**4. Results**

132 Toxicity and Drug Testing

rapid input of methadone, a decrease in fu will be indicated by an increase in Cp, because Vss is proportional to fu. On the other hand, Cu levels remain unchanged. So, if the Cu is the pharmacologically active concentration, a decrease in fu will not modify the maximum response. Thus, it has been suggested that AAG is significantly higher in patients exhibiting abstinence syndrome compared to those who are stable (Garrido *et al*, 2000) and AAG may

Other factors that may contribute to variability include age and sex. It has been suggested that these factors may explain about 33 percent of the inter-individual variations in Vss. These parameters are found to be higher in females and they are directly related to weight

Furthermore, it has also been suggested that a time-dependent increase in methadone clearance may result from auto-induction of its own metabolism by *CYP3A4*, and the change in Vss may be due to up or down-regulation of AAG (Rostami-Hodjegan *et al*, 1999). Therefore, a time-dependent decrease in Vss may be associated with the observed time-

Generally, there is a huge inter-individual variability in methadone clearance that can reach up to 20 -100 folds in magnitude (Eap *et al*, 2002; Li *et al*, 2008). Methadone is eliminated by hepatic metabolism and renal excretion. It has been shown that at urinary pH of six and above, renal clearance accounts for four percent only. However, when urinary pH was lower than 6, the clearance of unchanged drug will be increased by 33 percent (Rostami-Hodjegan *et al*, 1999). It was concluded that, about 20-50 percent of the inter-individual variability can be explained by urinary excretion (KuKanich and Borum, 2008). With regard to hepatic clearance, methadone can be recognized as a drug with a low extraction ratio, 0.16 in MMT patients.

To investigate factors that influence successful MMT in opiate-dependent individuals,

To investigate the impact of daily clinical methadone dose on plasma concentration of

The study involves opiate-dependent individuals who consented, met our study criteria and were invited to participate in the study. The study involved them taking prescribed doses of daily methadone according to Methadone Maintenance Therapy (MMT) guidelines prepared by the Malaysian Ministry of Health and be monitored regularly based on our study protocols. They were followed up for 12 months during the study period. At follow up, 5 ml of venous blood were drawn for the determination plasma methadone level using

However, at 12th month follow up, 88 out of the 128 participants fail to meet the inclusion criteria. Thus, in order to assess the efficacy of low dose methadone on the withdrawal effect

contribute to the variations in methadone plasma levels.

(Wolff *et al*, 2000).

**1.3.3 Elimination** 

dependent increase in AAG.

**2. Objective of clinical study** 

**2.1 General objective** 

**2.2 Specific objective** 

**3. Clinical study** 

in-house methadone ELISA kit.

methadone.

One hundred and twenty eight patients were enrolled for this pilot study. Their doses were titrated appropriately as tolerated. However, at 12th month follow up, 88 patients out of the 128 participants fail to meet the inclusion criteria. Thus, in order to assess the efficacy of low dose methadone on the withdrawal effect and sleeping quality, a subset of only 40 patients was further selected to participate where they were given a fixed 40 mg daily dose of methadone. Daily dose averaged 57.2 mg (SD ± 22.7) (Table 4.1) and ranged from 20 to 160 mg per day (Figure 4.1). The corresponding plasma methadone concentration averaged 281.3 ng/ml (SD ± 567.9) (Table 4.1) and ranged from 0 to 4634 ng/ml (Figure 4.2, Figure 4.3)


Table 4.1. The Summary of Statistics, Daily Methadone Dose (mg) and Plasma Methadone Concentration (ng/ml)

Fig. 4.1. Daily Methadone Dose in the Study Patients

Variability of Plasma Methadone Concentration in Opiate Dependent

(Table 4.2 and Table 4.3)

Received MMT 40 mg Daily

Received MMT 40 mg Daily

N Cumulative %

Plasma Methadone, up to mg/ml

Receiving Methadone: A Personalised Approach Towards Optimizing Dose 135

plasma concentration averaged 300 ng/ml, its median was only 181 ng/ml. A closer look revealed that 33% of patients had doses of 40 mg/day or lower, 54% received 40 – 80 mg/day dose and only 13% had doses 80 mg or more per day. In terms of plasma methadone, most, 84%, had concentrations of 400 ng/ml and 16% had 400 ng/ml and above, 400 ng/ml being the proposed minimum concentration for effectiveness. Six percent of patients on the other hand, had potentially toxic concentrations of more than 700 ng/ml.

Statistics Day 1 Day 7 Day 14 Day 21 Mean 136.25 242.91 196.94 216.52 Standard Error 13.49 21.13 18.27 19.66 Median 135.06 194.12 162.05 190.25 Standard Deviation 80.92 126.79 109.65 117.96 Sample Variance 6548.10 16075.43 12022.56 13913.47 Skewness 0.56 1.08 2.14 2.35 Range 317.65 463.53 573.99 584.88 Minimum 14.09 92.36 60.66 81.16 Maximum 331.74 555.89 634.65 666.04

Table 4.2. Plasma Methadone Concentrations (ng/ml) on Days 1, 7, 14 and 21 While Patients

N Cumulative %

The Subjective and Objective Withdrawal Score from patient taking MMT 40 mg daily was poorly manifested (Figure 4.4 and Figure 4.5). It showed that methadone at 40 mg a day was

Subjective withdrawal scores (SOW) were determined at four weeks for patients given 40 mg daily dose of methadone. Scores averaged 32 (SD ±10.4). The lowest score was 11 and the highest 51. Objective withdrawal scores (OOW) were also determined at four weeks for

not adequate to suppress the withdrawal from opiate dependence.

patients given 40 mg daily dose of methadone. Scores averaged 8.2 ( SD ±1.5 ).

100.00 10 32.26% 2 6.06% 0 0.00% 1 3.85% 200.00 10 64.52% 16 54.55% 17 56.67% 11 46.15% 300.00 10 96.77% 7 75.76% 5 73.33% 8 76.92% 400.00 1 100.00% 3 84.85% 7 96.67% 4 92.31% 500.00 0 100.00% 1 87.88% 0 96.67% 1 96.15% 600.00 0 100.00% 4 100.00% 0 96.67% 0 96.15% 700.00 0 100.00% 0 100.00% 1 100.00% 1 100.00% 800.00 0 100.00% 0 100.00% 0 100.00% 0 100.00% Table 4.3. Plasma Methadone Concentrations (ng/ml) on Days 1, 7, 14 and 21 While Patients

Day 1 Day 7 Day 14 Day 21

N Cumulativ e %

N Cumulativ e %

Fig. 4.2. Plasma Methadone Concentrations (ng/ml) as a function of daily methadone dose in the studied patients (outlying concentrations were removed).

Fig. 4.3. Plasma Methadone Concentrations (ng/ml) as a Function of Daily Methadone Dose (mg) in the Studied Patients

Both the daily doses and the resulting plasma concentrations showed a non-normal distribution, more so for the plasma concentrations compared to the daily dose. Thus, although the daily dose averaged 57 mg, its median was lower at 50 mg. Similarly, although

100 200 300 400 500 600 700 800 900 1000 More **Plasma Methadone**

0 20 40 60 80 100 120 140 160 180 **Daily Methadone Dose, mg**

Fig. 4.3. Plasma Methadone Concentrations (ng/ml) as a Function of Daily Methadone Dose

Both the daily doses and the resulting plasma concentrations showed a non-normal distribution, more so for the plasma concentrations compared to the daily dose. Thus, although the daily dose averaged 57 mg, its median was lower at 50 mg. Similarly, although

Fig. 4.2. Plasma Methadone Concentrations (ng/ml) as a function of daily methadone dose

in the studied patients (outlying concentrations were removed).

(mg) in the Studied Patients

**Plasma Methadone Concentration, ng/ml**

**Frequency**

plasma concentration averaged 300 ng/ml, its median was only 181 ng/ml. A closer look revealed that 33% of patients had doses of 40 mg/day or lower, 54% received 40 – 80 mg/day dose and only 13% had doses 80 mg or more per day. In terms of plasma methadone, most, 84%, had concentrations of 400 ng/ml and 16% had 400 ng/ml and above, 400 ng/ml being the proposed minimum concentration for effectiveness. Six percent of patients on the other hand, had potentially toxic concentrations of more than 700 ng/ml. (Table 4.2 and Table 4.3)




Table 4.3. Plasma Methadone Concentrations (ng/ml) on Days 1, 7, 14 and 21 While Patients Received MMT 40 mg Daily

The Subjective and Objective Withdrawal Score from patient taking MMT 40 mg daily was poorly manifested (Figure 4.4 and Figure 4.5). It showed that methadone at 40 mg a day was not adequate to suppress the withdrawal from opiate dependence.

Subjective withdrawal scores (SOW) were determined at four weeks for patients given 40 mg daily dose of methadone. Scores averaged 32 (SD ±10.4). The lowest score was 11 and the highest 51. Objective withdrawal scores (OOW) were also determined at four weeks for patients given 40 mg daily dose of methadone. Scores averaged 8.2 ( SD ±1.5 ).

Variability of Plasma Methadone Concentration in Opiate Dependent

with high withdrawal scores implying failure of therapy.

health-care costs.

dangerous to self, family and the society.

Receiving Methadone: A Personalised Approach Towards Optimizing Dose 137

achieve the desired results. This study was an attempt to comprehensively look at MMT. Among our notable findings included the variable ages of our patients, the male predominance, the variable daily methadone doses used and the importance of high daily maintenance dose, the variable plasma methadone obtained and its poor correlation with daily doses. Eighty eight patients were excluded from plasma concentration of methadone because they did not comply with the protocol. We investigated only 40 patients for the outcomes of MMT when the daily dose was fixed at 40 mg. We found that this daily dose was associated

In our clinical study, initially we enrolled 128 patients. They comprised of heroin/opiate dependent individuals receiving MMT in our clinics. As have been observed in many previous studies with MMT, patients enrolled in this study were mostly males with most in the productive age group. The youngest was 20, the oldest 56 years old. They were also mainly Malays. This fact underscores the importance of proper management of drug use disorder. These young and otherwise healthy males, if not successfully managed, are lost to the society and may lead a criminal life to feed their habits, given the difficulties, stigma and discrimination they face to be employed. Thus, instead of becoming the work force of the country needed to generate economic activity, these youngsters in turn add the burden of the country. There will be added burdens in terms of law enforcement costs, judiciary costs and other related costs. This would be over and above other costs like the society and

Of note was a high prevalence of HIV positivity at 36%. In most countries with good harm reduction programs for injecting drug users, the prevalence of HIV positivity is generally 1- 2% (Central Intelligence Agency). The high prevalence seen in our cohort underscores the need for urgent effective measures. As there is no cure for HIV/ AIDS, this high prevalence would mean that many young Malay males in Malaysia would eventually succumb to the disease. This would reduce the pool of available males for population growth and if this is allowed to go on unabated, this will impact on the demography of the Malaysian population. Ethnic proportions can change and population growth in some communities may be halted. They may face troubles to obtain gainful employment and may resort to crimes to feed their habits, themselves and may be even their families. Co-morbid conditions like psychiatric illnesses and stigma and discrimination may make them

No age is however spared by the drug use disorder. The youngest of our patients was a 20 year-old. They began their drug habit as early as when they were 12 years. The oldest patient was 56 years of age and the oldest age a patient started with the habit was 32 years. Drug use disorder is a chronic relapsing disease. The duration of illness among our patients ranged from two years to 38 years and averaged 13 years. These have implications. For one, preventive measures for drug use disorder must begin early and should be continued through all ages. Patients afflicted with the disease should also have long follow ups as they evidently continue with their habits right through their golden years. The longer they continue on the habit, the greater is the chance for them to contract diseases like HIV, if they have not yet been infected. Being young and otherwise healthy, young addicts may find themselves constrained in

Drug users do not live in isolation. They have sexual partners and families. Apart from transmission through the sharing of injection equipments, having the HIV reservoir, drug users can also transmit the disease to their sexual partners, through penetrative sex. Thus, what started as a concentrated epidemic among drug users is now showing evidence for a

various activities and this may lead them to many unhealthy practices.

Fig. 4.4. Subjective Objective Withdrawal Scores from Patients Taking MMT 40 mg daily

Fig. 4.5. Withdrawal Scores as a Function of Plasma Methadone Concentrations

(Series 1 = SOW; Series 2 = OOW)
