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Methadone is the most common and widely used drug for the opioid dependence in Ireland as in most of the countries in the E.U. Methadone treatment is undoubtedly effective however; the reports on methadone related mortalities have definitely stirred the public concern. The challenge for biotechnologists is to determine whether the application of pharmacogenomics can solve this dispute. The fact regarding any drug or opioid is that they affect different individuals in a different way. To solve this “Biological Puzzle” this case study links the role of methadone and CYP2D6 gene variations with the metaboliser status of individuals, which may serve as an adjunct in methadone related fatalities. CYP2D6 is a member of cytochrome P450 mixed oxidase system, which is involved in the metabolism of many toxicologically important drugs that commonly implicates in fatal poisoning. CYP2D6 gene is located on chromosome 22 and is highly polymorphic in nature. Single Nucleotide Polymorphism (SNP) variation at the exon 4 position of the gene results in a single nucleotide change of G to A, which ensue in poor metabolism of the drug. This variation is amongst 5 to 10% of the Caucasian population.
The specific aims of this report are as follows:
- Describe the methadone pharmacology and its mechanism of action, which will include the pharmacokinetics and the pharmacodynamics of the drug.
- The role of cytochrome P450 in the metabolism of methadone. The focus will be on the genetic polymorphism and the adverse drug reaction.
- This research will further investigate on methadone’s safety profile and mortalities associated with the drug.
Methadone is a synthetic opioid, invented during the Second World War (White & Torres, 2010). The first chemical synthesis of the drug was in 1939 at the pharmaceutical laboratories of I.G. Farbenkonzern, Germany. Methadone was introduced to the market during 1960’s and since then it is one of the most valued drug which has proved its effectiveness from the prevention of abstinence syndrome that occurs after rapid interruption of continuous opioid administration (Zweben & Payte, 1990; Dole & Nyswander, 1965). Methadone is also one of the most common medications administered for the treatment of heroin addiction, however; there are many fatal poisonings reported over the years (Bunten et al 2010).
Methadone is a liposoluble basic drug, often administered orally as a racemic mixture of two enantiomers i.e. R-Met and S-Met (Garrido & Troconiz, 2000). It has a long plasma elimination half-life that lies between 13 and 55 hours and a high bioavailability of 70% – 90% when administered orally (Moffet et al, 2004). It is extensively metabolised in liver and is converted into its primary metabolite which is 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) (Crettol, Monnat & Eap, 2007) and 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP) (Lugo et al, 2005). Blood methadone concentration in drug tolerant individuals reaches >0.84 mg/l, whereas in cases of fatality or poisoning concentrations typically range from 0.4 mg/l to 1.8 mg/l. Fatalities have also been reported with concentrations as low as 0.05 mg/l which is significantly lower than the average concentration in blood (Caplehorn, Drummer & Fatal, 2002). Studies suggests that the largest patient associated deaths are during the drug induction phase, when either individual drug tolerance is overestimated or the presence of other drugs are also found in the system (Bunten et al 2010; CSAT, 2004).
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The revolutions in the molecular techniques in postgenomic era provide us a significant platform for the diagnostics and clinical purposes. Pharmacogenomics is the study of the impact of heritable traits on pharmacology and toxicology that acts as bridge to certify opioid fatalities (Wong et al 2002). The significant inter-individual variation in blood methadone concentrations and individual susceptibility to methadone toxicity might be explained through genetic variations of the genes encoding the drug metabolism enzymes. Pharmacogenomics acts as the linkage between an individual’s genotype and individual’s ability to metabolise a foreign compound (Linder, Prough & Valdes 1997).
Most xenobiotics, including therapeutic drugs, are metabolised by cytochromes P450 to some extent (Guengerich, 2006). The metabolism of these drugs results in detoxification and elimination of drug or activation of the prodrug to its biologically active form. Cytochrome P450 (CYP450) shows a wide interindividual variation in their protein expression and/or catalytic activity, which results in unique drug metabolism (Jannetto et al 2002). Among the P450 subfamilies, CYP2D6 plays a critical role in determining the response to several drug groups/families (Sadee 1999). CYP2D6 gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are mono-oxygenases, consisting of more than 30 enzymes (Schur et al 2001) which catalyze many reactions involved in drug metabolism. This protein localizes to the endoplasmic reticulum and is known to metabolise as many as 20% of commonly prescribed drugs.
CYP2D6 gene substrates include debrisoquine (Wennerholm et al, 1999) an adrenergic-blocking drug; sparteine and propafenone, both anti-arrythmic drugs; and amitryptiline, an anti-depressant. CYP2D6 gene is highly polymorphic in population (Neafsey et al, 2009); certain alleles result in the poor metaboliser phenotype, characterized by a decreased ability to metabolise the enzyme’s substrates. The polymorphism is due to multiple mutations of the gene, which result in absent, functionally deficient, under-expressed or over-expressed protein (Shiran et al, 2003). The gene is located near two cytochrome P450 pseudogenes on chromosome 22q13.1 (Gouch et al, 1993). Alternatively spliced transcript variants encoding different isoforms have been found for this gene (Toscano et al, 2006). CYP2D6 is a polypeptide of 497 amino acids that accounts for only small a percentage of all hepatic P450s but its role in drug metabolism is extensively higher than its relative content (Zanger et al, 2010).
Methadone was introduced to the market in 1960’s (Serban, 2011; Liebrenz et al, 2010). The drug was approved by the Food and Drug Administration (FDA) in 1947 as an analgesic; by 1950 it was used for the treatment of painful symptoms from heroin withdrawal and other opioids (SAMSHA, 2004). In 1964, researchers discovered that continuous, daily maintenance doses of oral methadone allowed opioid-addicted patients to function more normally in the process of their recovery (Payte, 1991; Zweben and Payte, 1990; Dole, 1988; Gearing and Schweitzer, 1974).
Fig: 2 Methadone Chemical Structure
Methadone in the modern medicine is used both as an analgesic for severe pain relief as well as in the treatment of opioid dependence (Rowley, 2011; Potter, 2010). Many scientific articles reviewed methadone to be the currently preferred drug of choice for the treatment of opioid dependence in many countries, including the U.K. (Nosyk et al, 2010; Verster and Buning, 2000). Fredheim et al, (2008) in their review reported that currently, methadone has had a renaissance in the treatment of pain because it has proven its usefulness as a second line drug in opioid switching when other opioids fail to show their effectiveness. Methadone has also been found to be the valued medication for its effectiveness in reducing the number of deaths associated with opioid addiction as well as various medical and behavioural prevalence of diseases associated with addictive disorders (Maxwell, Pullum & Tannert 2005; Sheilds et al. 2007). However, the news headlines of many prominent newspapers including the New York Times and the Washington Times, in 2002 and 2003 hyped its publicity by reporting the opioid medications were the major cause of deaths in drug abuse treatment (Belluck, 2003a, 2003b, 2003c; Associated Press, 2002; Washington Times, 2003). New York Times even mentioned methadone as a “Killer Drug” which is widely abused and dangerous (Washington Times, 2003). After these issues it was decided by the U.N. to put methadone in the class of controlled drug. Methadone was declared in a controlled drug category by the United Nations convention and placed under the controlled substances (“narcotics”) by the Single Convention on Narcotic Drugs, 1961 (Single Convention) (Bosnjak et al,2011). However, it can only be prescribed in the UK, as in most countries, by prescription till present (Verster & Buning, 2000; CSAT 200b).
Methadone is one of the most preferred drugs not only in Ireland but also across several continents around the globe. In the report published by European Monitoring Centre for Drugs and Drug Addition (EMCDDA), there is a seven fold increase in the opioid treatment between 19993 -2000. The drug is widely recognised amongst doctors and patients due to its several socio-economic reasons. It is observed that there is a significant decrease in the crime graph and a noticeable increase in the employment services amongst the patients undergoing methadone maintenance treatment. No doubt, there is a reduction in illicit drug use by the opiate users and increase in social integration is one of the benefits of methadone. In addition, methadone also helps in reducing morbidity and mortality among opiate users.
Methadone is a highly potent drug for the treatment of opioid dependence and acts as an analgesic for second line management of chronic pain. However, increase in mortality due to methadone administration has instigated controversies regarding the drug use (Lowe, Brooks & Petry, 2010; Bunten et al 2010). Law enforcement agencies in the United States (U.S.) and the Drug abuse Warning Network (DAWN) ranked methadone as the third most apprehended analgesic used in the treatment of pain management, fourth among all controlled pharmaceuticals, and eighth among all controlled substances (Fig:2.1.1) (SAMSHA, 2007).
Various researches conducted amongst patients undergoing addiction treatment shows that the majority of methadone related deaths occur during the drug induction phase. Post-mortem sample predicts either an overestimation of the drug or combined usage of various other central nervous system (CNS) depressant in addition to the prescribed methadone (Bunten et al, 2010; Lowe, Johnson & Petry, 2007).
Fig: Methadone as the third most apprehended analgesic, fourth among all controlled pharmaceuticals, and eighth among all controlled substances (SAMASHA, 2007)
The side effects associated with methadone overdose includes nausea, vomiting, dizziness, clouding of consciousness and pruritus (itching) (Davis & Walsh, 2001). However, the primary toxic effect of excessive methadone is respiratory depression and hypoxia, sometimes accompanied by pulmonary edema and/or aspiration pneumonia (White and Irvine, 1999; Harding-Pink, 1993).
Methadone related deaths during later phases of the additiction treatment mainly signify the presence of other illicit drugs. Researchers generally use the term “poison cocktail” describing the fatality due to intake of multiple psychotropic drugs (Borron, et al., 2001) such as alcohol, benzodiazepines, and other opioids. Several opioids when used or prescribed alone are relatively moderate respiratory depressants; however, when combined with methadone, their additive or synergistic effects can be lethal (Kramer, 2003; Payte and Zweben, 1998).
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Safety Information and Adverse Event Reporting Program a subsidiary of Food and Drug Administration (FDA) confirms 1,114 cases of methadone-associated fatalities in adults from 1970 through 2002. Critically, a greater number of deaths were reported in 2001 alone than during the entire period from1990 through 1999; the number doubled itself in 2002. In the U.K. 225 individuals died whilst undergoing methadone treatment in 1993. In 1997, data confirms 449 deaths due to the same cause. However, the mortality graph went down in 2001 by reporting 279 deaths caused by methadone but in 2002, it again rose to 316. Therefore, we can conclude that there is no regular trend in methadone related deaths. However, Corkery et al (2004), mentions that it is always not necessary for methadone to be the cause of death even according to the death certificate of the individuals. In an individual study, methadone was detected in the post-mortem blood of 352 unexplained sudden deaths in Scotland between 1991 and 2001. 23 % of these deaths were not directly linked with methadone. However, there were other drugs and/or alcohol found in the blood sample of the individuals.
The Substance Abuse and Mental Health Services (CSAT) in 2004 states that all methadone related poisoning eventually leads to cardio-toxicity and respiratory depression.
Methadone deaths expressed as Percent of all poisoning deaths (CSAT, 2007).
United States Poison Control Centres states that the overall number of opioid-related deaths has been on the rise, with many cases involving other opioids that include oxycodone and hydrocodone (Litovitz, et al., 2002; Florida Department of Law Enforcement, 2002)
Methadone is a liposoluble basic drug with a pKa of 9.2 and is usually administered orally as a recemic mixture of two enantiomers: R-methadone (R-Met) and S-methadone (S-Met) (Fig.2.2) (Trescot, 2010). The plasma half-life of the drug is highly variable and is between 13 and 55 hours but it is usually assumed to be an average of 25 hours (Letsky et al, 2011; Albion et al, 2010; Wolff et al, 2002). The bioavailability is 70% to 90% when administered orally (Bunten et al, 2010; Lowe, Brooks & Petry, 2010). Studies indicate that in drug naive individuals, a single dose of methadone can show its clinical effects up to 72 hours in duration (Olsen et al, 1997). However, the peak plasma concentration reaches in 2 to 4 hours. The analgesic effect of the drug sets in about 15 minute after the subcutaneous injection (Eap et al, 2002).
The chemical structure of r-(-)-methadone and s-(+)-methadone (asterisk (*) denotes chiral centre).
There is a wide distribution of methadone amongst tissues, which generally range from 60 to 90%. As a result, the drug shows slow elimination and cumulative effect. Methadone is mostly metabolised in liver. The primary metabolite of the drug is 2-ethylidene-1, 5- dimethyl-3, 3-diphenylpyrrolidine (EDDP) (Fig) (Bunten et al, 2010) and to some extent 3, 3-diphenyl-1-pyrroline (EMDP) (Corkery et al, 2004). However, both of these metabolites are inactive and elimination of these inactive metabolies is through urine and faeces. Anggard and Inturrisi et al. (1975) (1990) mentioned that as a result of the basic (pKa =9.2) and lipophylic properties, methadone undergoes a hepatic metabolism and renal excretion.
Fig: 4 Metabolic Conversion of Methadone to EDDP
Cytochrome P450 (P450) is a large superfamily of enzymes. The origin of P450’s superfamily is since prokaryotes much before the existence of eukaryotes (Omura, 2010). The gene P450, commonly known as “CYP” is present in the genomes of virtually all organisms. Moreover, studies suggest that heme proteins are the building blocks of CYP450 enzymes. These enzymes play a crucial role in the metabolism of the various xenobiotics, steroids and other chemicals. Most of the drugs and chemicals are lipophilic to become more water soluble before excretion. Therefore, P450 superfamily of hemoproteins serves as terminal oxidases of the mixed function oxidase system (Wrighton and Stevens, 1992). The heme prosthetic group binds oxygen after electron transfer reactions from the reduced form of 24 nicotinamide adenine dinucleotide phosphate (NADPH). This reaction incorporates a single atom of molecular oxygen into a substrate with the concomitant reduction of the other atom to water (Synder, 2000; Omura, 1999).
In cytochrome P450, ‘P’ denotes the pigment and the number ‘450’ is the spectral properties for the absorption band at 450 nm of the reduced CO-bound complex (Benhardt, 2006; Reichhart & Feyereisen, 2000). However, according to the nomenclature society, the term “CYP” is followed by number of families which are generally group of proteins with more than 40% amino-acid sequence identity, a letter for subfamilies and a number for the gene e.g. – CYP2D6. Studies indicate that P450 superfamily is highly diverse (Mathew, 2010). Diversity of P450’s is mainly due to the extensive process of gene duplications. However, gene amplifications, conversions, genome duplications, gene loss, and lateral transfers are certain scenarios that are less documented.
Drugs affect different individuals in a different way. Genetic variations, which affect the response of the drug metabolism, can be of the most probable reasons (Mayer & Zanger, 1997). Johansson & Sunderberg (2010) also reported that the difference in drug metabolism among individuals might be due to several factors e.g. epigenetic, pathophysiological, or it might be due to some environmental factors. In a population, genetic polymorphism is divided according to individual ability to perform drug transformation reaction (Srivastava, 2003). Moreover, polymorphic trait is also noticed due to certain mutation in the genes and/or a single nucleotide polymorphism (SNP) which results in the enzyme variation and leads towards higher or lower activity. As a result, there is a partial or complete absence of an enzyme protein in the system. (FIG:)
Fig: Polymorphism of Drug Metabolism Enzymes (Evans & Relling, 1999).
As we can see from the above figure that the genetic polymorphism applies for a wide range of drugs and xenobiotic metabolizing enzymes. Identification of these variations were by the occurrence of adverse reactions after normal doses of drugs in patients or volunteers. In adverse drug reactions, drug-drug interactions have its key role. In fact, adverse drug reactions (ADRs) are one of the major causes of death which is reported in many scientific articles, reviews and even government scripts. According to Substance Abuse and Mental Health Administration (SAMSHA) (2007), there is a record of approximately 100,000 deaths in the United States due to drug toxicity. In addition, Eichelbaum et al., (2006) stated that ADRs is also responsible for up to 7% of hospitalizations and the number has increased to > 30% in the elderly population (> 70 years of age) (Paul et al., 2008). ADRs mainly affect cardiac function or cause liver toxicity (Need et al., 2005).
The CYP families metabolises approximately, 75% of all clinically used drugs (Bertz and Granneman, 1997; Evans and Relling, 1999).The human genome contains 115 CYP genes, out of which 57 are found to be functional and the rest are reported as pseudogenes (Johansson & Sundberg, 2010; Wang et al,2003). Among CYP families, there are 22 different P450 isoforms, which shows a high degree of polymorphism. Therefore, we can divide the polymorphic xenobiotic metabolizing CYP enzymes into two classes according to their interindividual susceptibility for xenobiotics:
- Class I: Composed of CYP1A1, CYP1A2, CYP2E1, and CYP3A4 without important functional polymorphism and active in metabolism of drugs.
- Class II: Composed of CYP2A6, CYP2B6, CYP2C9, CYP2C19, and CYP2D6, which are highly polymorphic and are important for the metabolism of drugs.
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