Clinical pharmacology of methadone for pain

Acta Anaesthesiologica Scandinavica

Volumn 52, Issue 7, 2008, Pages 879-889

  Fredheim, O M S ^a,b,c   Moksnes, K ^b   Borchgrevink, P C ^a,b   Kaasa, S ^a,b   Dale, O ^a,b  

^a TRONDHEIM UNIVERSITY HOSPITAL   (Norway)

^b NORWEGIAN UNIVERSITY OF SCIENCE AND TECHNOLOGY   (Norway)

^c Sandnessjoen Hospital   (Norway)

Author keywords

Chronic pain; Methadone; Palliative medicine; Pharmacology; QTc time

Indexed keywords

AMITRIPTYLINE; BARBITURIC ACID DERIVATIVE; CARBAMAZEPINE; CIPROFLOXACIN; CLOMIPRAMINE; CYTOCHROME P450 2B6; CYTOCHROME P450 3A4; DACTINOMYCIN; DOXORUBICIN; FLUCONAZOLE; FLUOXETINE; FLUVOXAMINE; GLUCOCORTICOID; HALOPERIDOL; LEVOMEPROMAZINE; MACROLIDE; METHADONE; MORPHINE; NEFAZODONE; NORFLUOXETINE; OLANZAPINE; OPIATE; PAROXETINE; PHENYTOIN; SERTRALINE; THIOPENTAL; VENLAFAXINE; VINBLASTINE;

ANALGESIA; CANCER PAIN; CHRONIC PAIN; DRUG BIOAVAILABILITY; DRUG DISTRIBUTION; DRUG HALF LIFE; DRUG METABOLISM; DRUG SUBSTITUTION; DRUG WITHDRAWAL; HUMAN; PAIN ASSESSMENT; PHARMACOGENETICS; PRIORITY JOURNAL; QT INTERVAL; QT PROLONGATION; RESPIRATION DEPRESSION; REVIEW; SEDATION; SIDE EFFECT; TORSADE DES POINTES;

ANALGESICS, OPIOID; ARRHYTHMIAS, CARDIAC; CHRONIC DISEASE; CLINICAL TRIALS AS TOPIC; DRUG INTERACTIONS; HUMANS; METHADONE; PAIN; PALLIATIVE CARE;

EID: 46749083807     PISSN: 00015172     EISSN: 13996576     Source Type: Journal    
DOI: 10.1111/j.1399-6576.2008.01597.x     Document Type: Review

References (95)

1. Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database Syst Rev 2004 CD004847.
2. Nicholson AB. Methadone for cancer pain. Cochrane Database Syst Rev 2004 CD003971.
3. Herrlin K, Segerdahl M, Gustafsson LL et al. Methadone, ciprofloxacin, and adverse drug reactions. Lancet 2000 356 : 2069 70.
4. Dale O, Hoffer C, Sheffels P et al. Disposition of nasal, intravenous, and oral methadone in healthy volunteers. Clin Pharmacol Ther 2002 72 : 536 45.
5. Gourlay GK, Cherry DA, Cousins MJ. 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 : 297 312.
6. 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 8.
7. Dale O, Sheffels P, Kharasch ED. Bioavailabilities of rectal and oral methadone in healthy subjects. Br J Clin Pharmacol 2004 58 : 156 62.
8. Nilsson MI, Meresaar U, Anggard E. Clinical pharmacokinetics of methadone. Acta Anaesthesiol Scand 1982 74 (Suppl.) : 66 9.
9. Inturrisi CE, Colburn WA, Kaiko RF et al. Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain. Clin Pharmacol Ther 1987 41 : 392 401.
10. Eap CB, Cuendet C, Baumann P. Binding of d-methadone, l-methadone, and dl-methadone to proteins in plasma of healthy volunteers: role of the variants of alpha 1-acid glycoprotein. Clin Pharmacol Ther 1990 47 : 338 46.
11. Ferrari A, Coccia CP, Bertolini A et al. Methadone - metabolism, pharmacokinetics and interactions. Pharmacol Res 2004 50 : 551 9.
12. Kristensen K, Christensen CB, Christrup LL. The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci 1995 56 : L45 50.
13. Gorman AL, Elliott KJ, Inturrisi CE. 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 8.
14. Thompson SJ, Koszdin K, Bernards CM. Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology 2000 92 : 1392 9.
15. Schinkel AH. The physiological function of drug-transporting P-glycoproteins. Semin Cancer Biol 1997 8 : 161 70.
16. Kharasch ED, Hoffer C, Whittington D. The effect of quinidine, used as a probe for the involvement of P-glycoprotein, on the intestinal absorption and pharmacodynamics of methadone. Br J Clin Pharmacol 2004 57 : 600 10.
17. 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 73.
18. Kharasch ED, Hoffer C, Whittington D et al. Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone. Clin Pharmacol Ther 2004 76 : 250 69.
19. 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 presystemic clearance and bioactivation. J Pharmacol Exp Ther 2001 298 : 1021 32.
20. 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 12.
21. Nilsson MI, Widerlov E, Meresaar U et al. Effect of urinary pH on the disposition of methadone in man. Eur J Clin Pharmacol 1982 22 : 337 42.
22. 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 52.
23. Foster DJ, Somogyi AA, White JM et al. Population pharmacokinetics of (R)-, (S)- and rac-methadone in methadone maintenance patients. Br J Clin Pharmacol 2004 57 : 742 55.
24. Foster DJ, 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 40.
25. Holmstrand J, Anggard E, Gunne LM. Methadone maintenance: plasma levels and therapeutic outcome. Clin Pharmacol Ther 1978 23 : 175 80.
26. 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 9.
27. Anggard E, Gunne LM, Homstrand J et al. Disposition of methadone in methadone maintenance. Clin Pharmacol Ther 1975 17 : 258 66.
28. Sawe J. High-dose morphine and methadone in cancer patients. Clinical pharmacokinetic considerations of oral treatment. Clin Pharmacokinet 1986 11 : 87 106.
29. Fredheim OM, Borchgrevink PC, Klepstad P et al. Long term methadone for chronic pain: a pilot study of pharmacokinetic aspects. Eur J Pain 2007 11 : 599 604.
30. Balayssac D, Authier N, Cayre A et al. Does inhibition of P-glycoprotein lead to drug-drug interactions? Toxicol Lett 2005 156 : 319 29.
31. Al-Khatib SM, LaPointe NM, Kramer JM et al. What clinicians should know about the QT interval. JAMA 2003 289 : 2120 7.
32. Haddad A, Davis M, Lagman R. The pharmacological importance of cytochrome CYP3A4 in the palliation of symptoms: review and recommendations for avoiding adverse drug interactions. Support Care Cancer 2007 15 : 251 7.
33. Begre S, von BU, 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 5.
34. Westphal JF. Macrolide-induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin. Br J Clin Pharmacol 2000 50 : 285 95.
35. Hersh EV, Moore PA. Drug interactions in dentistry: the importance of knowing your CYPs. J Am Dent Assoc 2004 135 : 298 311.
36. Davis R, Markham A, Balfour JA. Ciprofloxacin. An updated review of its pharmacology, therapeutic efficacy and tolerability. Drugs 1996 51 : 1019 74.
37. Aminimanizani A, Beringer P, Jelliffe R. Comparative pharmacokinetics and pharmacodynamics of the newer fluoroquinolone antibacterials. Clin Pharmacokinet 2001 40 : 169 87.
38. Eap CB, Broly F, Mino A et al. Cytochrome P450 2D6 genotype and methadone steady-state concentrations. J Clin Psychopharmacol 2001 21 : 229 34.
39. Crettol S, Deglon JJ, Besson J et al. Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment. Clin Pharmacol Ther 2005 78 : 593 604.
40. Lotsch J, Skarke C, Wieting J et al. Modulation of the central nervous effects of levomethadone by genetic polymorphisms potentially affecting its metabolism, distribution, and drug action. Clin Pharmacol Ther 2006 79 : 72 89.
41. Coller JK, Barratt DT, Dahlen K et al. ABCB1 genetic variability and methadone dosage requirements in opioid-dependent individuals. Clin Pharmacol Ther 2006 80 : 682 90.
42. Crettol S, Deglon JJ, Besson J et al. ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment. Clin Pharmacol Ther 2006 80 : 668 81.
43. Hanks GW, Conno F, Cherny N et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 2001 84 : 587 93.
44. Fisher K, Stiles C, Hagen NA. Characterization of the early pharmacodynamic profile of oral methadone for cancer-related breakthrough pain: a pilot study. J Pain Symptom Managem 2004 28 : 619 25.
45. Moryl N, Kogan M, Comfort C et al. Methadone in the treatment of pain and terminal delirum in advanced cancer patients. Palliat Support Care 2005 3 : 311 7.
46. Hays H, Woodroffe MA. Use of methadone in treating chronic noncancer pain. Pain Res Manag 1999 4 : 23 7.
47. Quang-Cantagrel ND, Wallace MS, Magnuson SK. Opioid substitution to improve the effectiveness of chronic noncancer pain control: a chart review. Anesth Analg 2000 90 : 933 7.
48. Thomsen AB, Becker N, Eriksen J. Opioid rotation in chronic non-malignant pain patients. A retrospective study. Acta Anaesthesiol Scand 1999 43 : 918 23.
49. Gardner-Nix JS. Oral methadone for managing chronic nonmalignant pain. J Pain Symptom Manage 1996 11 : 321 8.
50. Moulin DE, Palma D, Watling C et al. Methadone in the management of intractable neuropathic noncancer pain. Can J Neurol Sci 2005 32 : 340 3.
51. Altier N, Dion D, Boulanger A et al. Successful use of methadone in the treatment of chronic neuropathic pain arising from burn injuries: a case-study. Burns 2001 27 : 771 5.
52. Fredheim OM, Kaasa S, Dale O et al. Opioid switching from oral slow release morphine to oral methadone may improve pain control in chronic non-malignant pain: a nine-month follow-up study. Palliat Med 2006 20 : 35 41.
53. Altier N, Dion D, Boulanger A et al. Management of chronic neuropathic pain with methadone: a review of 13 cases. Clin J Pain 2005 21 : 364 9.
54. Morley JS, Bridson J, Nash TP et al. Low-dose methadone has an analgesic effect in neuropathic pain: a double-blind randomized controlled crossover trial. Palliat Med 2003 17 : 576 87.
55. Dworkin RH, Turk DC, Farrar JT et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 2005 113 : 9 19.
56. Farrar JT, Young JP Jr., LaMoreaux L et al. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 2001 94 : 149 58.
57. Rhodin A, Gronbladh L, Nilsson LH et al. Methadone treatment of chronic non-malignant pain and opioid dependence - A long-term follow-up. Eur J Pain 2006 10 : 271 8.
58. Arnaert A, Ciccotosto G. Response phases in methadone treatment for chronic nonmalignant pain. Pain Manag Nurs 2006 7 : 23 30.
59. Bruera E, Watanabe S, Fainsinger RL et al. Custom-made capsules and suppositories of methadone for patients on high-dose opioids for cancer pain. Pain 1995 62 : 141 6.
60. Bruera E, Fainsinger R, Moore M et al. Local toxicity with subcutaneous methadone. Experience of two centers. Pain 1991 45 : 141 3.
61. Mercadante S, Bruera E. Opioid switching: a systematic and critical review. Cancer Treat Rev 2006 32 : 304 15.
62. Lawlor PG, Turner KS, Hanson J et al. Dose ratio between morphine and methadone in patients with cancer pain: a retrospective study. Cancer 1998 82 : 1167 73.
63. Ripamonti C, Zecca E, Bruera E. An update on the clinical use of methadone for cancer pain. Pain 1997 70 : 109 15.
64. Mercadante S, Casuccio A, Calderone L. Rapid switching from morphine to methadone in cancer patients with poor response to morphine. J Clin Oncol 1999 17 : 3307 12.
65. Mercadante S, Bianchi M, Villari P et al. Opioid plasma concentration during switching from morphine to methadone: preliminary data. Support Care Cancer 2003 11 : 326 31.
66. Hagen NA, Wasylenko E. Methadone: outpatient titration and monitoring strategies in cancer patients. J Pain Symptom Manage 1999 18 : 369 75.
67. Tse DM, Sham MM, Ng DK et al. An ad libitum schedule for conversion of morphine to methadone in advanced cancer patients: an open uncontrolled prospective study in a Chinese population. Palliat Med 2003 17 : 206 11.
68. Ettinger DS, Vitale PJ, Trump DL. Important clinical pharmacologic considerations in the use of methadone in cancer patients. Cancer Treat Rep 1979 63 : 457 9.
69. Hernansanz S, Gutierrez C, Rubiales AS et al. Opioid rotation to methadone at home. J Pain Symptom Manage 2006 31 : 2 4.
70. Hunt G, Bruera E. Respiratory depression in a patient receiving oral methadone for cancer pain. J Pain Symptom Manage 1995 10 : 401 4.
71. Watanabe S, Tarumi Y, Oneschuk D et al. Opioid rotation to methadone: proceed with caution. J Clin Oncol 2002 20 : 2409 10.
72. Schug SA, Gandham N. Opioids: clinical use, 4th edn. 2005 : 443 57.
73. Hanks G, Cherny N, Fallon M. Opioid analgeix therapy, 3rd edn. 2004 : 316 41.
74. Gagnon B, Bruera E. Differences in the ratios of morphine to methadone in patients with neuropathic pain versus non-neuropathic pain. J Pain Symptom Manage 1999 18 : 120 5.
75. Ripamonti C, de CF, Groff L et al. Equianalgesic dose/ratio between methadone and other opioid agonists in cancer pain: comparison of two clinical experiences. Ann Oncol 1998 9 : 79 83.
76. Ripamonti C, Groff L, Brunelli C et al. Switching from morphine to oral methadone in treating cancer pai: what is the equianalgesic dose ratio? J Clin Oncol 1998 16 : 3216 21.
77. Anderson R, Saiers JH, Abram S et al. Accuracy in equianalgesic dosing. Conversion dilemmas. J Pain Symptom Manage 2001 21 : 397 406.
78. de Vos JW, Geerlings PJ, van den BW et al. Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts. Eur J Clin Pharmacol 1995 48 : 361 6.
79. 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 90.
80. Viskin S. Long QT syndromes and torsade de pointes. Lancet 1999 354 : 1625 33.
81. Krantz MJ, Lewkowiez L, Hays H et al. Torsade de pointes associated with very-high-dose methadone. Ann Intern Med 2002 137 : 501 4.
82. Hays H. High dosing methadone and a possible relationship to serious cardia arrhythmias. Pain Res Manag 2001 6 : 64.
83. Gil M, Sala M, Anguera I et al. QT prolongation and Torsades de Pointes in patients infected with human immunodeficiency virus and treated with methadone. Am J Cardiol 2003 92 : 995 7.
84. Walker PW, Klein D, Kasza L. High dose methadone and ventricular arrhythmias: a report of three cases. Pain 2003 103 : 321 4.
85. Ostvold C, Topper M. Methadone-induced heart arrhythmia. Tidsskr Nor Laegeforen 2005 125 : 2021 2.
86. Sanchez Hernandez AM, Atienza FF, Arenal MA et al. Torsades de pointes during methadone treatment. Rev Esp Cardiol 2005 58 : 1230 2.
87. Cruciani RA, Sekine R, Homel P et al. Measurement of QTc in patients receiving chronic methadone therapy. J Pain Symptom Manage 2005 29 : 385 91.
88. Kornick CA, Kilborn MJ, Santiago-Palma J et al. QTc interval prolongation associated with intravenous methadone. Pain 2003 105 : 499 506.
89. Maremmani I, Pacini M, Cesaroni C et al. QTc interval prolongation in patients on long-term methadone maintenance therapy. Eur Addict Res 2005 11 : 44 9.
90. Reddy S, Fisch M, Bruera E. Oral methadone for cancer pain: no indication of QT interval prolongation or torsades de pointes. J Pain Symptom Manage 2004 28 : 301 3.
91. Martell BA, Arnsten JH, Krantz MJ et al. Impact of methadone treatment on cardiac repolarization and conduction in opioid users. Am J Cardiol 2005 95 : 915 8.
92. Krantz MJ, Lowery CM, Martell BA et al. Effects of methadone on QT-interval dispersion. Pharmacotherapy 2005 25 : 1523 9.
93. Fredheim OM, Borchgrevink PC, Hegrenaes L et al. Opioid switching from morphine to methadone causes a minor but not clinically significant increase in QTc time: a prospective 9-month follow-up study. J Pain Symptom Manage 2006 32 : 180 5.
94. Krantz MJ, Kutinsky IB, Robertson AD et al. Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy 2003 23 : 802 5.
95. Chiang CE, Roden DM. The long QT syndromes: genetic basis and clinical implications. J Am Coll Cardiol 2000 36 : 1 12.