**5. Discussion**

Methadone has a complex pharmacology. There is widespread "opiophobia" and it is frequently perceived negatively by physicians, patients and the society so much so that many just accept it as a necessary evil. The complex pharmacology and "opiophobia" present a great challenge to patients, physician and programs in terms of finding the most appropriate dose to

Frequency Cumulative %

10 20 30 40 50 60 More **SOW Scores**

R = 0.069, SOW

R = 0.0721, OOW

0 2000 4000 6000 8000 10000 12000 **Plasma Methadone, ng/ml**

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

Methadone has a complex pharmacology. There is widespread "opiophobia" and it is frequently perceived negatively by physicians, patients and the society so much so that many just accept it as a necessary evil. The complex pharmacology and "opiophobia" present a great challenge to patients, physician and programs in terms of finding the most appropriate dose to

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

0.00%

Series1 Series2 Linear (Series1) Linear (Series2)

20.00%

40.00%

60.00%

80.00%

100.00%

120.00%

0

**5. Discussion** 

(Series 1 = SOW; Series 2 = OOW)

**Withdrawal Scores**

2

4

6

8

**Frequency**

10

12

14

16

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 with high withdrawal scores implying failure of therapy.

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 health-care costs.

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 dangerous to self, family and the society.

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

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

Variability of Plasma Methadone Concentration in Opiate Dependent

psycho-active drugs, such as the benzodiazepines.

withdrawals occurred in patients maintained on 40 mg daily.

has dire consequences.

**6. Conclusion** 

**7. Acknowledgement** 

sponsoring this project.

**8. References** 

withdrawal.

Receiving Methadone: A Personalised Approach Towards Optimizing Dose 139

doctors even hesitate to use opiates even when indications are clear. Efforts should therefore be made urgently to reeducate these doctors. In their hands is the future of the nation. Their failure to prescribe adequate methadone doses will lead to therapeutic failure for MMT. This

There is another problem. The expectation of the public, doctors and patients as regards treatment of addiction is to have a drug-free ending. This puts extra pressures on the doctor and patient alike and this will encourage doctors and patients to use low doses for the shortest possible time. This is despite the fact that maintenance therapy for at least two years with adequate doses is known to be associated with the maximum chance of remaining abstinent when methadone has been tapered. Many patients can thus receive less than two years of treatment with methadone with encouragements to discontinue maintenance frequently coming from health care providers working in maintenance programs. Most treating doctors also often do not try to discover reasons why patients started drug in the first place, or the existence of comorbid psychiatric illnesses. This less than holistic approach to MMT can result in increased anxiety among patients that can lead to the use of other

Notwithstanding the requirement for higher doses, as with any drugs, the dosing of methadone should be individualized (Latowsky, 2006). While low doses are associated with relapse and failure, too high a dose may lead to toxicities such as prolongation of QT interval and subsequent fatal polymorphic ventricular fibrillation (Fanoe *et al*, 2007). As regards plasma methadone concentrations, although we did not observe a clear correlation between plasma concentration and clinical effects, in the individual patients they may prove useful as illustrated in the cases we described above. Notwithstanding that, it is clear that a dose of 40 mg a day is generally inadequate. Subjective withdrawal scores (SOW) at four weeks for patients given 40 mg daily dose of methadone averaged 32 and the standard deviation was large at 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 ). It is evident that severe

We concluded that the variable plasma methadone obtained was poorly correlated with daily doses of methadone and low dose methadone was inadequate to suppress opiate

A daily dose of 40 mg was associated with a high incidence of opiate withdrawal. Thus, prescription of methadone dose should be individualised to achieve a higher success of MMT.

I would like to thank USM (Universiti Sains Malaysia) RU grant 1001/PSSP/812056 for

Abramson, F.P. Methadone plasma protein binding: alterations in cancer and displacement from alpha 1-acid glycoprotein. *Clin Pharmaco Ther.* 1982. 32(5): 652-658.

more generalized epidemic into the community through sexual transmission. In the beginning, less than one percent of HIV victims were females. Now it stands at about 20% and this clearly demonstrates the generalization of the HIV epidemic in Malaysia that began as a concentrated epidemic among drug users. Most of the afflicted females are also wives and spouses of drug users who are themselves HIV positive and not sex workers as many would have expected. There is however evidence for a growing epidemic among sex workers and this again has the potential to generalize into the community.

For the forty patients studied, their daily dose averaged 57.2 mg and ranged from 20 to 160 mg per day. Median dose was 50 mg per day. The corresponding plasma methadone averaged 281.3 ng/ml. It ranged from 0 to 4634 ng/ml. Daily methadone doses poorly predicted resulting plasma methadone concentrations, a hallmark for a drug metabolized by genetically polymorphic enzymes. Indeed when we measured plasma methadone concentrations in patients who received a fixed 40 mg daily methadone , they varied from 14 ng/ml to 331 ng/ml, a 23-fold difference. It is thus evident that no one dose fits all. As with many drugs used in the management of chronic diseases, methadone doses should be individualized to optimum outcomes that must be determined objectively.

It is also interesting to note that, despite claims by many physicians that relatively lower doses of methadone would be sufficient for our Malaysian patients, our observation of high withdrawal scores among patients who were maintained at 40 mg daily of methadone would imply this was not so. Severe withdrawal would discourage patients from remaining on treatment and by inference, they will not be retained. Indeed it has consistently been found that a sufficiently high dose of substitution therapy was required for improved outcome (Brady *et al*, 2005). High doses of methadone were significantly more effective in suppressing illicit heroin use and in retaining patients in the program (Family Health International; Mattick *et al*, 2003) and in producing optimum outcomes (Farré *et al*, 2002).

Inadequate doses and premature termination are the greatest threats to a successful MMT program in Malaysia. Malaysian doctors may outwardly say that they use lower methadone doses because of their fear for ethnic difference that would put their patients at higher risks for toxicity if they were to use doses as high as those recommended by the Western literature. What they may not want to admit is the fact that, inwardly, they have fears with methadone (and all opiates actually!) just for the simple reason that methadone is an opiate, just like the dreaded heroin and morphine! Indeed Malaysian doctors are not alone in this. Many doctors everywhere share the same view. Thus, despite ample evidence for the need to maintain patients at a daily dose of 80 mg to 100 mg, most patients are maintained on much less, and many are encouraged early termination.

It is probably understandable that the lay public may not understand the scientific basis for MMT and could be disparaging and become critical of it. It is however less clear why many physicians and other health care providers have the same views. Even those directly involved with MMT programs frequently fail to adhere to the basic principles of MMT. Most have actually received clear information on the pharmacologic principles underlying MMT and their claim that they want to prescribe as few medications as possible sound hollow, as they frequently easily prescribe other mood altering drugs, such as the benzodiazepines that are often prescribed with abandon and can produce psychological and physiologic dependency. Even if they claim they fear adverse effects, the adverse, physiologic effects of MMT are minimal and methadone is probably associated with the least side effects of any drug in a physician's pharmacologic armamentarium, when used appropriately. The real reason is probably more to do with the general "opiophobias" as it is known that some doctors even hesitate to use opiates even when indications are clear. Efforts should therefore be made urgently to reeducate these doctors. In their hands is the future of the nation. Their failure to prescribe adequate methadone doses will lead to therapeutic failure for MMT. This has dire consequences.

There is another problem. The expectation of the public, doctors and patients as regards treatment of addiction is to have a drug-free ending. This puts extra pressures on the doctor and patient alike and this will encourage doctors and patients to use low doses for the shortest possible time. This is despite the fact that maintenance therapy for at least two years with adequate doses is known to be associated with the maximum chance of remaining abstinent when methadone has been tapered. Many patients can thus receive less than two years of treatment with methadone with encouragements to discontinue maintenance frequently coming from health care providers working in maintenance programs. Most treating doctors also often do not try to discover reasons why patients started drug in the first place, or the existence of comorbid psychiatric illnesses. This less than holistic approach to MMT can result in increased anxiety among patients that can lead to the use of other psycho-active drugs, such as the benzodiazepines.

Notwithstanding the requirement for higher doses, as with any drugs, the dosing of methadone should be individualized (Latowsky, 2006). While low doses are associated with relapse and failure, too high a dose may lead to toxicities such as prolongation of QT interval and subsequent fatal polymorphic ventricular fibrillation (Fanoe *et al*, 2007). As regards plasma methadone concentrations, although we did not observe a clear correlation between plasma concentration and clinical effects, in the individual patients they may prove useful as illustrated in the cases we described above. Notwithstanding that, it is clear that a dose of 40 mg a day is generally inadequate. Subjective withdrawal scores (SOW) at four weeks for patients given 40 mg daily dose of methadone averaged 32 and the standard deviation was large at 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 ). It is evident that severe withdrawals occurred in patients maintained on 40 mg daily.
