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Pharmacogenomics

Pharmacogenomics of methadone maintenance treatment

Methadone is the major opioid substitution therapy for opioid dependence. Dosage is highly variable and is often controlled by the patient and prescriber according to local and national policy and guidelines. Nevertheless many genetic factors have been investigated including those affecting its metabolism (CYP2B6-consistent results), efflux transport (P-gp-inconsistent results), target μ-opioid receptor (μ-opioid receptor-inconsistent results) and a host of other receptors (DRD2) and signaling elements (GIRK2 and ARRB2; not replicated). None by themselves have been able to substantially explain dosage variation (the major but not sole end point). When multiple genes have been combined such as ABCB1, CYP2B6, OPRM1 and DRD2 a greater contribution to dosage variation was found but not as yet replicated. As stabilization of dosage needs to be made rapidly, it is imperative that larger internationally based studies be instigated so that genetic contribution to dosage can be properly assessed, which may or may not tailor to different ethnic groups and each country’s policy towards an outcome that benefits all. Keywords:  dependence • drug abuse treatment • enantiomers • metabolism • methadone • opiate • pharmacogenomics • receptors • response variability • transport

Methadone is an old opioid drug, having been discovered and developed by IG Farbenindustrie AG at Hoechst-am-Main (Germany) during World War II. Its ‘possession’ by the US forces and migration to the USA and UK resulted in substantial pharmacological interest. Being an opioid with a completely different chemical structure to the phenanthrenes such as morphine and oxycodone [1] , it was used as an analgesic. However, owing to a lack of understanding of its pharmacokinetics, it was thought to have too narrow a therapeutic index. In 1965 it was introduced by Dole and Nyswander [2] as a substitution therapy for the treatment of opiate (mainly diacetylmorphine) dependence. This purpose dominates the use of the drug today. The approach to treatment is to substitute one opioid (for example diacetylmorphine) with another (methadone or buprenorphine) under controlled conditions with psychosocial support. The use of methadone in main-

10.2217/PGS.14.56 © 2014 Future Medicine Ltd

Andrew A Somogyi*,1,2, Daniel T Barratt1, Robert L Ali1,3 & Janet K Coller1 Discipline of Pharmacology, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, Adelaide 5005, Australia 2 Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, 5005, Australia 3 DASSA World Health Organization Collaborating Centre for Research in the Treatment of Drug & Alcohol Problems, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, Adelaide 5005, Australia *Author for correspondence: Tel.: +61 8 8313 5572 Fax: +61 8 8224 0685 [email protected] 1

tenance treatment, commonly referred to as methadone maintenance treatment (MMT), has several quite unique features that are not found in most other forms of pharmacotherapy. These are discussed in the following sections. Rationale and policy: not only are there several different approaches but they differ between countries. For example, treatment can be provided in specialist clinic settings or in primary healthcare. It can require direct observation of dose administration to prevent diversion or there can be dose consumption without supervision (‘take aways’). Harm minimization is the focus in many countries whereby the person taking prescribed methadone reduces their health, social and economic harms and becomes reinstated into society. Often this means the amount of illicit opioids they use is substantially reduced but not necessarily fully eliminated. In some jurisdictions, total abstinence is a require-

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Review  Somogyi, Barratt, Ali & Coller ment for continuance in the program. There is a strong evidence base that longer-term treatment is associated with a greater likelihood of long-term abstinence from opioid drugs than are shorter periods of treatment [3] . Demographics: in general, people undergoing MMT are adults aged between 18 and 50 years. Universally males are more likely to be in treatment than females. Health status: globally, opioids make the largest contribution to illicit drug-related deaths. Estimates of annual mortality rates for opioid users typically are between 1–3% [4] . MMT reduces but does not eliminate the excess mortality rate [5] . Patients invariably have hepatitis C due to sharing injecting equipment; some have HIV/AIDS and many are in poor physical and mental health states. In 2010 the prevalence among injecting drug users of HIV was estimated at approximately 20%, hepatitis C at 46.7% and hepatitis B at 14.6% added to the global burden of disease [6] . Because of these factors, they may be prescribed other medications as well as taking medications illicitly (e.g., benzodiazepines). They also are commonly heavy smokers. Use of alcohol and cannabis varies between countries. The disease: not all people who use drugs become dependent. As with any other medical condition, individual vulnerability is determined by a combination of risk and protective factors, but with repeated drug use biological factors become important. It is estimated that genetic factors account for between 40 and 60% of a person’s vulnerability to addiction, including the effects of environment on gene expression and function [7] . Drug dependence is a chronic relapsing condition that leads to morbidity and mortality [8] . The key feature of dependence is a loss of control over drug use, which is seen as continued use despite drugrelated legal, interpersonal and health problems, as well as drug use taking priority over other activities and obligations. Dosing and subject involvement: in many countries in the western world, the individual plays a significant role in determining the eventual maintenance dose of methadone. This is relatively unique in pharmacotherapy but is essential as the motivated individual has control. Generally, individuals receiving a daily dose of 60 mg or more have better treatment outcomes (response is assessed as: no opioid withdrawal symptoms and negative for morphine urinalysis) than those receiving less than 60 mg [9] , in terms of treatment retention, unsanctioned opioid use, HIV risk-taking behavior and criminal activity. Too low a dose can provoke withdrawal symptoms, particularly towards the end of the interdosing interval, and too high a dose causes drowsiness, confusion and mental impairment.

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The major hazard associated with substitution treatment is the risk of overdose (respiratory depression), particularly with methadone. Induction onto MMT is more hazardous than induction onto buprenorphine [10] . In addition, some jurisdictions place a maximum dosing allowable owing to concerns regarding QTc prolongation and resultant Torsades de pointes. This has probably been overemphasized unless other risk factors are involved. QTc interval prolongation is evident in 10–15% of people on MMT [11] . Although the greatest prolongation of QTc interval has been observed in men receiving high daily methadone doses (110–150 mg), there is no clear evidence on the relationship between dose and QTc interval [12] . Formulation and clinic involvement: methadone is formulated as a solution with various excipients allowing individualized and discrete dosing, which is not available via solid dosage formulations. The dosing is often carried out in a specialized treatment clinic which the individual attends on a daily basis but then in some countries, once the dose is stabilized, treatment can be via approved pharmacies within the community as well as hospitals. This preamble sets the scene for reviewing the pharmacogenomics of methadone as variability at the gene level can also influence dosing requirements. Polymorphic genes can affect the metabolism and transport of methadone, hence affecting its pharmacokinetics, and various target/receptor sites with the potential for contributing to interpatient variability in effectiveness and adverse effects. An overview is first provided of the pharmacokinetics and pharmacodynamics of methadone highlighting proteins (enzymes, transporters and receptors) whose genetic polymorphisms could affect variability in response as assessed by dosing requirements, plasma concentrations, efficacy and adverse effects. This will be followed by an assessment of the genetic polymorphisms affecting methadone that have been specifically studied in this population. There have been reviews that have focused on the pharmacogenomics of opioids per se [13] , on pain therapy including opioids [14–16] and on drug dependence and treatment [17] , but none specifically on methadone in dependence treatment. The analgesic effect of methadone is to lower elevated pain scores and/or improve pain relief using Likert scales whereas for the maintenance effect for heroin dependence, methadone is to reduce the craving for heroin; thus there is a clear clinical but not necessarily pharmacological distinction between these two indications. Other opioids can be used to reduce the craving for heroin but methadone has the advantage of a long terminal half-life resulting in only daily dosing with a narrow peak to trough plasma concen-

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Pharmacogenomics of methadone maintenance treatment 

tration ratio reducing the likelihood of overdose (peak concentration) and withdrawal (trough). Methadone pharmacokinetics & pharmacodynamics: overview Methadone is used in almost all countries as a racemic mixture of (R)- and (S)-enantiomers, which have different pharmacodynamic and pharmacokinetic properties (see below). Methadone’s major target is the μ-opioid receptor (MOP [18]) with the affinity of the (R)-enantiomer being 10-times higher than the (S)-enantiomer [19] . Other targets with substantially lower affinity than MOP, but very unlikely to be clinically important, are the δ- and κ-opioid receptors [20] , serotonin reuptake transporters and noradrenaline reuptake transporters [20] , GLuN2A [21] and Kv11.1 for which (S)-methadone has a higher affinity [22] . Oral absorption of methadone is rapid and extensive with peak plasma concentrations from a liquid formulation occurring at 2–3 h and bioavailability exceeding 80% but with some variability [23,24] . Once in the bloodstream, methadone is highly plasma bound (>80%) with α1-acid glycoprotein being the major binding protein and stereoselectivity with the active (R)-methadone having a lower unbound fraction than the less active (S)-methadone [25,26] . Methadone is also a substrate for the efflux transporter P-gp (see below). The major elimination mechanism is metabolism by CYP3A4 and CYP2B6. Pharmacokinetically, methadone is a low hepatic clearance drug of G SNP (Asn40Asp, rs1799971), which results in the loss of a putative N-glycosylation site in the extracellular receptor region of MOP [36] . In vitro studies indicate this SNP is likely to reduce methadone effects via decreased OPRM1 expression [37] , with no significant effect on methadone binding affinity [38] . Clinical studies have provided strong evidence that the G variant is associated with reduced analgesic response and side effects to exogenous opioids [13,39] . Impact of OPRM1 genetics on methadone requirements

Whilst the OPRM1 118A>G variant has been associated with decreased methadone miotic potency in healthy controls [40] , it has not been shown to relate to methadone requirements (dose or trough plasma concentration) in MMT when analyzed in isolation [41–43] . However, when controlling for ABCB1 variability (see below), we recently demonstrated that the OPRM1 118G variant allele is associated with significantly higher (2.3-fold) median trough plasma (R)-methadone concentrations, reflected by a nearly 1.8-fold higher (although not statistically significant) median MMT dose. Thus variants of OPRM1 and ABCB1 may interact to determine methadone requirements in a similar gene–gene interaction to that previously observed for morphine analgesia [44] . Similarly, OPRM1 118A>G was found to be a significant modulator of maximum methadone doses in Han Chinese patients [43] when combined with other SNPs altering methadone pharmaco­

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Table 1. Outcome measures used to assess the effect of pharmacogenomic factors in methadone maintenance treatment studies together with their advantages and disadvantages. Outcome variable

Advantages

Disadvantages

Dose

Highly relevant as a predictive indicator for clinical application Combination of variability in PK and PD factors

Often a product of rationale and policy within a treatment setting Dose data may be confounded by compliance/ diversion (unsupervised dosing) Maybe difficult to discern modest effects of single genetic factors affecting only PK or PD

Ctrough (trough plasma concentration)

Potential marker of plasma concentration required to suppress withdrawal symptoms, especially approaching the end of the interdosing interval Useful for identifying genetic factors influencing PK–PD

Clinical translation would require coupling with TDM Cannot distinguish between PK and PD as the source of variation Requires venepuncture, which is often difficult in this population

Ctrough /dose

Simple measure to indicate variability in PK (bioavailability and/or clearance metabolism)

Poor linear relationship between Ctroughand dose at higher (>80–100 mg/day) doses [24,29–31]

High dose versus low dose

Useful for statistical analysis, particularly in cases of multimodal distribution of dose data

Designation of cutoff somewhat arbitrary and/or variable depending on clinical setting (rationale and policy) Unclear relevance/utility for implementing personalized dosing

Responders versus nonresponders

May identify high-risk patients

Varied definitions of response, depending on clinical setting (rationale and policy) Course of action not clear

PD: Pharmacodynamic; PK: Pharmacokinetic; TDM: Therapeutic drug monitoring.

kinetics (ABCB1, CYP2B6 ) and pharmacodynamics (ANKK1, DRD2). Regarding other OPRM1 SNPs, the frequency of the rs1074287 (5´ near gene; ∼25% frequency in Caucasians) SNP was not significantly different between Caucasian MMT responders (n = 83) and nonresponders (n = 33) [45] , while no significant effect of the 643+31G>A SNP (rs9479757) on methadone dose requirements was observed in Han Chinese MMT patients [43] . Impact of OPRM1 genetics on methadone adverse effects

A recent study of 15 SNPs (including rs1799971 and rs1074287) spanning the OPRM1 gene in 366 Taiwanese MMT patients found no significant association with methadone dose, but a potential association between 12 strongly linked SNPs (rs1074287, rs6912029, rs12209447, rs510769, rs3798676, rs7748401, rs495491, rs10457090, rs589046, rs3778152, rs563649 and rs2075572) and change in libido and insomnia side effects [46] . There is also recent evidence that neonates with the OPRM1 118A>G AG/GG genotype may be at lower risk of or experience less severe neonatal abstinence syndrome as a result of maternal MMT treatment [47] .

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In summary, despite the highly polymorphic nature of OPRM1, only the 118A>G SNP has been extensively studied in regards to methadone pharmacogenetics. There is evidence that the 118A>G variant may alter methadone pharmacodynamics, but a significant association with MMT dose requirements has yet to be clearly demonstrated due to additional confounding variability in methadone pharmacokinetics and the nature of dose selection itself. More recent putative associations between OPRM1 polymorphisms and MMT adverse effects have identified an important new area for future investigation with regards to MMT pharmacogenomics. Metabolizing enzymes Role of CYP450 enzymes in methadone metabolism

Methadone undergoes extensive N-demethylation to 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) by CYP450 enzymes. The predominant CYP450 is CYP3A4, with some discordance in the microsomal metabolism literature surrounding the contributions of CYP2D6 and CYP2B6 [48–52] . A significant role for CYP2D6 in EDDP formation and impact on plasma concentrations in humans also

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Pharmacogenomics of methadone maintenance treatment 

remains unconvincing [48,49,53] . In addition, given the overlapping substrate specificity of CYP3A5 with CYP3A4, there remains the possibility that methadone is also a substrate for CYP3A5; no confirmatory in vitro studies have been conducted to our knowledge. There is evidence of stereoselectivity of metabolism in vitro, with CYP2B6 clearing (S)-methadone faster compared with (R)-methadone [Li Y, Coller, JK, Somogyi AA, Unpublished data] ; however, no difference has been observed with CYP3A4 [52] . Genetic variability in CYP2B6, 2D6 & 3A4/5

The CYP2B6 gene is highly polymorphic, with 61 distinct allelic variants of which 16 variants are associated with either no or reduced CYP2B6 expression and/or activity (*5–*8, *11, *12, *14–*16, *18–*21, *26–*28; for a summary see [54]). In addition, the *4 and *22 alleles have been associated with either increased expression and/or activity, whereas there are no consistent data for the *9 variant; for a summary see [54] . There are large interethnic differences in the frequencies of these variant alleles [55,56] . However, the functional effects of the variants in vitro and in vivo remain somewhat unclear, particularly with regards to the substrate specificity of the effect [56] . The CYP2D6 gene is also highly polymorphic, with 140 distinct allelic variants, of which approximately 24 are nonfunctional (*3–8, *11–*15, *18–*21, *31, *36, *38, *40, *42, *51, *56, *57, *62), 12 have reduced function (*9-10x2, *14B, *17, *29, *41, *49, *50, *54, *55, *59, *69, *72) and three can be duplicated resulting in greatly increased expression of functional CYP2D6 (*1xN, *2xN, *35x2; for a summary see [54]). Similar to CYP2B6, there are large interethnic differences in the frequencies of CYP2D6 allelic variants [57–59] . Allele combinations determine the CYP2D6 phenotype: two nonfunctional = poor metabolizer (PM); at least one reduced function = intermediate metabolizer (IM); at least one functional = extensive metabolizer (EM); multiple copies of a functional and/or allele with promoter mutation [60] = ultrarapid metabolizer (UM). In comparison to the CYP2B6 and 2D6 genes, the CYP3A4 gene has less genetic variability, with only 41 distinct allelic variants currently identified [54] . Of these, nine have either no or reduced enzyme activity compared with the major (wild-type) allele (for a summary see [54]). Given the rarity of most of these allelic variants (except *22), genotyping methods only capture a small proportion of interindividual variability in CYP3A4, and hence, the clinical impact of these variants remains to be comprehensively investigated. The role of other genes (e.g., PXR) that may affect CYP3A4 activity towards methadone is unclear.

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Impact of CYP450 genetics on methadone pharmacokinetics & dose requirements

Indirect evidence that the CYP2B6*6 (rs3745274 and rs2279343) allele could have an impact on methadone pharmacokinetics comes from recent studies that have demonstrated in vivo and in vitro changes in doseadjusted plasma concentrations or clearance to EDDP, respectively. Firstly in vitro data have shown the intrinsic clearance of (R)- and (S)-methadone to EDDP by expressed CYP2B6.6 variant protein was decreased three- and six-fold, respectively, in comparison to the expressed CYP2B6.1 wild-type protein [61] . More direct in vivo studies have investigated the association between CYP2B6*6 genotypes with higher plasma (S)-, and to a lesser extent, (R)-methadone concentrations (Table 2), such that patients carrying a *6 allelic variant had approximately twofold higher doseadjusted trough concentrations compared with noncarriers [22,62,63] . Recent resequencing of a select cohort of MMT with high and low trough plasma (S)-methadone concentrations by these researchers has revealed differences in the frequencies of several additional variants, namely that the CYP2B6*4 (rs2279343), *9 (rs3745274) and *11 (rs35303484), and intronic variants (rs2279342, rs2279344, rs8192719) were more frequent in the high compared with the low concentration group [64] . These observations are similar to an earlier study in a Taiwanese cohort that also reported a significant impact of other tag, exonic and intronic CYP2B6 allelic variants in addition to the *6 variant [65] . By contrast, higher post-mortem racemic methadone concentrations were only observed in CYP2B6*6 allele carriers (0.96 ng/ml *6 vs 0.58 ng/ml *1 and *4) [66] . Nonetheless, collectively these observations indicate that the *6 allele is not the only contributor determining the impact of CYP2B6 genetic variability on methadone plasma concentrations and consequently, this needs to be investigated further in ethnic groups who carry these rarer variants. In addition, it appears that future studies must consider the cumulative contribution of carrying multiple metabolic genetic variants and the impact that this can have on plasma methadone concentrations. Indeed, the power of such a cumulative approach has been shown with the impact of genetic variants in PXR (known to regulate expression of CYP450s) together with CYP2B6*6 on (S)-methadone plasma concentrations [67] , such that significant interactions between variant SNPs in both genes contributing to significantly higher (twofold) concentrations. In addition to the literature investigating the impact on methadone pharmacokinetics, further studies have related lower stabilized dose requirements to CYP2B6 allelic variants (Table 2) . Han Chinese subjects that

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Table 2. Summary of pharmacogenomic studies investigating the role of CYP2B6, 2D6 and 3A4/5 variant alleles in methadone requirements, pharmacokinetics and clinical outcomes in methadone maintenance treatment programs. Country

Dose

Switzerland

Switzerland

Switzerland

n

Ethnicity

CYP450 variant allele

Phenotype(s)

Findings

5-400 mg/day 235

Not stated

CYP2D6*3, *4, *5, *6, *xN

Dose to weight trough plasma (R)-, (S)-MD concentration

CYP2D6*xN = lower

[68]

3–430 mg/day 209 (n = 163 once daily; n = 46 split dosing 2 or 3/day)

White (n = 199) CYP2B6*4, *5, and other *6, *7, *9 unspecified

Dose-adjusted peak and trough plasma (R)-, (S)- and (R,S)MD concentration Peak:trough plasma (R)-, (S)- and (R,S)MD ratio

CYP2B6*6 = higher peak and trough (S)and (R,S)-MD

[62]

3–430 mg/day 245 (n = 199 once daily; n = 46 split dosing 2 or 3/day)

White (n = 235) CYP2B6*4, *5, and other *9 unspecified  CYP2D6*3, *4, *5, *6, *xN  CYP3A4*1B  CYP3A5*3

Dose-adjusted peak and trough plasma (R)-, (S)- and (R,S)MD concentration

CYP2B6*6 = higher peak and trough (S)-MD; CYP2D6*xN = lower trough (S)-MD only; CYP3A4*1B = higher peak and trough (S)MD only; CYP3A5*3 no significant effect CP2B6*6 = lower (S)-MD; CYP2D6 and CYP3A4*1B no significant effect CYP2B6*6 = lower; CYP3A4*1B no significant effect

[69]

Dose-adjusted trough plasma (R)-, (S)- and (R,S)-MD concentration

CYP2B6*6 = higher trough (S)- and (R,S)MD

[22]

No significant effect

[53]

Peak:trough plasma (R)-, (S)-MD ratio

Plasma (R)-:(S)-MD ratio

Ref.

CYP2B6*6 = lower (S)-MD

Switzerland

3–430 mg/day 179

Not defined

Australia

Average 53.1 mg/day

51

White (n = 45); CYP2D6*2–*10, Indigenous *16, *28, *33, Australian *41, *xN (n = 5); Asian (n = 1)

Oral clearance of (R)-, (S)- and (R,S)MD

UK

Post-mortem study

40

Not defined

CYP2B6*4, *6

Post-mortem plasma CYP2B6*6 = higher MD concentration

[66]

China

54.7 ± 28.1 (SD) mg/day

366

Han Chinese

CYP3A4*18 and  intronic variants

MD adverse effects and withdrawal severity

[70]

CYP2B6*4, *5, *6, *7, *9

CYP3A4 intronic variants (rs3735451, rs4646440, rs2242480, rs2246709) = severe withdrawal CYP3A4 intronic variant (rs4646437) = severe adverse effects

ADME: Absorption, distribution, metabolism, and excretion; MD: Methadone; SD: Standard deviation; UM: Ultrarapid metabolizer.

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Pharmacogenomics of methadone maintenance treatment 

Review

Table 2. Summary of pharmacogenomic studies investigating the role of CYP2B6, 2D6 and 3A4/5 variant alleles in methadone requirements, pharmacokinetics and clinical outcomes in methadone maintenance treatment programs (cont.). Country

Dose

n

Ethnicity

CYP450 variant allele

Phenotype(s)

Findings

Spain

Mean ± SD: 98 ± 64 mg/ day

105

Caucasian

CYP2B6*4, *6 -CYP2D6, CYP3A5 ADME chip variants

Dose; trough plasma (R)-, (S)- and (R,S)MD concentrations; dose-adjusted trough plasma (R)-, (S)- and (R,S)-MD concentrations; treatment responders vs nonresponders

CYP2B6, CYP3A5 = no significant effect CYP2D6 variants resulting in UM phenotype = higher

[71]

China

≤150 mg/day

321

Han Chinese

CYP2B6*4, *5, *6, *7, *9

Low dose (T (rs1045642, exon 26, synonymous). Findings from in vitro and clinical studies examining the functional significance of these SNPs for other substrates have been inconsistent, but on balance suggest they are associated with decreased expression (3435C>T), decreased function (61A>G, 1236C>T, 2677G>T, 3435C>T), or both increased and decreased (substrate-dependent) function (1199G>A) [91,92] . Given the presence of multiple SNPs with potential functional significance, and strong linkage disequilibrium between several SNPs (in particular 1236C>T, 2677G>T, 3435C>T), ABCB1 haplotypes have also been examined. In vitro studies have identified 61G:1199A, 61G:2677T, 1199A:2677T, 1236T:2677T, 1236T:3435T, 2677T:3435T, 1236T:2677T:3435T, 61G:1236T:2677T:3435T as reduced activity ­haplotypes, but not always, and not for all substrates [93–97] . Impact of ABCB1 genetics on methadone pharmacokinetics & dose requirements

Clinical pharmacogenetic studies of ABCB1 and methadone in MMT subjects, summarized in Table 3, have reflected inconsistent findings for other P-gp substrates. No single ABCB1 SNP has been directly associated with dose requirements in MMT patients. However, in 2006 we identified a significant association between an ABCB1 haplotype (61A:1199G:1236C:2677T:3435T) and MMT dose requirements. In Australian MMT patients receiving 15–110 mg/day, carriers of the rare (3.6%) variant 61A-1199G-1236C-2677T-3435T haplotype required significantly lower doses (mean 38 vs 61 mg/day for noncarriers) [98] . In a small subset of these subjects with plasma concentration data (n = 5 carriers and 18 noncarriers), this was reflected in

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lower trough plasma (R)-methadone concentrations (mean 70 vs 107 ng/ml, Mann–Whitney p = 0.08, [Barratt DT, Coller JK, Somogyi AA, Unpublished data] ), but no difference in dose-adjusted trough (R)-methadone concentrations (mean 1.82 vs 2.00 ng.ml-1. mg-1, Mann–Whitney p = 0.8 [Barratt DT, Coller JK, Somogyi AA, Unpublished data] ), suggesting an underlying mechanism of reduced BBB efflux and increased methadone CNS distribution in carriers of the variant haplotype. These findings were not replicated in two subsequent studies in treatment populations receiving higher and broader ranges of methadone doses [42,99] , at least when examining ABCB1 as a single factor. A significant relationship between the 61A-1199G1236C-2677T-3435T haplotype, lower dose and trough plasma (R)-methadone concentrations (but not dose-adjusted trough (R)-methadone concentrations) was found, however, when accounting for confounding OPRM1 genetic variability in methadone ­maintenance patients receiving higher doses [42] . In vitro data for other P-gp substrates would suggest the most common variant haplotypes containing the 1236T, 2677T and 3435T variants should also be associated with reduced methadone requirements. However, most studies to date [42,98,99] have found no significant association between this haplotype and methadone requirements, whilst Levran and colleagues reported that individuals with 1236CT-2677GT3435CT or 1236TT-2677TT-3435TT diplotypes had significantly greater likelihood of requiring low (150 mg/day) MMT doses, respectively [101] . The mechanisms behind these associations are unclear, particularly in the absence of supporting in vitro data on the functional effects of ABCB1 SNPs or haplotypes on methadone transport and given the apparent opposing effects between the heterozygous and homozygous variant diplotypes compared with wild-type. A small but significant reduction in dose-adjusted trough plasma (R)-methadone concentrations associated with the 61A>G, 2677G>T and 3435C>T variants has previously been reported, which may provide some mechanistic support for the observations of Levran and colleagues [101] ; however, this did not translate into a significant difference in dose requirement or response in the study by Crettol and colleagues [69] . An association between the 3435T variant and a greater likelihood of high dose was reported in a Han Chinese MMT population [43] , but was not significant in Levran and colleagues [101] or other Caucasian population [69,71] studies. Methadone is also a P-gp inhibitor, and Hung and colleagues recently demonstrated that methadone inhibition of 1236T:2677T:3435T variant

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3–430 mg/day (once daily and split dosing)

30–280 mg/day

Switzerland

Israel

SNPs/haplotypes

Sephardic (39%); Ashkenazi (22%); Oriental (Iraq, Iran, Yemen and Syria) (16%); mixed (13%); unknown (10%)

Mostly white

White

White (n = 235) and other unspecified

1236, 2677, 3435, intronic SNPs (rs6949448, rs2235067, rs2032583, rs1922242, rs2520464, rs3789243)/ 1236:2677:3435; 9 SNP haplotype

61:1199:1236:2677:3435

3435

61, 2677, 3435/ 61:2677:3435

White (n = 55); 61, 1199, 1236, 2677, Indigenous 3435/61:1199:1236:2677:3435 Australian (n = 4); Torres Strait islander (n = 1)

Ethnicity

MD: Methadone; MMT: Methadone maintence treatment.

98

279

14

12–240 mg/day

Switzerland

60

n

3–430 mg/day 245 (n = 199 once daily; n = 46 split dosing 2 or 3/day)

15–110 mg/day (once daily)

Australia

Switzerland

Dose

Country

No significant effect

No significant effect

No significant effect

No significant effect

61G or 3435T allele = lower trough (R), (S), (R,S); 2677T allele = lower trough (R); 61A:2677G:3435C = higher trough (R), (S) 61G or 2677T allele = higher ratio; 61A:2677G:3435C = lower ratio No significant effect

61AA:1199GG:1236CC:2677GG :3435CC = higher; 61AA:1199GG:1236CC:2677GT :3435CT or  61AA:1199GG:123 6CC:2677TT:3435TT = lower

Findings

Low dose (≤150 mg/day) vs high 1236TT genotype greater dose (>150 mg/day) likelihood of high dose; 1236TT:2677TT:3435TT greater likelihood of high dose; 1236CT:2677GT:3435CT greater likelihood of low dose

Dose (SNPs only)

Dose

Change in trough plasma (R)-, (S)- and (R,S)-MD concentrations after quetiapine

Plasma (R)-:(S)-MD concentration ratio Low dose (40–80 mg/day) responders vs high dose (>120 mg/day) responders vs high dose nonresponders

Peak:trough plasma (R,S)-MD concentration ratio

Dose-adjusted peak and trough plasma (R)-, (S)- and (R,S)-MD concentration

Dose

Phenotype(s)

Table 3. Summary of pharmacogenomic studies investigating the role of ABCB1 SNPs in methadone requirements, pharmacokinetics and clinical outcomes in methadone maintenance treatment programs.

[101]

[99]

[100]

[69]

[98]

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≤150 mg/day

15–300 mg/day

Mean (95% CI): 106.3 (88.5–124.1) mg/day

China

Australia

USA: neonates of mothers in MMT

White (98%)

Caucasian

Han Chinese

Caucasian

Ethnicity

MD: Methadone; MMT: Methadone maintence treatment.

86

119

Mean ± SD: 98 ± 105 64 mg/day

Spain

n

Dose

Country

1236, 2677, 3435 (neonate)

61, 1199, 1236, 2677, 3435/ 61:1199:1236:2677:3435

1236, 2677, 3435

3435

SNPs/haplotypes No significant effect

Findings

Neonatal abstinence syndrome

Dose; trough plasma (R)-MD concentration; dose-adjusted trough plasma (R)-MD concentration

No significant effect

No significant effect

Low dose (T, 2677G>T and 3435C>T) and neonatal abstinence syndrome in infants of mothers in MMT [47] . In summary, studies so far indicate that any relationship between ABCB1 haplotypes and MMT dose requirements is likely to be dependent on the clinical context (e.g., treatment population, clinical policy and/or dosing practice), and that ABCB1 pharmacogenetic studies must incorporate a haplotype analysis approach in addition to investigating individual SNPs. For ABCB1 haplotypes to be developed as a pharmacogenetic marker for personalizing MMT dosing, further studies need to: identify if saturation or autoinhibition of methadone P-gp transport occurs at clinically relevant concentrations using appropriate in vitro models of BBB transport, which might explain differing relationships between ABCB1 genetic variability and methadone requirements over different dose ranges [42] ; investigate trough plasma methadone concentrations (not dose adjusted) clinically as an alternative marker of the influence of ABCB1 variability on methadone CNS distribution, since P-gp might affect CNS exposure but not whole body exposure; and consider ABCB1 genetic variability in the context of other important genetic, environmental and individual determinants of methadone requirements [42,43] . Other drug transporters

BCRP (encoded by ABCG2) is more highly expressed at the BBB in humans than P-gp [101] ; however, methadone is not a substrate [74] . To our knowledge methadone has not been investigated as a substrate for other efflux or uptake drug transporters.

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Other genes Several other genes have been investigated in what should be considered are mainly exploratory studies. Some of the gene products have a functional role that can be used to generate a hypothesis and several are based on associations with opioid and other dependencies. It is important to highlight that the patient numbers are small and replication (internal or external) studies have often not been reported. The analysis is summarized in Table 4. UGT2B7

Although methadone is not a substrate for UGT2B7, Tian et al. [102] argued that it is an inhibitor in vitro [108] and in vivo [109] , that it shows cross tolerance to morphine and that patients on insufficient doses of methadone often relapse to morphine. In 361 Han Chinese heroin-dependent subjects in an outpatient setting (>3 months), assessments were made of opioid withdrawal (as Clinical Opiate Withdrawal Scale [COWS]), treatment emergent symptoms (TESS) and urinalysis in subjects on doses from 5–160 mg/day; half the patients tested positive and 12 UGT2B7 SNPs were evaluated. In urine positive subjects, ten SNPs were significantly associated with withdrawal symptoms and tremor, and some SNPs with pupil size. Using a ten SNP haplotype block, there was a significant association with pupil size and tremor for one of the four haplotypes found but the global p-values when all haplotypes were compared were 0.136 and 0.081, respectively. Although the authors argued that these UGT2B7 SNPs may be a useful identifier of subjects that might experience withdrawal symptoms, it is unlikely given the large block size, that urinalysis appeared to have been tested on one occasion only, and that it seemed that dosage may not have been optimized for each subject (Table 4) . ARRB2

ARRB2 is an important intracellular protein involved in MOP desensitization and receptor internalization. It is also involved in dopamine receptor activation and some evidence for an association with dependence to nicotine and methamphetamine. In a retrospective study, Oneda and colleagues [103] , divided 278 MMT subjects (with 40 excluded) into low-dose (40–80 mg) responders (n = 87), high-dose (>120 mg) responders (n = 78) and high-dose (>120 mg) nonresponders (n = 73). Response was based on absence of urinary opiates or cocaine for at least 3 months, no self-report of opioid consumption, no complaints of withdrawal symptoms and regular attendance at therapeutic programs. Four ARRB2 SNPs were selected based on several criteria (such as minor allele frequency, functionality and disease association). Three SNPs were

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5–160

3–430

Dose titration

106 ± 71 (n = 68) R; 90 ± 50 (n = 23) NR

12.5–260

100 ± 68 R; 78 ± 43 NR (mean ± SD)

Taiwan

Switzerland

Germany

Spain

Israel

Spain

116

72

91

85

238

361

n

 

Phenotype(s)

MYOCD rs1714984G>A, rs965972, rs1867898 GRM8 rs1034576, GRM6 rs953741A>G, CRY1 rs1861591, NR4A2 rs1405735, OPRM1 rs1074287

Genotype: HV/HET higher frequency of nonresponder vs HW Overall 3% contribution to response rs1045280C (OR [95% CI]: 3.1 [1.5–6.3]) for nonresponse rs2036657G (OR [95% CI]: 2.5 [2.1–5.1]) for nonresponse Overall 6% contribution to response

COWS: urine (+)ve group: Genotype: HV/ HET vs HET lower scores; allele: variant vs WT lower scores Pupil: urine (+)ve group: rs6600880; urine (-ve) group: rs28365062 Tremor: urine (+)ve and (-)ve groups Pupil size and tremor

Findings

R (83); NR (33)

Dosage

No significant difference in genotype distribution after multiple testing adjustment MYOCD rs1714984A carriers + GRM6 rs953741A/G carriers increased risk of nonresponder (OR [95% CI]: 10.83 [2.5–47]); p = 0.006

rs2239622C>T: HV 81.7 ± 11.8 mg (n = 9); HET 153.1 ± 7.9 mg (n = 37); HW 139.7 ± 7.9 mg (n = 26); p = 0.0002 (recessive model)

No SNP associated with responder vs nonresponder Six SNP CCGCCG haplotype block associated with risk of poor response after cooperativeness adjustment (OR [95% CI]: 20.3 [1.46–281])

Dose titration (based Max daily dose year 1: HV group: 119.7 ± on clinical judgement 49.6 vs HW/HET 77.5 ± 26.2 and withdrawal symptoms)

BDNF: 30 SNPs tested including R vs NR rs6265 (Val/Met) Haplotype block; rs7127507 (C>T), rs1967554 (C), rs11030118 (G), rs988748 (C>G), rs2030324 (C>T), rs11030119 (A>G)

KCNJ6 rs2070995G>A

ARRB2 rs37866047, rs1045280 R vs NR rs2036657 rs37866047, rs1045280 rs2036657 plus DRD2 rs6277 C/C

UGT2B7 rs6600879 (G>C), Withdrawal (COWS) rs6600880 (A>T), rs4554144 (T>C), rs11940316 (C>T), rs7438135 (A>G), rs7662029 Pupil size (G>A), rs7668258 (C>T), rs7439366 (C>T), rs4292394 Tremor (G>C), rs6600893 (C>T) GATCAGCCGC and CTCTGATTCT

Gene/SNPs/haplotypes

Jewish (62; NGFB Non-Jewish 15 SNPs assessed (10)

Caucasian

Caucasian

Caucasian

Han Chinese

Ethnicity

(+)ve: Positive; (-)-ve: Negative; COWS: Clinical Opiate Withdrawal Scale; HV: Homozygous variant (minor); HET: Heterozygous; HW: Homozygous wild-type (major); NR: Nonresponder; OR: Odds ratio; R: Responder; SD: Standard deviation; WT: Wild-type.

Dose (mg/day)

Country

Table 4. Summary of pharmacogenomic studies investigating the role of pharmacodynamic SNPs in methadone clinical outcomes in methadone maintenance treatment programs.

[45]

[106]

[105]

[104]

[103]

[102]

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1019

1020

(+)ve: Positive; (-)-ve: Negative; COWS: Clinical Opiate Withdrawal Scale; HV: Homozygous variant (minor); HET: Heterozygous; HW: Homozygous wild-type (major); NR: Nonresponder; OR: Odds ratio; R: Responder; SD: Standard deviation; WT: Wild-type.

[41]

R (165); NR (73) Switzerland

Switzerland   

Taiwan

Pharmacogenomics (2014) 15(7)

3–430

238

OPRD1 rs2234918 921T>C Caucasian

  

R (165); NR (73)    Caucasian   

 

[41]

Dose Han Chinese

No difference in genotype frequency between R and NR (p = 0.5)

[43]

[107]

Carriers of T variant allele required higher dose (∼97 mg/day) compared with noncarriers (∼74 mg/day) (p = 0.03) Carriers of T variant allele had a twofold chance of requiring lower dose (OR [95% CI]: 0.50 [0.32–30.76]; p = 0.001) Homozygous CC more likely to be nonresponder (OR [95% CI]: 2.4 [1.2–4.8], p = 0.015) Dose DRD2 rs6275C>T Germany

∼20–170 T: HW higher frequency (25%) of nonresponders vs responders (12%) ANNK1 rs1800497 (TaqIA) DRD2 957C>T 3–430 Switzerland

238

Caucasian

R (165)

Findings Phenotype(s) Gene/SNPs/haplotypes Ethnicity n Dose (mg/day) Country

Table 4. Summary of pharmacogenomic studies investigating the role of pharmacodynamic SNPs in methadone clinical outcomes in methadone maintenance treatment programs (cont.).

Ref.

Review  Somogyi, Barratt, Ali & Coller significantly associated with response but their overall contribution to MMT response variability was only 3%. Two SNPs were associated with the risk of nonresponse, rs1045280 (OR [95% CI]: 3.1 [1.5 to 6.3]) and rs2036657 (OR [95% CI]: 2.5 [1.2 to 5.1]). No SNP was associated with methadone dose, duration of MMT and patients estimation of holding time. When three SNPs (rs1045280, rs2036657, rs3786047) were combined with a DRD2 SNP rs6277 C/C genotype in a logistic regression model, the regression was improved to 6%, suggesting impact of a combination of SNPs in DRD2 and ARRB2 on MMT response (Table 4) . KCNJ6

GIRK2 is a member of the transmembrane G-protein activated inward rectifier potassium channel 2 (K ir3.2). The channel is linked to the signal transduction of opioids on postsynaptic transmission and hence to analgesia. The rationale for investigating polymorphisms in the gene (KCNJ6 ) is that in a Japanese group of patients after abdominal surgery, opioid requirements were increased in those with the SNP rs2070995 [110] . In a study that collated data from a previous study, Lötsch and colleagues investigated 85 MMT subjects who had their daily dose titrated in an outpatient centre with the maximum dose based on withdrawal symptoms and other relevant criteria [104] . They investigated the rs2070995 SNP in particular. The average (119.7 ± 49.6 vs 77.5 ± 26.2 mg, p = 0.003) and maximum (132.8 ± 54.7 vs 91.3 ± 30.7 mg, p = 0.013) daily doses were significantly higher in the four homozygous carriers compared with the combined (n = 81) heterozygous and homozygous minor allele groups (Table 4) . In addition, in the four homozygous variant subjects, no withdrawal symptoms were reported in contrast to 55 of the remaining 81 (homozygous major allele and heterozygous, p = 0.006) subjects. The significance of this finding in such a small cohort needs replication. BDNF

This neurotrophin plays several roles in the brain including modulating neurotransmission and the most frequently studied SNP rs6265 Val66Met has been associated with opioid dependence [111] . In a study in 91 MMT subjects who had been enrolled for 6 months with no upper dose restriction, and on a stable dose for 2 months, de Cid and colleagues subdivided subjects into 68 responders (previous four urinalysis testing negative) and 23 nonresponders (≥2 of last four urinalysis testing positive) and studied the BDNF 63.8 kb region [105] . They found no effect of the Val66Met SNP on methadone response but a haplotype block involving 13 SNPs was more frequent in nonresponders (4/42) than in responders (1/135; pcorr = 0.023) and a

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Pharmacogenomics of methadone maintenance treatment 

smaller six SNP block comprising homozygotes and heterozygotes increased the risk of a poor response (OR [95% CI]: 11.92 [1.24 to 116.3]; p = 0.031); after adjusting for co-operativeness, the latter was increased to 20.3 (1.46–281). Such large confidence intervals point towards an effect of unknown size magnitude (Table 4) . NGFB

This is another member of the neurotrophin family and a clear rationale for investigating its gene in MMT was similar to that for BDNF. Levran et al. [106] described two cohorts: 72 former heroin addicts from Israel in ≥6 months of MMT and having a 4 week stable methadone dose and a case–control association study of heroin addiction from two previous publications involving 350 former heroin addicts on methadone and 184 controls [106] . Fifteen NGFB SNPs were genotyped of which three were excluded. There was no difference in allele frequencies between the three groups but one intronic SNP rs2239622 showed a difference in dosage in the Israeli MMT group. Using a recessive-based model, the mean dosage in homozygous variants was 81.7 mg (n = 9) compared with the homozygous major allele (mean 140 mg, n = 26) and heterozygotes (153 mg, n = 37, p = 0.007 codominant model; Table 4) . MYOCD/GRM6

The genes GRM6, GRM8, NR4A2, CRY1 and MYOCD have been associated with heroin dependence. Whether they are associated with methadone response per se was not mechanistically clarified as a hypothesis. Nevertheless, Fonseca et al. studied 116 MMT subjects (from an initial cohort of 169) who had been enrolled in MMT for ≥6 months, were on a 2 week stable dose and who underwent 1–2 weekly urinalysis for opioids [45] . Responders were defined as those with negative urinalysis in the previous four tests and nonresponders as those with positive urinalysis. None of the three MYOCD, or single GRM6, GRM8, CRY1, NR4A2 SNPs were associated with the risk of nonresponse when corrected for multiple testing. However, an epistatic factor was noted when MYOCD (rs1714984) and GRM6 (rs953741) were combined such that those with the A allele of MYOCD rs1714984 G>A had an increased risk of nonresponse only if they were also AG carriers of GRM6 rs953741 A>G, even after adjustment for duration of treatment (OR [95% CI]: 10.8 [2.52 to 46.7]; p = 0.006). However the role of this myocardial protein myocardin in MMT is not known and it should be noted that the sample size was small and response assessment difficult to establish (Table 4) .

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DRD2

The rewarding effects of opioids are considered to be mediated principally via dopamine acting on dopamine receptors 1 (D1 encoded by DRD1) and 2 (D2 encoded by DRD2). The TaqI A allele (rs1800497) of DRD2 was initially shown to be associated with nonresponse (heroin use: self-report, medical examination, random weekly urine screen) to methadone (42% responders [n = 19] and 9.3% [n = 54] nonresponders p = 0.00002; 95 subjects and 22 dropouts [112] ). However, this was not confirmed (successful n = 30; poor n = 13: based on self-report of opioid use/plasma morphine/urine drug screens) in a subsequent study [113] . This gene has now been shown to reside in a coding region of ANNK1 and therefore may affect the signal transduction pathway in the dopaminergic system [41] . This group found no effect (p = 0.9) of the SNP on response (nonconsumption of heroin or cocaine [self-declaration and confirmation of negative urines for opiates or cocaine for 3 months], an absence of complaints of withdrawal symptoms, and a steady and regular attendance at the therapeutic program) to methadone in a cohort of 238 Caucasian subjects [41] . Other DRD2 SNPs

Doehring et al. found that a synonymous SNP DRD2 rs6275 was associated with the daily methadone dose in 85 MMT subjects [107] . Specifically, homozygous major allele subjects had a lower dose (∼65 mg) compared with homozygous variant and heterozygotes (∼86 mg). Hung et al. in Taiwanese methadone subjects found the opposite, in that carriers of the variant had a twofold chance of requiring lower doses (OR [95% CI]: 0.50 [0.32 to 30.8]) [43] . This SNP (rs6275, 939T>C) is in close proximity to and is in strong linkage disequilibrium with SNP rs6277, which alters mRNA folding, decreases mRNA stability and protein synthesis, and reduces dopamineinduced upregulation of DRD2 receptor expression. Crettol et al. showed that rs6277 homozygous major allele subjects were more likely to be nonresponders (OR [95%CI]: 2.4 [1.2 to 4.8]; p = 0.02; Table 4 ) [41] . OPRD1

In 238 MMT subjects, there was no influence (p = 0.5) of the δ-opioid receptor SNP 921T>C (OPRD1 rs2234918) on response to methadone and its dosage (Table 4) [41] . Multiple gene studies It is quite obvious from the above studies that investigating specific candidate genes due to a plausible mechanism (the so called targeted gene approach)

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1022

results in false-positive and -negative results and overall often uninterpretable findings as to the genetic contributions to intersubject variability in methadone treatment. Some studies have now focused on multiple genes in order to try and gain a better understanding of association. Hung et al. after adjusting for a number of cofactors showed that genetic variants in ABCB1, CYP2B6, OPRM1, ANKK1 and DRD2 and their interaction terms were correlated with the optimal methadone dose (r2 = 0.53) in their 321 opioiddependent subjects [43] . More recently, Levran et al. investigated 11 genes (OPRM1, POMC, ARRB2, GRIN1, GRIN2A, DRD2, ANKK1, NGFB, BDNF, NTRK1, NTRK2) and showed through logistic regression that five SNPs involving NTRK2, BDNF and ANKK1 were able to discriminate between high (>120 mg/day) and low dose (80%. • Metabolism is by CYP3A4 and 2B6 and it is a substrate for P-gp. • It has a long terminal half-life of over 48 h. • (R)-methadone has a much higher affinity for the μ-opioid receptor than (S)-methadone. • Stereoselectivity in metabolism and pharmacokinetics is apparent.

Receptors/targets • The OPRM1 118A>G variant is associated with methadone requirements only when taking into account confounding variability in other genes. • Putative associations between OPRM1 polymorphisms and methadone adverse effects have identified an important new area for future investigation.

Methadone metabolism • CYP2B6 variants, including *6, have been associated with altered pharmacokinetics and methadone requirements. • The evidence for CYP2D6 and CYP3A4/5 variants being associated with altered pharmacokinetics and methadone requirements is either contradictory, or from small studies, requiring further investigation utilizing a cumulative approach.

Drug transporters • ABCB1 haplotypes have been associated with methadone requirements, but findings vary depending on clinical context and variability in other genes. • Altered methadone CNS distribution appears the most likely mechanism; however, there are competing hypotheses as to whether ABCB1 variants might affect P-gp function directly, or indirectly by altering methadone autoinhibition of P-gp.

Other genes • Variants in ARRB2, BDNF, ANNK1 and DRD2 genes, often in a haplotype block, have been associated with response. • Variants in GIRK2, NGF and DRD2 have been associated with dosage (high–low). • Identification of new genes affecting outcomes is likely to require large international studies coupled with genome-wide association study analysis.

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Pharmacogenomics of methadone maintenance treatment.

Methadone is the major opioid substitution therapy for opioid dependence. Dosage is highly variable and is often controlled by the patient and prescri...
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