海洛因是一種在生理及社會等各方面影響人體的鴉片類成癮物質。美沙冬 (Methadone) 是一種被用來治療海洛因成癮的合成鴉片類藥品。到目前為止美沙冬治療鴉片成癮的療效已有許多文獻證明。但是美沙冬劑量與血中濃度的關係在個體之間變化相當大，也造成治療上的困難。尿液酸鹼值及代謝酵素基因變異等因子都被證明會影響美沙冬劑量與血中濃度的關係。Dextromethorphan是另一種被證明過可以改善鴉片成癮患者的戒斷症狀、渴藥行為的藥物。本研究主要目的即在探討影響美沙冬劑量與血中濃度關係之個體間差異的可能因子以及美沙冬劑量或血中濃度與治療之副作用及戒除海洛因使用間的相關性。此外亦評估外加dextromethorphan是否能改善美沙冬治療海洛因成癮的效果。
從2007年12月起，70位符合收案標準的海洛因成癮者除接受美沙冬替代治療並依隨機分配外加使用dextromethorphan 60 mg, 120 mg或者是安慰劑。我們利用HPLC分析病患血液中的美沙冬與dextromethorphan濃度，同時測量其他如尿液酸鹼值、體脂肪、體重、每日美沙冬劑量、代謝基因變異等影響美沙冬血中濃度的因子。我們發現在研究個案中有9%的病患感染人類免疫不全病毒、77% 感染C型肝炎病毒。每日使用美沙冬平均劑量為50 mg、平均血中濃度為250 ng/mL。美沙冬血中濃度與劑量及鴉片成癮年數有統計學上顯著的相關，與尿液酸鹼值、體脂肪、體重、代謝基因ABCB1C3435T、ABCB1G2677T及CYP2D6*10變異無顯著相關。美沙冬血中濃度與心悸、心律不整、便秘等副作用有顯著統計學上之正相關。此外，外加dextromethorphan可能增加戒除海洛因的機率 (53.8% v.s. 73.5%, p=0.0604)，且可顯著降低美沙冬替代治療特定之副作用。
在本研究發現受試者中有相當高比例的人類免疫不全病毒感染率，這樣的資料指出美沙冬替代療法在台灣的重要性。我們在尋找美沙冬劑量與血中濃度關係時，無法在本研究當中再現其他文獻證實的因子，但發現美沙冬濃度與鴉片成癮年數間有相關性存在。我們也發現美沙冬血中濃度相較於劑量是一個比較好的參考因子。最後，外加dextromethorphan對於海洛因使用的減少似有幫助，同時可以改善美沙冬替代治療對認知功能之影響。

Heroin is a problematic opioid substance that affecting human in various aspects. Methadone is a synthetic opioid used to treat opioid dependence. The effect of methadone on opoid dependence treatment has been proved in literatures and, however, the relationship between methadone dosage and blood concentration (CMTD) were highly varied. Urine pH and genetic variations in metabolism enzymes were factors which have been demonstrated affecting the relationship between methadone dosage and CMTD. Dextromethorphan is an old antitussive agent which has been reported as an effective agent in improving symptoms of dependence, reduce craving behavior. Objectives of this study are evaluating the factors affecting inter-individual relationship between methadone dosage and CMTD and evaluating the factors predicting side effect and heroin abstinence. In additional to that, we also investigated whether dextromethorphan add-on to methadone could improve outcomes or not.
Seventy patients who met inclusion criteria were recruited and randomized to receive dextromethorphan 120 mg, 60 mg or placebo based on methadone maintenance therapy in NCKUH since December 2007. We measured the blood concentration of dextromethorphan and methadone with HPLC and other factors which may affect blood concentration, such as urine pH, body fat, body weight, daily methadone dosage, CYP enzyme genetic variations. We found a 9% of HIV and 77% of HCV infected patients in our population. Fifty mg methadone per day and 250ng/mL of CMTD on average was observed. The CMTD and methadone dosage significantly correlated with heroin dependence history and did not correlate with urine pH, body fat, body weight, ABCB1C3435T, ABCB1G2677T and CYP2D6*10 variations. CMTD was positively correlated with side effects such as palpitation, arrhythmia and constipation. In additional to that, dextromethorphan add-on therapy showed a marginal significant reduction in urine morphine test positive rate (53.8% v.s. 73.5%, p=0.0604) and improvement in side effects complaints.
In this study, we shown a high prevalence of HIV infected patients in our population and that revealed the significant of methadone maintenance therapy in Taiwan. We failed to show the relationship between methadone dosage and CMTD which have been demonstrated in literatures and however we shown a correlation between CMTD and heroin dependence history. We also found methadone CMTD could be a better parameter in predicting self-reported side effects, such as palpitation, arrhythmia and constipation. Finally, dextromethorphan add-on therapy may reduce heroin use and significantly improve psychological side effect complaints.

1. World Drug Report 2007. (Accessed Nov., 2007, at
2. Maurer HH, Sauer C, Theobald DS. Toxicokinetics of drugs of abuse: current knowledge of the isoenzymes involved in the human metabolism of tetrahydrocannabinol, cocaine, heroin, morphine, and codeine. Ther Drug Monit 2006;28:447-53.
3. Selley DE, Cao CC, Sexton T, Schwegel JA, Martin TJ, Childers SR. mu Opioid receptor-mediated G-protein activation by heroin metabolites: evidence for greater efficacy of 6-monoacetylmorphine compared with morphine. Biochem Pharmacol 2001;62:447-55.
4. Brown R. Heroin dependence. Wmj 2004;103:20-6.
5. Nutt D, King LA, Saulsbury W, Blakemore C. Development of a rational scale to assess the harm of drugs of potential misuse. The Lancet 2007;369:1047-53.
6. Sporer KA. Acute heroin overdose. Annals of Internal Medicine 1999;130:584.
7. Baozhang T, Kaining Z, Jinxing K, et al. Infection with human immunodeficiency virus and hepatitis viruses in Chinese drug addicts. Epidemiol Infect 1997;119:343-7.
8. Ruan Y, Qin G, Yin L, et al. Incidence of HIV, hepatitis C and hepatitis B viruses among injection drug users in southwestern China: a 3-year follow-up study. Aids 2007;21 Suppl 8:S39-46.
9. Liao KF, Peng CY, Lai SW, Chang WL, Hsu NY. Descriptive epidemiology of hepatitis C virus among male heroin abusers in Taiwan. South Med J 2006;99:348-51.
10. Mark TL, Woody GE, Juday T, Kleber HD. The economic costs of heroin addiction in the United States. Drug and Alcohol Dependence 2001;61:195-206.
11. Aceijas C, Stimson GV, Hickman M, Rhodes T. Global overview of injecting drug use and HIV infection among injecting drug users. Aids 2004;18:2295-303.
12. Miller CL, Strathdee SA, Li K, Kerr T, Wood E. A longitudinal investigation into excess risk for blood-borne infection among young injection drug users (IUDs). Am J Drug Alcohol Abuse 2007;33:527-36.
13. Chiang SC, Chen CY, Chang YY, Sun HJ, Chen WJ. Prevalence of heroin and methamphetamine male users in the northern Taiwan, 1999-2002: capture-recapture estimates. BMC Public Health 2007;7:292.
14. 藥物濫用資料暨檢驗統計資料. (Accessed 2008, Jan, at
15. . (Accessed 4/29, 2008, at http://www.moj.gov.tw/site/moj/public/MMO/moj/stat/new/newtxt5.pdf.)
16. Hymes K, Greene J, Marcus A, et al. KAPOSI'S SARCOMA IN HOMOSEXUAL MEN--A REPORT OF EIGHT CASES. The Lancet 1981;318:598-600.
17. 衛生署疾病管制局.
18. Chen Y-MA, Kuo SH-S. HIV-1 in Taiwan. Lancet 2007;369:623-5.
19. Hutchinson AB, Farnham PG, Dean HD, et al. The economic burden of HIV in the United States in the era of highly active antiretroviral therapy: evidence of continuing racial and ethnic differences. J Acquir Immune Defic Syndr 2006;43:451-7.
20. Shiing-Jer T, Yen-Fang H, An-Chi L, Nai M, Ih-Jen S. Updateand Projection on HIV/AIDS in Taiwan. AIDS Education & Prevention 2004;16:53-63.
21. Harm Reduction Coalition, . (Accessed 2008/0517, at http://www.harmreduction.org/index.php.)
22. UNAIDS. AIDS epidemic update; 2007.
23. WHO. Effectiveness of Sterile Needle and Syringe Programming in Reducing HIV/AIDS among Injecting Drug Users. Geneva; 2004.
24. Bravo MJ, Royuela L, Barrio G, de la Fuente L, Suarez M, Teresa Brugal M. More free syringes, fewer drug injectors in the case of Spain. Soc Sci Med 2007;65:1773-8.
25. Huo D, Bailey SL, Ouellet LJ. Cessation of injection drug use and change in injection frequency: the Chicago Needle Exchange Evaluation Study. Addiction 2006;101:1606-13.
26. Joseph H, Stancliff S, Langrod J. Methadone maintenance treatment (MMT): a review of historical and clinical issues. Mt Sinai J Med 2000;67:347-64.
27. Isbell H, Vogel VH. The addiction liability of methadon (amidone, dolophine, 10820) and its use in the treatment of the morphine abstinence syndrome. Am J Psychiatry 1949;105:909-14.
28. Davis AM, Inturrisi CE. d-Methadone Blocks Morphine Tolerance and N-Methyl-D-Aspartate-Induced Hyperalgesia. J Pharmacol Exp Ther 1999;289:1048-53.
29. Garrido MJ, Troconiz IF. Methadone: a review of its pharmacokinetic/pharmacodynamic properties. J Pharmacol Toxicol Methods 1999;42:61-6.
30. Bisaga A, Popik P. In search of a new pharmacological treatment for drug and alcohol addiction: N-methyl--aspartate (NMDA) antagonists. Drug and Alcohol Dependence 2000;59:1-15.
31. Chaturvedi K, Shahrestanifar M, Howells RD. [mu] Opioid receptor: role for the amino terminus as a determinant of ligand binding affinity. Molecular Brain Research 2000;76:64-72.
32. Saidak Z, Blake-Palmer K, Hay DL, Northup JK, Glass M. Differential activation of G-proteins by mu-opioid receptor agonists. Br J Pharmacol 2006;147:671-80.
33. Blake AD, Bot G, Freeman JC, Reisine T. Differential opioid agonist regulation of the mouse mu opioid receptor. J Biol Chem 1997;272:782-90.
34. 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.
35. Inturrisi CE, Verebely K. Disposition of methadone in man after a single oral dose. Clin Pharmacol Ther 1972;13:923-30.
36. Wolff K, Hay AW, Raistrick D, Calvert R. Steady-state pharmacokinetics of methadone in opioid addicts. Eur J Clin Pharmacol 1993;44:189-94.
37. Ferrari A, Coccia CP, Bertolini A, Sternieri E. Methadone--metabolism, pharmacokinetics and interactions. Pharmacol Res 2004;50:551-9.
38. Boulton DW, Arnaud P, DeVane CL. Pharmacokinetics and pharmacodynamics of methadone enantiomers after a single oral dose of racemate. Clin Pharmacol Ther 2001;70:48-57.
39. 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.
40. Eap CBP, Broly FMDP, Mino AMD, et al. Cytochrome P450 2D6 Genotype and Methadone Steady-State Concentrations. Journal of Clinical Psychopharmacology 2001;21:229-34.
41. Gerber JG, Rhodes RJ, Gal J. Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19. Chirality 2004;16:36-44.
42. 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;23:1-3.
43. Coller JK, Barratt DT, Dahlen K, Loennechen MH, Somogyi AA. ABCB1 genetic variability and methadone dosage requirements in opioid-dependent individuals. Clin Pharmacol Ther 2006;80:682-90.
44. Launay-Vacher V, Izzedine H, Karie S, Hulot JS, Baumelou A, Deray G. Renal tubular drug transporters. Nephron Physiol 2006;103:97-106.
45. Somogyi AA, Barratt DT, Coller JK. Pharmacogenetics of opioids. Clin Pharmacol Ther 2007;81:429-44.
46. Lin JH, Yamazaki M. Clinical Relevance of P-Glycoprotein in Drug Therapy. Drug Metabolism Reviews 2003;35:417-54.
47. Verebely K, Volavka J, Mule S, Resnick R. Methadone in man: pharmacokinetic and excretion studies in acute and chronic treatment. Clin Pharmacol Ther 1975;18:180-90.
48. Amato L, Davoli M, C AP, Ferri M, Faggiano F, R PM. An overview of systematic reviews of the effectiveness of opiate maintenance therapies: available evidence to inform clinical practice and research. J Subst Abuse Treat 2005;28:321-9.
49. Mattick R, Kimber J, Breen C, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev 2008:CD002207.
50. Soyka M, Zingg C, Koller G, Kuefner H. Retention rate and substance use in methadone and buprenorphine maintenance therapy and predictors of outcome: results from a randomized study. Int J Neuropsychopharmacol 2008:1-13.
51. Anglin MD, Conner BT, Annon J, Longshore D. Levo-alpha-acetylmethadol (LAAM) versus methadone maintenance: 1-year treatment retention, outcomes and status. Addiction 2007;102:1432-42.
52. Longshore D, Annon J, Anglin MD, Rawson RA. Levo-alpha-acetylmethadol (LAAM) versus methadone: treatment retention and opiate use. Addiction 2005;100:1131-9.
53. Clark N, Lintzeris N, Gijsbers A, et al. LAAM maintenance vs methadone maintenance for heroin dependence. In: Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2002.
54. Ferri M, Davoli M, Perucci CA. Heroin maintenance for chronic heroin dependents. In: Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2005.
55. 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.
56. Faggiano F, Vigna-Taglianti F, Versino E, Lemma P. Methadone maintenance at different dosages for opioid dependence. Cochrane Database Syst Rev 2003:CD002208.
57. Tennant FS, Jr., Rawson RA, Cohen A, Tarver A, Clabough D. Methadone plasma levels and persistent drug abuse in high dose maintenance patients. Subst Alcohol Actions Misuse (Alcohol And Drug Research) 1983;4:369-74.
58. Loimer N, Schmid R. The use of plasma levels to optimize methadone maintenance treatment. Drug Alcohol Depend 1992;30:241-6.
59. Bell J, Seres V, Bowron P, Lewis J, Batey R. The use of serum methadone levels in patients receiving methadone maintenance. Clin Pharmacol Ther 1988;43:623-9.
60. 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;61:47-54.
61. Hallinan R, Ray J, Byrne A, Agho K, Attia J. Therapeutic thresholds in methadone maintenance treatment: a receiver operating characteristic analysis. Drug Alcohol Depend 2006;81:129-36.
62. Strain EC, Bigelow GE, Liebson IA, Stitzer ML. Moderate- vs High-Dose Methadone in the Treatment of Opioid Dependence: A Randomized Trial. Jama 1999;281:1000-5.
63. Sees KL, Delucchi KL, Masson C, et al. Methadone maintenance vs 180-day psychosocially enriched detoxification for treatment of opioid dependence: a randomized controlled trial. Jama 2000;283:1303-10.
64. Masson CL, Barnett PG, Sees KL, et al. Cost and cost-effectiveness of standard methadone maintenance treatment compared to enriched 180-day methadone detoxification. Addiction 2004;99:718-26.
65. Gruber VA, Delucchi KL, Kielstein A, Batki SL. A randomized trial of 6-month methadone maintenance with standard or minimal counseling versus 21-day methadone detoxification. Drug Alcohol Depend 2008;94:199-206.
66. Senay EC, Dorus W, Goldberg F, Thornton W. Withdrawal from methadone maintenance. Rate of withdrawal and expectation. Arch Gen Psychiatry 1977;34:361-7.
67. Hiltunen AJ, Eklund C. Withdrawal from methadone maintenance treatment. Reasons for not trying to quit methadone. Eur Addict Res 2002;8:38-44.
68. Magura S, Rosenblum A. Leaving methadone treatment: lessons learned, lessons forgotten, lessons ignored. Mt Sinai J Med 2001;68:62-74.
69. Netzer R, Pflimlin P, Trube G. Dextromethorphan blocks N-methyl-D-aspartate-induced currents and voltage-operated inward currents in cultured cortical neurons. Eur J Pharmacol 1993;238:209-16.
70. Bristow LJ, Hogg JE, Hutson PH. Competitive and glycine/NMDA receptor antagonists attenuate withdrawal-induced behaviours and increased hippocampal acetylcholine efflux in morphine-dependent rats. Neuropharmacology 1997;36:241-50.
71. Bisaga A, Gianelli P, Popik P. Opiate withdrawal with dextromethorphan. Am J Psychiatry 1997;154:584.
72. Cornish JW, Herman BH, Ehrman RN, et al. A randomized, double-blind, placebo-controlled safety study of high-dose dextromethorphan in methadone-maintained male inpatients. Drug Alcohol Depend 2002;67:177-83.
73. Li G, Liu Y, Tzeng NS, et al. Protective effect of dextromethorphan against endotoxic shock in mice. Biochem Pharmacol 2005;69:233-40.
74. Liu Y, Qin L, Li G, et al. Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. J Pharmacol Exp Ther 2003;305:212-8.
75. Hsieh KP, Lin YY, Cheng CL, et al. Novel mutations of CYP3A4 in Chinese. Drug Metab Dispos 2001;29:268-73.
76. Liu CH, Peck K, Huang JD, et al. Screening CYP3A single nucleotide polymorphisms in a Han Chinese population with a genotyping chip. Pharmacogenomics 2005;6:731-47.
77. Guan S, Huang M, Chan E, Chen X, Duan W, Zhou SF. Genetic polymorphisms of cytochrome P450 2B6 gene in Han Chinese. Eur J Pharm Sci 2006;29:14-21.
78. Liou YH, Lin CT, Wu YJ, Wu LS. The high prevalence of the poor and ultrarapid metabolite alleles of CYP2D6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 in Taiwanese population. J Hum Genet 2006;51:857-63.
79. Hung CC, Tai JJ, Lin CJ, Lee MJ, Liou HH. Complex haplotypic effects of the ABCB1 gene on epilepsy treatment response. Pharmacogenomics 2005;6:411-7.
80. Pierce TL, Murray AG, Hope W. Determination of methadone and its metabolites by high performance liquid chromatography following solid-phase extraction in rat plasma. J Chromatogr Sci 1992;30:443-7.
81. Rosner B. Fundamentals of Biostatistics. 6 ed.
82. Wolff K, Hay A. Methadone concentrations in plasma and their relationship to drug dosage. Clin Chem 1992;38:438-9.
83. Schwartz RP, Brooner RK, Montoya ID, Currens M, Hayes M. A 12-year follow-up of a methadone medical maintenance program. Am J Addict 1999;8:293-9.
84. Wolff K, Sanderson M, Hay AW, Raistrick D. Methadone concentrations in plasma and their relationship to drug dosage. Clin Chem 1991;37:205-9.
85. Eap CB, Bertschy G, Baumann P, Finkbeiner T, Gastpar M, Scherbaum N. High Interindividual Variability of Methadone Enantiomer Blood Levels to Dose Ratios. Arch Gen Psychiatry 1998;55:89-90.
86. Ehret GB, Voide C, Gex-Fabry M, et al. Drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors. Arch Intern Med 2006;166:1280-7.
87. Peles E, Bodner G, Kreek MJ, Rados V, Adelson M. Corrected-QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients: a cross-sectional study. Addiction 2007;102:289-300.
88. Vormfelde SV, Poser W. Death attributed to methadone. Pharmacopsychiatry 2001;34:217-22.
89. Rook EJ, van Ree JM, van den Brink W, et al. Pharmacokinetics and pharmacodynamics of high doses of pharmaceutically prepared heroin, by intravenous or by inhalation route in opioid-dependent patients. Basic Clin Pharmacol Toxicol 2006;98:86-96.