methadone exposure in healthy volunteers [abstract 342]. Proceeding of the 5th Conference on Retroviruses and Opportunistic Infections; 1998; ChicagoGoogle Scholar
  119. 119.
    Gerber JG, Rosenkranz S, Segal Y, et al. Effect of ritonavir/saquinavir on stereoselective pharmacokinetics of methadone: results of AIDS Clinical Trials Group (ACTG) 401. J Acquir Immune Defic Syndr 2001; 27: 153–60PubMedGoogle Scholar
  120. 120.
    Geletko SM, Erickson AD. Decreased methadone effect after ritonavir initiation. Pharmacotherapy 2000; 20: 93–4PubMedGoogle Scholar
  121. 121.
    Cobb MN, Desai J, Brown LS Jr, et al. The effect of fluconazole on the clinical pharmacokinetics of methadone. Clin Pharmacol Ther 1998; 63: 655–62PubMedGoogle Scholar
  122. 122.
    Batki SL, Manfredi LB, Jacob P III, et al. Fluoxetine for cocaine dependence in methadone maintenance: quantitative plasma and urine cocaine benzoylecgonine concentrations. J Clin Psychopharmacol 1993; 13: 243–50PubMedGoogle Scholar
  123. 123.
    Bertschy G, Eap CB, Powell K, et al. Fluoxetine addition to methadone in addicts: pharmacokinetic aspects. Ther Drug Monit 1996; 18: 570–2PubMedGoogle Scholar
  124. 124.
    Begré S, von Bardeleben U, Ladewig D, et al. Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers. J Clin Psychopharmacol 2002; 22: 211–5PubMedGoogle Scholar
  125. 125.
    Hamilton SP, Nunes EV, Janal M, et al. The effect of sertraline on methadone plasma levels in methadone-maintenance patients. Am J Addict 2000; 9: 63–9PubMedGoogle Scholar
  126. 126.
    Herrlin K, Segerdahl M, Gustafsson LL, et al. Methadone, ciprofloxacin, and adverse drug reactions. Lancet 2000; 356: 2069–70PubMedGoogle Scholar
  127. 127.
    Bertschy G, Baumann P, Eap CB, et al. Probable metabolic interaction between methadone and fluvoxamine in addict patients. Ther Drug Monit 1994; 16: 42–5PubMedGoogle Scholar
  128. 128.
    Alderman CP, Frith PA. Fluvoxamine-methadone interaction. Aust N Z J Psychiatry 1999; 33: 99–101PubMedGoogle Scholar
  129. 129.
    DeMaria PA Jr, Serota RD. A therapeutic use of the methadone fluvoxamine drug interaction. J Addict Dis 1999; 18: 5–12PubMedGoogle Scholar
  130. 130.
    Gram LF, Guentert TW, Grange S, et al. Moclobemide, a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6, and CYP1A2: a panel study. Clin Pharmacol Ther 1995; 57: 670–7PubMedGoogle Scholar
  131. 131.
    Reimann G, Barthel B, Rockstroh JK, et al. Effect of fusidic acid on the hepatic cytochrome P450 enzyme system. Int J Clin Pharmacol Ther 1999; 37: 562–6PubMedGoogle Scholar
  132. 132.
    Venkatakrishnan K, Greenblatt DJ, von Moltke LL, et al. Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP2C19 and 3A4. J Clin Pharmacol 1998; 38: 112–21PubMedGoogle Scholar
  133. 133.
    Borowsky SA, Lieber CS. Interaction of methadone and ethanol metabolism. J Pharmacol Exp Ther 1978; 207: 123–9PubMedGoogle Scholar
  134. 134.
    Kreek MJ. Metabolic interactions between opiates and alcohol. Ann N Y Acad Sci 1976; 281: 36–49Google Scholar
  135. 135.
    Iribarne C, Berthou F, Baird S, et al. Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes. Chem Res Toxicol 1996; 9: 365–73PubMedGoogle Scholar
  136. 136.
    Moody DE, Alburges ME, Parker RJ, et al. The involvement of cytochrome P450 3A4 in the N-demethylation of L-alpha-acetylmethadol (LAAM), norlaam, and methadone. Drug Metab Dispos 1997; 25: 1347–53PubMedGoogle Scholar
  137. 137.
    Foster DJ, Somogyi AA, Bochner F. Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4. Br J Clin Pharmacol 1999; 47: 403–12PubMedGoogle Scholar
  138. 138.
    Iribarne C, Picart D, Dreano Y, et al. In vitro interactions between fluoxetine or fluvoxamine and methadone or buprenorphine. Fundam Clin Pharmacol 1998; 12: 194–9PubMedGoogle Scholar
  139. 139.
    Lang F. Zur Umstellung von Polamidon auf Methadon. Berliner Tinke Magazin 1994; 5: 4–6Google Scholar
  140. 140.
    Charlier C, Dessalles MC, Plomteux G. Methadone maintenance treatment: is it possible to adapt the daily doses to the metabolic activity of the patient? Ther Drug Monit 2001; 23: 1–3PubMedGoogle Scholar
  141. 141.
    Hunt CM, Watkins PB, Saenger P, et al. Heterogeneity of CYP3A isoforms metabolizing erythromycin and cortisol. Clin Pharmacol Ther 1992; 51: 18–23PubMedGoogle Scholar
  142. 142.
    Boulton DW, Arnaud P, DeVane CL. A single dose of methadone inhibits cytochrome P-4503A activity in healthy volunteers as assessed by the urinary cortisol ratio. Br J Clin Pharmacol 2001; 51: 350–4PubMedGoogle Scholar
  143. 143.
    Shinderman M, Maxwell S, Brawand-Amey M, et al. Cytochrome P4503A4 metabolic activity, methadone blood concentrations, and methadone doses. Drug Alcohol Depend. In pressGoogle Scholar
  144. 144.
    Brown LS, Sawyer RC, Li R, et al. Lack of a pharmacologic interaction between rifabutin and methadone in HIV-infected former injecting drug users. Drug Alcohol Depend 1996; 43: 71–7PubMedGoogle Scholar
  145. 145.
    Wilkinson GR. Cytochrome P4503A (CYP3A) metabolism: prediction of in vivo activity in humans. J Pharmacokinet Biopharm 1996; 24: 475–90PubMedGoogle Scholar
  146. 146.
    Saxon AJ, Whittaker S, Hawker CS. Valproic acid, unlike other anticonvulsants, has no effect on methadone metabolism: two cases. J Clin Psychiatry 1989; 50: 228–9PubMedGoogle Scholar
  147. 147.
    Gourevitch MN, Friedland GH. Interactions between methadone and medications used to treat HIV infection: a review. Mt Sinai J Med 2000; 67: 429–36PubMedGoogle Scholar
  148. 148.
    Taburet AM, Singlas E. Drug interactions with antiviral drugs. Clin Pharmacokinet 1996; 30: 385–401PubMedGoogle Scholar
  149. 149.
    Trapnell CB, Klecker RW, Jamis-Dow C, et al. Glucuronidation of 3′-azido-3′-deoxythymidine (zidovudine) by human liver microsomes: relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and valproic acid. Antimicrob Agents Chemother 1998; 42: 1592–6PubMedGoogle Scholar
  150. 150.
    Sellers E, Lam R, McDowell J, et al. The pharmacokinetics (PK) of abacavir (ABC) and methadone (M) following coadministration [abstract]. Proceedings of the 39th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999; San FranciscoGoogle Scholar
  151. 151.
    Clarke SM, Mulcahy FM, Tjia J, et al. Pharmacokinetic interactions of nevirapine and methadone and guidelines for use of nevirapine to treat injection drug users. Clin Infect Dis 2001; 33: 1595–7PubMedGoogle Scholar
  152. 152.
    Eap CB. Comment: opiate withdrawal symptoms induced by antiretroviral drugs. Ann Pharmacother 2000; 34: 1077–8PubMedGoogle Scholar
  153. 153.
    Barry M, Gibbons S, Back D, et al. Protease inhibitors in patients with HIV disease: clinically important pharmacokinetic considerations. Clin Pharmacokinet 1997; 32: 194–209PubMedGoogle Scholar
  154. 154.
    Barry M, Mulcahy F, Merry C, et al. Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection. Clin Pharmacokinet 1999; 36: 289–304PubMedGoogle Scholar
  155. 155.
    Huang L, Wring SA, Woolley JL, et al. Induction of P-glycoprotein and cytochrome P450 3A by HIV protease inhibitors. Drug Metab Dispos 2001; 29: 754–60PubMedGoogle Scholar
  156. 156.
    Greenblatt DJ, von Moltke LL, Daily JP, et al. Extensive impairment of triazolam and alprazolam clearance by short-term low-dose ritonavir: the clinical dilemma of concurrent inhibition and induction. J Clin Psychopharmacol 1999; 19: 293–5PubMedGoogle Scholar
  157. 157.
    Beauverie P, Furlan V, Edel YA. Slow metabolism and long half-life of methadone in a patient with lung cancer and cirrohsis. Ann Med Interne 2001; 152 Suppl. 7: 50–2Google Scholar
  158. 158.
    Ketter TA, Flockhart DA, Post RM, et al. The emerging role of cytochrome P450 3A in psychopharmacology. J Clin Psychopharmacol 1995; 15: 387–98PubMedGoogle Scholar
  159. 159.
    Spaulding TC, Minium L, Kotake AN, et al. The effect of diazepam on the metabolism of methadone by the liver of methadone-dependent rats. Drug Metab Dispos 1974; 2: 458–63PubMedGoogle Scholar
  160. 160.
    Iribarne C, Dreano Y, Bardou LG, et al. Interaction of methadone with substrates of human hepatic cytochrome P450 3A4. Toxicology 1997; 117: 13–23PubMedGoogle Scholar
  161. 161.
    Bailey DG, Malcolm J, Arnold O, et al. Grapefruit juice-drug interactions. Br J Clin Pharmacol 1998; 46: 101–10PubMedGoogle Scholar
  162. 162.
    Eagling VA, Profit L, Back DJ. The effect of grapefruit juice constituents on the CYP3A4- mediated metabolism and P-glycoprotein-mediated transport of saquinavir [abstract]. Br J Clin Pharmacol 1999; 47: 593PGoogle Scholar
  163. 163.
    Sai Y, Dai R, Yang TJ, et al. Assessment of specificity of eight chemical inhibitors using cDNA-expressed cytochromes P450. Xenobiotica 2000; 30: 327–43PubMedGoogle Scholar
  164. 164.
    Mikus G, Somogyi AA, Bochner F, et al. Codeine O-demethylation: rat strain differences and the effects of inhibitors. Biochem Pharmacol 1991; 41: 757–62PubMedGoogle Scholar
  165. 165.
    Wu D, Otton SV, Sproule BA, et al. Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone. Br J Clin Pharmacol 1993; 35: 30–4PubMedGoogle Scholar
  166. 166.
    Kerry NL, Somogyi AA, Bochner F, et al. The role of CYP2D6 in primary and secondary oxidative metabolism of dextromethorphan: in vitro studies using human liver microsomes. Br J Clin Pharmacol 1994; 38: 243–8PubMedGoogle Scholar
  167. 167.
    Brøsen K, Hansen JG, Nielsen KK, et al. Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur J Clin Pharmacol 1993; 44: 349–55PubMedGoogle Scholar
  168. 168.
    Maany I, Dhopesh V, Arndt IO, et al. Increase in desipramine serum levels associated with methadone treatment. Am J Psychiatry 1989; 146: 1611–3PubMedGoogle Scholar
  169. 169.
    Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Human cytochromes and some newer antidepressants: kinetics, metabolism, and drug interactions. J Clin Psychopharmacol 1999; 19 Suppl. 1: 23S–35SPubMedGoogle Scholar
  170. 170.
    Yue QY, Svensson JO, Bertilsson L, et al. Racemic methadone kinetics in relation to the debrisoquine hydroxylation polymorphism in man [abstract 88]. Therapie (Suppl), Proceedings of the 1st Congress of the European Association for Clinical Pharmacology and Therapeutics; 1995; ParisGoogle Scholar
  171. 171.
    Eap CB, Broly F, Mino A, et al. Cytochrome P4502D6 genotype and methadone steady-state concentrations. J Clin Psychopharmacol 2000; 21: 229–34Google Scholar
  172. 172.
    Myers ED, Branthwaite A. Out-patient compliance with anti-depressant medication. Br J Psychiatry 1992; 160: 83–6PubMedGoogle Scholar
  173. 173.
    Tacke U, Wolff K, Finch E, et al. The effect of tobacco smoking on subjective symptoms of inadequacy (’not holding’) of methadone dose among opiate addicts in methadone maintenance treatment. Addict Biol 2001; 6: 137–45PubMedGoogle Scholar
  174. 174.
    Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors: an overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet 1997; 32 Suppl. 1: 1–21PubMedGoogle Scholar
  175. 175.
    Lieber CS. Biochemical and molecular basis of alcohol-induced injury to liver and other tissues. N Engl J Med 1988; 319: 1639–50PubMedGoogle Scholar
  176. 176.
    Tong TG, Benowitz NL, Kreek MJ. Methadone:disulfiram interaction during methadone maintenance. J Clin Pharmacol 1980; 10: 506–13Google Scholar
  177. 177.
    Hoffmeyer S, Burk O, von Richter O, et al. Functional polymorphisms of the human multidrug-resistant gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A 2000; 97: 3473–8PubMedGoogle Scholar
  178. 178.
    Ingelman-Sundberg M, Oscarson M, McLellan RA. Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment. Trends Pharmacol Sci 1999; 20: 342–9PubMedGoogle Scholar
  179. 179.
    Schweikl H, Taylor JA, Kitareewan S, et al. Expression of CYP1A1 and CYP1A2 genes in human liver. Pharmacogenetics 1993; 3: 239–49PubMedGoogle Scholar
  180. 180.
    Bertilsson L, Dahl ML, Sjoqvist F, et al. Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine [letter]. Lancet 1993; 341: 63PubMedGoogle Scholar
  181. 181.
    Conus P, Bondolfi G, Eap CB, et al. Pharmacokinetic fluvoxamine-clomipramine interaction with favorable therapeutic consequences in therapy-resistant depressive patient. Pharmacopsychiatry 1996; 29: 108–10PubMedGoogle Scholar
  182. 182.
    Baumann P, Broly F, Kosel M, et al. Ultrarapid metabolism of clomipramine in a therapy-resistant depressive patient, as confirmed by CYP2D6 genotyping [letter]. Pharmacopsychiatry 1998; 31: 72PubMedGoogle Scholar
  183. 183.
    Bender S, Eap CB. Very high cytochrome P4501A2 activity and nonresponse to clozapine. Arch Gen Psychiatry 1998; 55: 1048–50PubMedGoogle Scholar
  184. 184.
    Gamaleya N, Dmitrieva I, Borg S, et al. Induction of antibodies to methadone during methadone maintenance treatment of heroin addicts and its possible clinical implications. Eur J Pharmacol 1999; 369: 357–64PubMedGoogle Scholar
  185. 185.
    Gourlay GK, Willis RJ, Wilson PR. Postoperative pain control with methadone: influence of supplementary methadone doses and blood concentration-response relationships. Anesthesiology 1984; 61: 19–26PubMedGoogle Scholar
  186. 186.
    Gourlay GK, Willis RJ, Lamberty J. A double-blind comparison of the efficacy of methadone and morphine in postoperative pain control. Anesthesiology 1986; 64: 322–7PubMedGoogle Scholar
  187. 187.
    Inturrisi CE, Portenoy RK, Max MB, et al. Pharmacokinetic-pharmacodynamic relationships of methadone infusions in patients with cancer pain. Clin Pharmacol Ther 1990; 47: 565–77PubMedGoogle Scholar
  188. 188.
    Dyer KR, Foster DJ, White JM, et al. Steady-state pharmacokinetics and pharmacodynamics in methadone maintenance patients: comparison of those who do and do not experience withdrawal and concentration-effect relationships. Clin Pharmacol Ther 1999; 65: 685–94PubMedGoogle Scholar
  189. 189.
    Dyer KR, White JM, Foster DJ, et al. The relationship between mood state and plasma methadone concentration in maintenance patients. J Clin Psychopharmacol 2001; 21: 78–84PubMedGoogle Scholar
  190. 190.
    Bond C, LaForge KS, Tian M, et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci U S A 1998; 95: 9608–13PubMedGoogle Scholar
  191. 191.
    Lawford BR, Young RM, Noble EP, et al. The D2 dopamine receptor A1 allele and opioid dependence: association with heroin use and response to methadone treatment. Am J Med Genet 2000; 96: 592–8PubMedGoogle Scholar
  192. 192.
    Maldonado R, Saiardi A, Valverde O, et al. Absence of opiate rewarding effects in mice lacking dopamine D2 receptors. Nature 1997; 388: 586–9PubMedGoogle Scholar
  193. 193.
    Wolff K, Hay A. Methadone concentrations in plasma and their relationship to drug dosage. Clin Chem 1992; 38: 438–9PubMedGoogle Scholar
  194. 194.
    Eap CB, Bertschy G, Baumann P, et al. High interindividual variability of methadone enantiomer blood levels to dose ratios. Arch Gen Psychiatry 1998; 55: 89–90PubMedGoogle Scholar
  195. 195.
    Wolff K, Strang J. Therapeutic drug monitoring for methadone: scanning the horizon. Eur Addict Res 1999; 5: 36–42PubMedGoogle Scholar
  196. 196.
    Wolff K, Hay A, Raistrick D, et al. Measuring compliance in methadone maintenance patients: use of a pharmacologic indicator to ‘estimate’ methadone plasma levels. Clin Pharmacol Ther 1991; 50: 199–207PubMedGoogle Scholar
  197. 197.
    Holmstrand J, Anggard E, Gunne LM. Methadone maintenance: plasma levels and therapeutic outcome. Clin Pharmacol Ther 1978; 23: 175–80PubMedGoogle Scholar
  198. 198.
    Wolff K, Hay A, Raistrick D. High-dose methadone and the need for drug measurements in plasma. Clin Chem 1991; 37: 1651–64PubMedGoogle Scholar
  199. 199.
    Bell J, Seres V, Bowron P, et al. The use of serum methadone levels in patients receiving methadone maintenance. Clin Pharmacol Ther 1988; 43: 623–9PubMedGoogle Scholar
  200. 200.
    Tennant FS Jr. Inadequate plasma concentrations in some highdose methadone maintenance patients. Am J Psychiatry 1987; 144: 1349–50PubMedGoogle Scholar
  201. 201.
    Loimer N, Schmid R. The use of plasma levels to optimize methadone maintenance treatment. Drug Alcohol Depend 1992; 30: 241–6PubMedGoogle Scholar
  202. 202.
    Kell MJ. Utilization of plasma and urine methadone concentration measurements to limit narcotics use in methadone maintenance patients: II. generation of plasma concentration response curves. J Addict Dis 1995; 14: 85–108PubMedGoogle Scholar
  203. 203.
    Bell J, Bowron P, Lewis J, et al. Serum levels of methadone in maintenance clients who persist in illicit drug use. Br J Addict 1990; 85: 1599–602PubMedGoogle Scholar
  204. 204.
    Horns WH, Rado M, Goldstein A. Plasma levels and symptom complaints in patients maintained on daily dosage of methadone hydrochloride. Clin Pharmacol Ther 1975; 17: 636–49PubMedGoogle Scholar
  205. 205.
    Torrens M, Castillo C, San L, et al. Plasma methadone concentrations as an indicator of opioid withdrawal symptoms and heroin use in a methadone maintenance program. Drug Alcohol Depend 1998; 52: 193–200PubMedGoogle Scholar
  206. 206.
    Wolff K, Hay AW, Raistrick D. Plasma methadone measurements and their role in methadone detoxification programs. Clin Chem 1992; 38: 420–5PubMedGoogle Scholar
  207. 207.
    Loimer N, Schmid R, Grunberger J, et al. Psychophysiological reactions in methadone maintenance patients do not correlate with methadone plasma levels. Psychopharmacology (Berl) 1991; 103: 538–40Google Scholar
  208. 208.
    Borg L, Broe DM, Ho A, et al. Cocaine abuse sharply reduced in an effective methadone maintenance program. J Addict Dis 1999; 18: 63–75PubMedGoogle Scholar
  209. 209.
    Leavitt SB, Shinderman M, Maxwell S, et al. When ‘enough’ is not enough: new perspectives on optimal methadone maintenance dose. Mt Sinai J Med 2000; 67: 404–11PubMedGoogle Scholar
  210. 210.
    D’Aunno T, Folz-Murphy N, Lin X. Changes in methadone treatment practices: results from a panel study, 1988–1995. Am J Drug Alcohol Abuse 1999; 25: 681–99PubMedGoogle Scholar
  211. 211.
    D’Aunno T, Pollack HA. Changes in methadone treatment practices. Results from a national panel study, 1988–2000. JAMA 2002; 288: 850–6PubMedGoogle Scholar
  212. 212.
    Maxwell S, Shinderman MS. Optimizing long-term response to methadone maintenance treatment: a 152-week follow-up using higher-dose methadone. J Addict Dis 2002; 21: 1–12PubMedGoogle Scholar
  213. 213.
    Reisine T, Pasternak G. Opioid analgesics and antagonists. In: Hardman JG, Limbird LE, Goodman Gilman A, editors. Goodman & Gilman’s the pharmacological basis of therapeutics. New York: McGraw-Hill, 1996: 521–55Google Scholar
  214. 214.
    Commonwealth Department of Health and Aged Care. Proceedings of expert workshop on the induction and stabilisation of patients onto methadone: defining the nature of problem; 2000; Canberra, Australia: Commonwealth Department of Health, 2000Google Scholar
  215. 215.
    Drummer OH, Syrjanen M, Opeskin K, et al. Deaths of heroin addicts starting on a methadone maintenance programme [letter]. Lancet 1990; 335: 108PubMedGoogle Scholar
  216. 216.
    Reilly JG, Ayis SA, Ferrier IN, et al. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 2000; 355: 1048–52PubMedGoogle Scholar
  217. 217.
    Mathot F, Kurz X, Noël C, et al. Long QTc and psychotropic drugs use [abstract]. Int J Neuropsychopharmacol 2000; 3 Suppl. 1: P.02.18Google Scholar
  218. 218.
    European Agency for the Evaluation of Medicinal Products. Evaluation of medicines for human use. EMEA public statement on the recommendation to suspend the marketing authorisation for ORLAAM (levacetylmethadol) in the European Union. Available from URL: [Accessed 2002 Oct]
  219. 219.
    European Agency for the Evaluation of Medicinal Products, Human Medicines Evaluation Unit. EMEA public statement on levacetylmethadol (ORLAAM): life threatening cardiac rhythm disorders. EMEA 1999Google Scholar
  220. 220.
    European Agency for the Evaluation of Medicinal Products, Human Medicines Evaluation Unit. EMEA public statement on levacetylmethadol (ORLAAM): life threatening ventricular rhythm disorders. EMEA 2000.Google Scholar
  221. 221.
    Parrino MW. Interim guidelines for the continuation and initiation of LAAM maintenance treatment [memorandum]. New York: American Methadone Treatment Association, 2000Google Scholar
  222. 222.
    Mantelli L, Corti V, Bini R, et al. Effects of dl-methadone on the response to physiological transmitters and on several functional parameters of the isolated guinea-pig heart. Arch Int Pharmacody Ther 1986; 282: 298–313Google Scholar
  223. 223.
    Wu C, Henry JA. Interaction between ethanol and opioids in a protozoan assay. Hum Exp Toxicol 1994; 13: 145–8PubMedGoogle Scholar
  224. 224.
    Katchman AN, Ebert SN, McGroary KA, et al. Methadone blocks HERG current in transfected HEK cells [abstract LB253]. Proceedings of the American Society for Pharmacology and Experimental Therapeutics Conference, 2001Google Scholar
  225. 225.
    Bittar P, Piguet V, Oestreicher MK, et al. Methadone induced long ATc and “torsade de pointe” [abstract]. Forum Med Suisse 2002; Suppl. 8: 36SGoogle Scholar
  226. 226.
    Krantz MJ, Lewkowiez L, Hays H, et al. Torsade de pointes associated with very-high doses methadone. Ann Intern Med 2002; 137: 501–4PubMedGoogle Scholar
  227. 227.
    Viskin S. Long QT syndromes and torsade de pointes. Lancet 1999; 354: 1625–33PubMedGoogle Scholar
  228. 228.
    Pond SM, Kreek MJ, Tong TG, et al. Altered methadone pharmacokinetics in methadone-maintained pregnant women. J Pharmacol Exp Ther 1985; 233: 1–6PubMedGoogle Scholar
  229. 229.
    Rostami-Hodjegan A, Foster DJR, Charlier C, et al. Meta-analysis of the dose-concentration relationship for methadone and a nomogram to assess compliance and metabolic variability [abstract]. J Psychopharmacol 2001; 15(3): A35Google Scholar
  230. 230.
    Strang J, Sheridan J, Barber N. Prescribing injectable and oral methadone to opiate addicts: results from the 1995 national postal survey of community pharmacies in England and Wales. BMJ 1996; 313: 270–2PubMedGoogle Scholar
  231. 231.
    Darke S, Ross J, Hall W. Prevalence and correlates of the injection of methadone syrup in Sydney, Australia. Drug Alcohol Depend 1996; 43: 191–8PubMedGoogle Scholar
  232. 232.
    Lintzeris N, Lenne M, Ritter A. Methadone injecting in Australia: a tale of two cities. Addiction 1999; 94: 1175–8PubMedGoogle Scholar
  233. 233.
    Waldvogel D, Uehlinger C. Zur Häufigkeit der Injektion von Methadon-Trinklösung an einem Behandlungszentrum für Opiatabhängige. Fortschr Neurol Psychiatr 1999; 67: 281–3PubMedGoogle Scholar
  234. 234.
    Felder C, Uehlinger C, Baumann P, et al. Oral and intravenous methadone use: some clinical and pharmacokinetic aspects. Drug Alcohol Depend 1999; 55: 137–43PubMedGoogle Scholar
  235. 235.
    Quinn DI, Wodak A, Day RO. Pharmacokinetic and pharmacodynamic principles of illicit drug use and treatment of illicit drug users. Clin Pharmacokinet 1997; 33: 344–400PubMedGoogle Scholar
  236. 236.
    Eap CB, Felder C, Powell-Golay K, et al. Increase of oral methadone dose in methadone injecting patients: a pilot study. J Addict Dis. In pressGoogle Scholar

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© Adis International Limited 2002

Authors and Affiliations

  1. 1.Unit of Biochemistry and Clinical PsychopharmacologyUniversity Department of Adult Psychiatry, Cery HospitalPrilly-LausanneSwitzerland
  2. 2.Division of Clinical PharmacologyLausanne University HospitalLausanneSwitzerland

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