**1.1 Methadone and methadone maintenance therapy (MMT): An overview**

Methadone acts on the opioid receptors and produces many of the same effects of morphine and heroin. In the treatment of opioid dependence, methadone has cross-tolerance with other opioid, including heroin and morphine and a long duration of effect. Higher doses of methadone can block the euphoric effects of heroin, morphine, and similar drugs. As a result, properly dosed methadone patients can reduce or stop altogether their use of these substances.

Methadone is a misunderstood drug and ignorance about it is common. Even professionals, physicians and pharmacists who are supposed to be the "guardians" of MMT receive very little training about the very medication that they are responsible for. To compound the issue, addiction is mostly viewed not as a disease and its care is frequently relegated to the lay public, at least until very recently. In Malaysia, addiction has solely been under the charge of "*Agensi Anti Dadah Kebangsaan"* (AADK), an agency that has mainly adopted a criminal approach to addiction. However, this has recently changed in Malaysia. Addiction is now recognized as a medical illness, under the purview of the medical professionals.

Nevertheless, many in the medical profession only have a rudimentary understanding of addiction. Most physicians, pharmacists and nurses receive very little training about addiction and much less regarding methadone. Thus, generally, both medical and other caregivers have very limited knowledge about addiction and much less about methadone. They have generally been taught to approach addiction as a character disorder and administer methadone as a substitute.

Variability of Plasma Methadone Concentration in Opiate Dependent

still cannot hold on methadone with high doses.

**1.3.1 Absorption** 

**1.3.2 Distribution** 

Receiving Methadone: A Personalised Approach Towards Optimizing Dose 131

Several attributes have been suggested such as clearance and *CYP3A4*. Accordingly, several pharmacokinetic studies have been carried out to investigate whether therapeutic drug monitoring (TDM) is effective as a clinical endpoint, on the one hand, and to study the methadone kinetic profile, on the other. There has been suggestive evidence to nonfrequently monitor the kinetic of methadone to explain some unpredicted clinical response (Loimer and Schmid, 1992; Schmidt *et al*, 1993; Wolff and Hay, 1994; de Vos *et al*, 1996). It may be useful especially when all other measures have been taken adequately and a patient

It should be noted that methadone Cp cannot be used directly to describe the clinical response, as a certain time is required for the drug to distribute adequately in the nervous system. Thus, some researchers have suggested the use of an effect-compartment or linkmodel to describe the effect appropriately (Ekblom *et al*, 1993). So far, only four studies have modeled methadone by this approach and only one among them for MMT patients (Dyer *et al*, 1999). It was noticed that there is an inverse relationship between plasma concentrations and withdrawal scores and pupil diameters. On the other hand, there was a direct relationship between plasma concentrations and pain threshold in the same patients. The area under the curve did not differ between those who reported withdrawal symptoms and those who did not. The study suggested that there is correlation between methadone clinical

The absorption of methadone following oral administration is fast and almost complete. The mean time to achieve peak concentration ranges from 2.5 - 30 hours depending on the formulation (Wolff *et al*, 1991). Oral bioavailability of methadone may range from as little as 45 percent up to 90 percent following a single dose (Meresaar *et al*, 1981). As methadone is a basic drug, acid secretions may contribute to such huge variability (Kukanich *et al*, 2005).

Being a lipo-soluble drug, methadone distributes widely in body tissues such as: liver, lung, kidney, gut, brain, and muscle with different distribution coefficients (Sawe, 1986). In opioid addicts, the volume of distribution at a steady state (Vss) ranged from 0.2 to 9.2 L/kg. On the other hand, in patients with chronic pain, Vss ranged from 1.71 to 5.34 L/kg (Inturrisi *et* 

Methadone pharmacokinetic is described as a two-compartment model. Although there are wide differences in the reported clearance, the reported terminal half-life was estimated to range from 23-26 hours. Half-life depends also on the volume of distribution, making the

Methadone binds to plasma protein to a high degree of 86 percent, predominantly to acute α-glycoprotein (AAG) (Romach *et al*, 1981; Eap *et al*, 1990). AAG is an acute phase protein that exhibits significant variations in its plasma levels according to the physiological and/or pathological situation of the patient (Fournier *et al*, 2000; Yang *et al*, 2006; Mestriner *et al*, 2007). AAG levels are significantly increased in stress, leading to very low concentrations in the free fraction (fu) of methadone in cancer patients compared to healthy participants (Abramson, 1982; Gómez *et al*, 1995). Therefore, some studies have measured the concentration of AAG itself to study the impact of their concentration on methadone concentration and / or clinical outcomes. Rowland and Tozer (1995) have stated that 'after a

explanations much more complicated and inconclusive (Eap *et al*, 2002; Li *et al*, 2008)

responses and changes in the plasma levels for methadone racemic mixture.

*al*, 1990), though higher doses are usually given in such situations.
