Zeljko Kljucevic, MD -Public Health Institute of Split-Dalmatia County, 21 000 Split, Croatia

Davorka Sutlovic, Full. Professor. - Toxicology laboratory, Department of Pathology and Forensic Medicine, University Hospital Centre Split, 21 000 Split, Croatia; Department of Forensic Medicine, University of Split School of Medicine, 21 000 Split, Croatia

We agree with Wu et. all. which concluded that HCV may influence the methadone dose and Plasma S-EDDP/methadone ratio in MMT patient 1.
With our reaction and with the results of our pilot study we would like to warn all those who take part in determining the daily dose of methadone in MMT patients on the importance in determining the degree of liver damage.
Opiate addicts sometimes perceive the side effects of HCV treatment with interferon as withdrawal symptoms, therefore it is extremely important to examine the concentration of MTD and its main metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) 2,3. This is especially important in patients suffering from liver disease, because damage to hepatic drug-metabolizing systems may impair the capacity of the liver to store and release unchanged methadone 4.
In our preliminary study based on 26 MMT patients, adult males aged ? 21, after excluding 8 patients, a total of 18 patients were included, 6 not infected with HCV, 7 infected with HCV and 5 cured of HCV, we confirmed the importance of the impact of HCV infection on the daily methadone dose determination (Table 1).
The age and BMI average of patients from both studies did not significantly differ. However due to the patients included in this study, who were significantly longer in the treatment (11-12 times longer) and with higher daily therapeutic methadone dose (50% higher), without diminishing the values of the Wu et. al. study, we believe that the results of our study are more informative.

Table 1. Mean value of demographic characteristics: age, body mass index (BMI), methadone daily dose and treatment duration in the MMT patients that were not infected with HCV (-), patients infected with HCV (+) (from our study and from Wu et.al. study) and cured of HCV from our study.

Not infected with HCV (-) Infected with HCV (+) Cured of HCV+
Our study Wu et.al. study Our study Wu et.al. study Our study
N 6 18 7 334 5
age (years) 39.83�6.33 37.17� 6.35 42.00 � 9.23 38.34� 7,81 45,20�10.34
BMI (kg/m2) 24.61�3.19 22.66� 2.54 25.42� 5.02 23.61� 3.54 25.30�3.26
RS dose MTD(mg/day)
75.00� 48.21 40.56�25.26 81.42�27.61 55.20�27.78 58.00�28.03
Treatment duration (week)
725.10�253.15 56.31�28.48 727.35 � 8.99 64.57�168.83 718.47�250.77

The results of our studies show different concentrations and different ratios of EDDP metabolites and methadone concentrations (Table 2).
Namely, we believe that, in order to determine methadone concentrations in blood samples and the ratio between the methadone metabolites and methadone concentrations, it is extremely important to know the time of sampling, especially regarding the time of taking methadone therapeutic dose.
Wu et al. did not specify sampling time in their study so it is not clear in which metabolic phase the methadone was found in the body. Also their results refer exclusively to the plasma samples while the results of the urine samples were unknown (Table 2).
The results from our study on methadone and EDDP plasma concentration, despite the fact that a higher average daily methadone dose is significantly lower. In our study, blood samples were collected immediately before therapy administration while the urine samples were collected before and 1.5 hours after administration of the therapy. So, considering the metabolic phase and real concentration of methadone and its metabolites it is possible to determine more precisely the real concentration of methadone and its metabolites when time of sampling is defined.


Table 2. Mean value of laboratory findings: concentration of methadone (MTD) and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in plasma of the respondents in the MMT patients that were not infected with HCV (-), patients infected with HCV (+) (from our study and from Wu et.al. study) and cured of HCV.

Not infected with HCV (-) Infected with HCV (+) Cured of HCV+
Our study Wu et.al. study Our study Wu et.al. study Our study
N 6 18 7 334 5
RS MTD ng/mL 0.023�0.031 260.9�204.4 0.026 � 0.034 339.8�208.8 0.028 �0.028
RS EDDP ng/mL 0.028 �0.090 27.55�19.67 0.001 � 0.002 28.73�23.94 0.017�0.022
RS EDDP/MTD urine
1.5 h after dose 3.73�6.36 - 0.86�1.33 - 1.417�1.66

Patients had in HCV + group RS EDDP plasma concentration significantly lower than other two groups but had not significant differences between RS MTD plasma concentrations, as well as the lower RS MTD dose in cured HCV group had similar RS MTD plasma concentration in relation to the other two groups.
The liver is the primary target organ of hepatitis C (HCV) infection and is also the main organ responsible for metabolism of drugs. Liver damage may affect methadone metabolism but this has rarely been studied. In our present study, we hypothesized that the liver damage would determine the methadone metabolic profiles [1].
Using the FIB 4 index as a criterion for the liver damage we found 3,5 times higher damage in HCV+ group than HCV- group and 2,5 times higher damage in cured group than HCV- group 5,6. We also found that HCV + group had higher AST and ALT level than other two groups.


Table 3. Mean value of laboratory findings: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of the respondents in the MMT patients that were not infected with HCV (-), patients infected with HCV (+) (from our study and from Wu et.al. study) and cured of HCV.

Not infected with HCV (-) Infected with HCV (+) Cured of HCV+
Our study Wu et.al. study Our study Wu et.al. study Our study
N 6 18 7 334 5
AST (U/L) 39.16�10.730 31.44�11.72 71.28�5.44 53.66�57.73 53.60� 48.26
ALT (U/L) 63.00�23.28 37.06�27.94 84.71�17.91 62.90�76.68 34.80 �25.02
AST/ALT(U/L) 0.83 �0.39 less than1 ( 0.83) 0.93�0.30 less than1( 0.85) 1,55 � 0.46
FIB- 4 index 0.84 �0.18 - 2.88�1.54 - 2.15 �1.94

Wu et al. have used AST and ALT ratio to determine the degree of liver damage. We believe that the FIB 4 index is significantly better indicator of the liver damage degree and additionally only requires determination of the Platelet (Plt) level. According to the results obtained in our preliminary study, the stage of liver damage can have an impact on decreased concentration of EDDP in the blood and urine of patients with HCV infection in a methadone maintenance program.
Therefore, there is a great value in the results of FIB4 index as a degree of liver damage which would be necessary for the adjustment of methadone daily dose, particularly in patients who are longer in treatment. For that purpose our study is in progress and it includes a larger number of patients from whom we take samples 3 times every 15 days. The subjects were pre-tested and must be negative for other substances of abuse.

References:

1. Wu SL, Wang SC, Tsou HH, Kuo HW, Ho IK, Liu SW, et al. (2013) Hepatitis C virus infection influences the S-methadone metabolite plasma concentration. PloS one 8(7): e69310. PubMed PMID: 23935979. Pubmed Central PMCID: 3720619.
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4. Novick DM, Kreek MJ, Arns PA, Lau LL, Yancovitz SR, Gelb AM (1985) Effect of severe alcoholic liver disease on the disposition of methadone in maintenance patients. Alcoholism, clinical and experimental research 9(4): 349-54. PubMed PMID: 3901806.
5. Tamaki N, Kurosaki M, Tanaka K, Suzuki Y, Hoshioka Y, Kato T, et al. (2013) Noninvasive estimation of fibrosis progression overtime using the FIB-4 index in chronic hepatitis C. J Viral Hepat 20(1): 72-6. PubMed PMID: 23231087. Epub 2012/12/13. eng.
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