Last advances in Methadone

Mi psiquiatra, que conoce mi afición por el inglés, me encargó la traducción de este trabajo de fin de curso de una alumna de Farmacia. La traducción al final pareció defectuosa y no fue utilizada. También me pidió en su día que eliminase el post original, como hice. Pero la entrada (LIX) he visto que queda en blanco y he vuelto a colgarlo salvo una parte que resume los artículos consultados. El blog ya es bastante caótico de por si, y me molestaba esa laguna. En general, lo poco que he vuelto a releer, no se por qué, me suena un poco a William Burroughs.

Latest advances in Methadone

INDEX

ABSTRACT

KEY WORDS

INTRODUCTION

• Addiction disorder
• Definition and epidemiology
• Etiopathogeny
• Etiology
• Comorbodities
• Treatments
• Methadone (background)
• Definition and state of the question
• Pharmacology
• Pharmacokinetiks and pharmacodynamics
• Metabolism
• Pharmacogenomics

OBJECTIVES

MATERIAL AND METHODS

• Search tools
• Search strategy design
• Key words
• Filters
• Selection criteria

RESULTS

• Pharmacokinetics
• Pharmacodynamics
• Conclusion

DISCUSSION

• Therapeutic individualization in methadone maintenance therapy
• Prospects, limitations and future

CONCLUSION

ANNEX

• Glossary of terms

BIBLIOGRAPHY

ACKNOWLEDGEMENTS

Abstract: Drug addiction is a disease that is characterized by the compulsive search and consumption of drugs.  Evidences gathered in recent years allow us to affirm that addictive disorders are chronic diseases whose origin is based in the central nervous system.  Treatment can be pharmacological, behavioral, or a combination of both.  Currently, the most widespread pharmacological treatment is methadone maintenance therapy, especially in patients who do not respond correctly to other treatments.

Objectives: Carrying out a systematic review of the most important genetic biomarkers in relation to methadone as a treatment for breaking the habit of using heroin.

Material and methods: Applying the principles in the PRISMA declaration we intend to carry out a systematic review of all the articles between the years 2000 and 2022. The databases used were the following: Pubmed, Scopus, Web of Science and Psycinfo.

Results: Nineteen articles met the selection criteria . The most prominent genes were CYP2D6, CYP3A, CYP2B6 and ABCB1. The articles reviewed established the importance of the ABCB1 gene for its role in drug toxicity and CYP2B6*6 polymorphism.

conclusions: the conclusions we draw from the texts analyzed in our review is that there’s a trend to consider pharmacogenomics, the study of the role of the genome in drug response, the analysis of how the genetic make-up of an individual affects their response to drugs, far more important than pharmacokinetics, the branch of pharmacology  dedicated to determine the fate of substances administered to a living organism and to analyze chemical metabolism to discover their fate from the moment that they enter the organism up to the point at which they’re completely eliminated from it. In spite of this emphasis on pharmacogenomics, on how the genoma of the patient shapes his response to the drug, there is a need, though,  to carry out  studies on pharmacokinetics to gather more evidence, for instance, about the genes that play a significant role in methadone metabolism and methadone performance .[Nota: La “fármacogenetica” estudia el efecto de la variabilidad genética de individuo en respuesta a determinadas drogas (Wikipedia s.v.); La “farmacodinamica” estudia los efectos bioquímicos y fisiológicos de los fármacos y de sus mecanismos de acción y la relación entre la concentración del fármaco y el efecto de este sobre un organismo. HASTA AHÍ, BIEN. No entiendo bien por qué hay que incrementar los estudios sobre “fármacocinética,” la rama que estudia los procesos a los que un fármaco es sometido a su paso por el organismo, que le sucede desde el momento en que es administrado hasta su total eliminación del cuerpo, par reunir más evidencia sobre los genes que desempeñan un papel significativo en relación con la metadona.]

KEY WORDS 

Metabolism, Genes, Biomarkers, Maintenance Therapies.

Introduction.  

Addiction disorder.  

Definition and epidemiology.  

Drug addiction is a disease characterized by the compulsive or uncontrollable search and consumption of drugs, despite the harmful consequences that this may entail.  It should be noted that one of the most important characteristics is its relapsing chronicity (1.2). 

At first drug addicts use drugs of their own free will but this voluntary nature of drug consumption doesn’t last, sooner or later addiction, the addiction caused by drugs, makes an appearance and the subject passes from voluntarily doing drugs to have a need to consume them. 

Addiction affects areas of the brain that regulate motivation, reward, learning, memory, and the control of behavior.  Due to the affectation of these areas, behavioral changes and behavioral disorders occur making social relationships difficult and posing a problem for society (1).

Maybe it will be useful to provide a few data on the use of heroin to situate the work in its context.  In 2017, 0.6 of the Spanish population between the ages of 15 and 64 had used heroin at some time, 0.1% in the last year and 0.1% in the last month.  The average age at onset is 22.7 years and the consumer profile is that of a man over 45. Heroin consumption, however, has remained stable since the mid- of the 1990s (3).

The number of those admitted to treatment for heroin use was around ten thousand addicts in 2018, a number that confirms the downward trend began in 2010. This trend is justified both by the decrease in the number of people admitted to treatment, due to the fact that many of those who had previously been treated for this substance had not relapsed since and also because the number of those admitted to treatment for the first time also decreased. The following graph, taken from the 2021 Report of the Spanish Observatory on Drugs and Addictions, shows this (3).

[ILUSTRACIÓN 1: “Prevalencia”: Incidence; “Edad (años)”: Age, years; “Alguna vez en la vida”: Occasionally in life; “Ultimos 12 meses”: Last twelve months;  “Ultimos 30 días”: Last thirty days; “Edad Media de inicio en el consumo”: Mean age of initiation of consumption.

Evolution of the incidence of heroin consumption (%) and mean age of initiation in its use (years) in the population aged 15-64.  Spain, 1995-2019/2020.  

Source: Report on Alcohol, tobacco and illegal drugs in Spain (3)].

ETIOPATHOGENY

The transition from a sporadic user to an addict depends on three factors: pharmacological, genetic and environmental. Genetics are crucial to understand the different degrees of attachment to the use of drugs of abuse in different individuals. 

On the other hand, environmental stimuli, and often the very experiences related to drug use, may act as agents that can easily trigger the consumption of drugs of abuse, even after a long period of abstinence.  

ETIOLOGY

Drug addiction is related to neurobiological mechanisms of brain function.  The use of substances for recreational purposes is due to the fact that these substances cause reinforcing effects through mesolimbocortical dopaminergic pathways.  Dopamine intervenes in motivational processes by enhancing brain function or attracting it towards surprising or significant external events.

Drug abuse, moreover, is associated with a series of adaptive changes in brain function.

Drugs of abuse, by activating reward pathways, enhance the mechanisms through which primary stimuli acquire a motivational and action oriented sense. (2)

COMORBIDITIES

Studies carried out by the Vall d’Hebron Psychiatric Service show that 67% of the cases, that is just about the 70% of heroin addicts analyzed, exhibited more than one psychiatric disorder simultaneously.  The most frequent associated disorder is anxiety, followed by changes in mood, sleep, changes due to substance abuse and personality changes.

The proportion of patients with at least one psychiatric comorbidity increases significantly with the dose of methadone the patient receives.  This is another of the reasons why it is convenient to carry out conclusive studies for the administration of the required dose to be to be individualized, personalized, tailored for each patient, since a high dose of methadone could aggravate these disorders.

It’s important, therefore, to accurately diagnose psychiatric disorders in heroin addicts, but it must be taken into account the diagnosis is even more difficult due to the tangles and the side-effects of dependency itself.

TREATMENTS

The evidence accumulated in recent years allows us to affirm that addictive disorders are chronic diseases the origin of which is based in the central nervous system.

Although the first step in the treatment of any addiction is acute detoxification, the key to the treatment of drug dependency focuses on relapse prevention.

The treatments  for this disorder are of two types: behavioral and pharmacological.  Both seek a certain degree of normality in the patient’s life, especially in the social and labor field. The most effective approach at present is the integration of both (1).

According to a large number of scientific studies, pharmacological treatment increases adherence to cessation programs,and decreases the transmission of diseases and criminal activity.  This is because pharmacological treatments today focus on the treatment of withdrawal symptoms. They are not a treatment for addiction itself, but they help not to prolong consumption once detoxification is achieved (1).

The drugs used for this type of addiction act on the same receptors as the drug of addiction, but with greater safety and fewer harmful effects on the patient’s behavior.  There are three possible drugs that interact with the above mentioned biological targets: (a) agonists, (b) partial agonists and (c) antagonists.  The use of a particular one is determined according to the consumption of the patient and medical needs.  The drugs currently used are these ones:

• Methadone, a slow-acting opioid agonist.  It is reiteratedly used in patients who do not respond correctly to other medications.  It is only available through approved programs.

• Buprenorphine, a partial opioid agonist.  It alleviates the desire for consumption, without producing euphoria or other distinctive effects of opioids.  The Food and Drug Administration in the United States (FDA) approved it in 2002, and it was the first drug prescribed by certified doctors in the Drug Addiction Treatment Act.

• Naltrexone, an opioid antagonist.  Its mechanism of action lies in blocking the action of opioids. It is not addictive or sedative, and it does not create physical dependence, but patients often have problems complying with treatment, and this limits its effectiveness.

As to behavioral therapies, the main approaches are “contingency control”, based  on a point system in which the patient earns points every time he gets a negative result on drug tests, and “cognitive behavioral therapy” which contributes to modify behavior, the patient’s expectations in relation to consumption and how to face stressful factors in his life are used (1).

One of the challenges in treating heroin addiction is identifying the best treatment according to the needs of each patient.

METHADONE (BACKGROUND)

DEFINITION AND STATE OF THE QUESTION

Methadone is a synthetic opioid mu-opioid receptor (MOR) agonist and N-methyl-D-aspartate (NMDA) receptor antagonist, these two being its main therapeutic targets.  It comes in the form of a white powder with a bitter taste (5).

As a drug it can be prescribed as an analgesic to relieve severe pain that is difficult to treat or for opioid substitution therapy.  The use of methadone for opioid addiction dates back to 1946, the year in which it was also included in the Pharmacopoeia. At that time it was used as a treatment for the suppression of Morphine.  Methadone in this type of treatment reduces the effects of the withdrawal syndrome for a period of between 24 and 36 hours and creates less tolerance to opioids, probably due to its antagonistic effect on the NMDA receptor (5,6).

In 1962 Dr. Vincent P. Dole worked on a project on obesity and observed that the uncontrolled desire that obese patients had for food could be similar to the addiction that drug addicts had for drugs. Because of this he began a study together with the psychiatrist Marie Nyswander, in which a series of addicted individuals began treatment with methadone (7).

It was not until 1964, two years later, when Dole and Nyswander began to use Methadone for patients addicted to heroin. They considered that the administration of Methadone was the best choice for a number of reasons: its good oral bioavailability, which avoids the use of the parenteral route, thus avoiding the contraction of diseases such as HIV (Human Immunodeficiency Virus);  and a longer half-life, so that the doses can be administered more spaced apart, something that also entails an improvement in social inclusion. Nowadays, Methadone maintenance programs are a widespread form of treatment, fully regulated and for which a series of requirements must be met (5,6).

Dole and Nyswander hypothesized that opiate dependence was a physiological disease caused by a permanent metabolic deficiency and that the best way to control it was administering a certain amount of opiate to the addict to stabilize his levels (8).

It may be important to highlight the evolution of drugs in the United States in recent years, since it probably reflects the course of events in Europe.  An outstanding event to comment on is the increase in deaths from poisoning between 1999 and 2006. Referring to this, multiple studies were carried out to clarify different issues.  Methadone is a widely used drug because it relieves pain from 4 to 8 hours, but it remains in the body for around 59 hours, that is, more than two days. This means that it takes a long time to eliminate it, which can cause unwanted effects. Lack of knowledge about certain unique properties of methadone was found to contribute to some deaths in the United States. Most of them were caused by the use of more than one drug, in particular the joint use of methadone and benzodiazepines which combined increased the risk of death , comparing numbers with the separate use of each of them (9).  Anyway, although the health risks of the joint use of these two drugs are almost certainly greater, the effects of their interactions aren’t yet fully understood (10).

Different studies have shown an increase in the distribution and prescription of opioids, but there are data that establish that several of the deceased acquired opioid analgesics illegally (9).  In the article “Drug involvement in fatal overdose” in the journal SSM – Population Health, a study was published trying to find out which drugs were responsible for the growth in overdose deaths in the United States between 1999 and 2014. One of the obstacles that the study encountered  was that death certificates didn’t identify the drugs. On the other hand, in many cases what was found was a  mixture of drugs, and a cause of death could not be identified, because death would probably be the result of the interaction of various drugs.  In the specific case of heroin, which is one of the main drugs to be treated in this work, deaths skyrocketed 498% between 2004 and 2014.. Most of this increase took place after 2010.

Additional shortcomings of this study were failures regarding the misclassification of deaths not related to the use of drugs and the lack of details in the death certificates, which might lack data even if they contained the specific name of the drug.  The aim of the study  was to achieve a better understanding of the risk factors associated with the combined use of drugs, and with the explosive growth of deaths caused by heroin (10

There are reasons for this. The market of heroine and methadone has increased. A fourth part of the opioid user population in Denmark is reported to use methadone without any medical reason.. The amounts of buprenorphine and methadone available increased by 34 % since 1999. Until 2009 only a small amount of opioids was sized worldwide; this quantity increased an average of 6,3 tons annually during the years 2009 – 2013 and peaked in 2014 with 203 tons. Since then this amounts have always been high, and global heroin seizures increased almost every year.  

PHARMACOLOGY

Opium is a juice extracted from the capsules of the poppy (papaver somniferum). It contains multiple active alkaloids, among which morphine stands out, codeine and Noscapine, and others  The juice of the plant has been used for therapeutic purposes since ancient times.

The chemical structure of morphine was discovered in 1925 by Gulland and Robinson.This molecule has a pentacyclic alkaloid structure with a rigid T-shaped structure. With small alterations in it’s  structure, semi-synthetic alkaloids can be obtained, such as methadone, as shown in figure (5). 

Years later it was discovered that exogenous opioids activated a series of receptors in the nervous system to which endogenous opioids secreted  by the organism bound (12).These substances (·endogenous opioids”?) are of a peptide nature and  form three groups: enkephalins, dynorphin and endorphins, with common characteristics between them. The receptors they bind to are also three: mu (mi), delta,[“delta”] and kappa [“kappa”], and are membrane receptors associated with proteine (7, 13).          

Methadone is a type of exogenous opioid classified as a “pure agonist,” the same as morphine, and was developed in Germany in 1937. It’s the simplest structure derived from morphine but maintains the fundamental traits of the group and interacts with the appropriate receptors.      

PHARMACOKINETICS  AND PHARMACODYNAMICS

Methadone shows an asymmetric carbon in its structure and this means it has two isomeres, R and S. R isomer is the one with the fundamental pharmacological activity but it’s usual to administer the racemic mixture since both [?] are difficult to separate and the effect is like that of administering just the active formulation. In spite of this, it’s important to take into account that some metabolizing enzymes are stereoselective for this compound, and this makes the clearance of both formulations different. There’s clear evidence that Enantiomer R is the one which prevents the withdrawal syndrome in addicts, and S is ineffective (7). 

As for its pharmacokinetics, methadone is orally administered and is detected in plasma thirty minutes after administration. As has been said, methadone is characterized by a large (response) variability, and the same dose can produce different concentrations in different patients.  

Administered in a single dose methadone´s potency is similar to morphine’s, but in clinical practice, when it is long-term, chronically administered, its potency is several times bigger. The reason is that, by repeated use,  it reaches tissues where it accrues as in a reservoir, mainly fatty tissues and a dose readjustment is needed in this type of treatments (7). In the case of methadone, the administered dose and the effect are proportional, but eventually receptors saturate, and increasing the dose doesn’t increase the effect.

Methadone’s excretion is fundamentally renal, but the possibility exists in a minor proportion of a fecal excretion. Urinary, renal excretion is variable and is determined by urine’s PH, that’s why maintaining the PH constant 

lessens Inter-individual variations (6,14). 

Though it has effects and risks similar to those of other opioids, methadone also has certain pharmacokinetic and pharmacodynamic features that make it useful in the treatment of opioid addiction (6). As for its pharmacodynamics, it produces the typical effects of the opioid group: analgesia, sedation, hypotension, bradycardia, nausea, vomiting and constipation. As compared with other opioids it generates a minor number of active metabolites, providing, then a lesser risk of neuropsychiatric toxicity (6). It’s also worth noting that it’s a drug extremely prone to interactions. 

METABOLISM

Cytochromes P450 are a superfamily of hemeproteins with a catalytic function that are anchored to the membrane of  cells by means of a series of structures; and face most of them the cytosolic facet of the cell’s membrane they belong to. They are are distributed through numerous tissues of the organism, mainly  the liver and small intestine and are the most important enzymes in the biotransformation of xenobiotics (15).   

Methadone is strongly affected by first-pass metabolism. Cytochromes P450, performing as  monooxygenases, are the main cause for this biotransformation of xenobiotics (15). Cytochromes are formed by a great number of enzymes. The ones triggering this biotransformation  are specifically CYP3A4, CYP2B6, CYP2C19, y CYP2D6. Methadone is at first biotransformed into an extremely unstable metabolite which soon changes into EDDP (2 – etil – 1,5 – dimetil – 3,3 – difenilpirrolidina) after going through a process of ciclation and drying, dehidratation ,which will, in a next stage, lead to another molecule, EDMP (2 – etil – 5 – 3,3 – difenil – 1 – pirrolina) (6,7). This metabolic pathway appears outlined in illustration (3), taken from the article Arribas E et al. 2009 (7) published by the science divulging outlet Acta Bioquímica Clinica Americana.   

As was previously said, methadone is an isomeric molecule and its biotransformation is determined by that. Stereoselective cytochromes are CYP2B6 and CYP2C19. CYP2B6 has a preference for inactive (S)-methadone and CYP2C19) metabolizes mainly active (R) – methadone (7).

Single-nucleotide polymorphisms (SNP) can importantly affect the pharmacokinetics of methadone and add to the interindividual variation. CYP2B6 polymorphisms cause the different responses of patients since they are basically involved in the biotransformation and clearance of methadone. They include a number of polymorphisms that increase the concentration of the drug in plasma (?). Due to the extreme variation  in the metabolism of methadone it’s been impossible to find out a clear relation between dose, blood test results and effect, and this makes unavoidable a careful exam of the patient and a readjustment of dose, if necessary.  

PHARMACOGENOMICS

Pharmacogenomics considers the relation between variations in DNA sequences of patients and their response to pharmaceuticals (17). 

One of the principal databases is PharmGKB. It’s a source of information about genetics, about how genotype and phenotype relate, clinical guidances to deal with it and genetic associations. Its primary aim is to collect, select and diffuse information on the impact of genetic differences in the response to pharmaceuticals, that is,  prescription medicines, over the counter drugs and illegal drugs (18).This page arises from the need of free and truel information concerning phenotypical and genotypical data that could be used by the scientific community to carry out research about and promote pharmacogenomics,  pharmacogenetics. In it it is possible to perform searches using as criteria molecule, gen or illness and according what’s asked for an information will appear or other but in all cases with a similar design. Browsing is intuitive and someone has taken the care of classifying the info under different tabs.  

There is a great deal of  ongoing research on methadone and the interdividual variations related to it in different fields: genetics and its links to receptors (OPRM1, OPRD1), metabolism (CYP450), excretion, absortion and others.  

OBJECTIVES

As the addiction to heroine, as was mentioned above,  is a disorder highly prevalent in society, which deteriorates social convivency and the quality of life of patients and families,  and being aware that pharmacogenomics  is one of the fields of enquiry that attracts a large number of scholars and will make it possible in the future to tailor pharmacological therapies for large numbers of individual patients, we’ve chosen as subject of this work  a systematic review of the most relevant genetic biomarkers concerning methadone as treatment for the dependence of heroine. 

For the carrying of this piece of research, there will be a need in first place of thinking about the importance of the work and which important questions we aim to answer. 

Doses administered to patients in maintenance programs  are established taking only into account to which drugs patients are addicted, and genetic biomarkers are not pondered to gauge an appropriate dosage nor to predict a response to the treatment. Besides identifying and clinically using those biiomarkers to determine the individual genetic  response of each patient to the methadone treatment) we will try to shed light on different questions about the metabolism of methadone, its fate in the organism, because that’s also related with adjusting the right dosage. The metabolism of methadone is a difficult process and has also todo with genes. We will limit the search for evidence about those genes  in the European population the genotype of which would be important to determine. 

This information is intended to be useful for health professionals since will allow them to have at hand all the evidence collected to the present. Besides, the patient will also be given access to the data and, if he is able to,  

will talk to his doctor in order and get his values analyzed. 

MATERIAL AND METHODS

SEARCH TOOLS

What’s written here is the result of perusing  nineteen articles covering years 2000 – 2022  we found systematically reviewing the literature on our subject, the relation between genotypes and the different effects of methadone, when used for the treatment of addiction, and we have selected them and try to expose them according the directions  in the  “PRISMA statement.” The “PRISMA statement” was published in 2009, following the change of the Quorum statement as a guide for authors of systematic reviews in order these reviews  to be done in a transparent way and be publishable, which, it seems, serves to provide a characteristic form to  research and tights the team and, secondly, that the piece reviewed had been actualized in 2020. (19).

Our search tools had been:

• Pubmed, a database with free access and which deals in health sciences. It allows to realize both simple and complex searche (20)
• Scopus, a database of books data, and quotes of the firm Elsevier (21, 22)
• Web of Science, a company owned by Clarivate  Analytics, a database collecting bibliographic references and quotes since 1900 to the present. ContainsHas place for different themes as Sciences, Social Sciences, Arts and Humanities (23).
• Psycinfo, another database published by the American Psychological Association, considered one of the most important institutions in the field of psychology, though it collects information about kindred sciences too and that’s why we’ve made our mind to mention it.

SEARCH STRATEGY DESIGN

KEY WORDS

The words that will be used in the search to make easier to find the premises we pose are:

(Methadone) AND (metabolism) AND (gene* OR polimorphism OR biomarger*).

FILTERS

We’ll start setting in the aforementioned database the following filters:

a) Date: 1st January 2000 – 30 th March 2022. This period, twenty years of time, is chosen because it’s necessary to set a limit somewhere, and this period looks right because one shroud not travel afar too long in time in order the strategies we read about be similar to the ones we experience.

b) Especies: human

c) Language: English, since it’s the language employed as vehicle in science.

d) The sample of subjects is restrained to the habitants of Europe.  As the usual gene polymorphisms frequent in this continent are different than that of others, to study those polymorphisms at a global level would be really useful, but it would be necessary to establish different strategies for each of the places surveyed, that’s to say, undertake the study of different biomarkers in each continent. 

e) Prescribed format: articles, clinical trials or controlled random experiments.

As each of the base dates has a design of its own it’s not possible to set the same filters as limits in all of them, so that keywords might not work in some and it would be necessary to revisit the articles searching them by the words in their title and the resume drafted to classify it. 

SELECTION CRITERIA 

From the articles that weren’t barred by those filters we will select those fulfilling the following criteria in title and resume:

a) Humans

b) Sample of Europeans or countries of Europe.

c) Texts formatted as articles, a clinical trial or a controlled random essay.

d) those not containing particular circumstances as pregnancy … or joint (?), additional(?) comorbidities

e) Reference to Methadone in title or resume

f)Theme: Genetics

(…)

RESULTS

The search in the different databases to achieve the aforementioned objectives of the review, using the available filters listed as such had as result 560 articles. With the elimination of duplicates, 29, we were left with a total of 531 articles. This group of texts is sifted in accord to a list of selection criteria assessing title and resume to check it meets to the selection criteria posed in the present revision. After checking this, 511 articles were excluded and nineteen selected therefore to be sifted in brief a few times more. Accessing the full text of them, it’s also possible to finde the resume of their content in the graph belAs a resume of the results and conclusions we draw from the articles we’ve been left with after the sifting process, we consider genes CYP2D6, CYP3A, CYP2B6 and ABCB1 the more relevant in them. Conclusions will be addressed referring individually to genes to have a global vision of the results of all the studies. 

• CYP2D6: This gene influences the blood concentrations os methadone and also the response of this drug, but not remarkably. It’s influence on the dose requirement is small.
• CYP3A: This enzyme is considered to have a poor influence on the response to the methadone maintenance treatment and the dose requirement (25,29,31), and it’s settled that SNP POR*28 polymorphism is a better marker of this gene than the genetic variants of CYP3A4, CYP3A5 and CYP3A7 (26).
• CYP2B6: This enzyme of cytochrome P450 is characterized by stereoselectivity, and that’s why preferentially metabolizes (S) – methadone (33). The effect exerted by methadone in the organism is fundamentally exerted by enantiomer (R), not (S), so it is expected that the CYP2B6 genotype has no significant influence on the treatment.
• ABCB1: This is the gene associated to P-glycoprotein, which plays a role in the absorption of methadone, since it’s an inverse (?) transporter at the level of the gastrointestinal tract. This transporter shows a weak stereoselectivity towards enantiomer (S), which doesn’t have a significant effect in the response to the treatment or the dose requirement, because (S) is the less active of the two enantiomers of  the molecule (32). Genotypification of this gene lacks any interest because it’s established that it has little influence in the response to the treatment and the dose requirement needed by the patient, although it’s true that it can affect the concentration of methadone both in the brain and in the place where it acts. It’s been established, too, that it affects the level of toxicity and, as a consequence, the probability of death by this drug. One of the studies establishes that rs9282564 and TT genotypes in patients reduce the risk of death by this type of intoxication (26).

Some of the articles in the chart are very specific on the effects of methadone, according to pharmacogenetics, at cardiovascular level, and the conclusions drawn are that a heart level there’s a major risk of  prolonged QTc. This is due to the concentrations of (S) – methadone. By the administration of (R) methadone alone, without administrating the racemic mixture, most of this type of problems could be fixed. This is why the identification of CYP2B6*6 polymorphism might be considered a useful risk management strategy, obtaining that way information to know if the dextro enantiomer is going to be metabolized most of it by the presence of this enzyme or if, on the contrary, the concentration of this enantiomer of the drug will be larger than expected by its failure.

Finally, mentioning in this section that some of the studies analyzed establish that most of the interest should be currently focused on pharmacogenetics in the field of pharmacodynamics, and not so much on pharmacokinetics. This maybe due to the lack of association we’ve already mentioned, to the infrequency of mutations in a random sample or because studies in this field usually have rather low sample sizes, which can compromise finding a possible valid biomarker

CONCLUSION

The conclusion we draw from the texts analyzed for methadone maintenance therapy in this review is that pharmacogenetic analysis at the pharmacodynamic level is considered more important than pharmacokinetics. As for the genes at pharmacodynamic level, more studies corroborating the obtained data are needed, but everything suggests that the most interesting genes to analyze for now are OPRM1 referring to the opioid receptor and, maybe, ARRB2 also. As for pharmacokinetics, the most interesting one would be CYP2B6 mainly because it is stereoselective to (S) – methadone, and (S) methadone has effect at cardiovascular level. Finally, it should also be highlighted the importance of the genotypification of gene ABCB2 which codifies P-glycoprotein, because of its role in the toxicity of the drug.  

DISCUSSION

THERAPEUTIC INDIVIDUALIZATION IN METHADONE MAINTENANCE THERAPY

The number of persons addicted to different drugs is rising daily, and the need of  therapies to treat that dependency is as much in the rise. The principal objective of this work is to look for genetic markers related with metabolism of methadone that could be used, in methadone maintenance therapies, to personalize dose requirements and, as a consequence, a greater adherence of patients to the treatment.   

Drug addicts usually get involved crimes and are also the cause of expenditures to society. Pharmacogenetics allow for the personalization of the dose of methadone, but the published articles up to now haven’t been able to find pharmacokinetic biomarkers that definitely could provide us with an explanation of methadone dose. It must be allowed that the small size of the samples in many of the articles, as well as the coexistence of various pathologies in most of the patients in the roll of the surveys, can make it difficult to find a correct biomarker. That’s the reason why more numerous and homogeneous studies are needed. As for pharmacokinetics, appealing evidences related to particular genes have been observed, which would be becoming to replicate and validate in larger cohorts of patients. This last, gene-related, field, which relates a few genes of the patient to his body’s response to methadone treatment, looks like an interesting topic to conduct  further investigations henceforth, or even for tackling a meta-analysis in order to achieve a higher degree of scientific conviction and,  be that way able to determine the most important genes with a role in methadone metabolism, genotype them and design an specific therapy for each patient.    

PROSPECTS, LIMITATIONS AND FUTURE

Various limitations exist in the studies included in this systematic revision. The greater limitations probably are the low size of the samples object of study and the coexistence os different pathologies in the majority of the patients. Data pertaining to patients with serious ailment of any type, were deleted, or at least, authors did they best to do that, but the major part of these patients, of addicts, even without a  diagnose, have episodes derived from other pathologies, specially at psychiatric level. Limiting our references to  just European samples may have lead us to exclude from the analysis articles that might be more specific or could provide more solid evidence.

The individualization of the different therapies, and above all of those, as the breaking – habit therapies for heroine addicts, in which discontinuation and failure are both  two of the most important factors to consider, is the future of medicine and the form to lessen unwanted reactions to the different medicines. The prospect of future is hopeful, because there’s a growing awareness of the importance of genetics at pharmacological level, but there’s still a long way off, due to the high costs they entail.

ANNEX

GLOSSARY OF TERMS

GENE : Gene is the basic fisic unit of heredity. Genes are transmitted from parents to their offspring and contain the information needed to define their features. Genes are arranged, one after another, in an orderly succession. in structures called chromosomes. A single chromosome contains a single large molecule of ADN, only a part of which corresponds to an individual gene (43).       

ALLELE: An allele is each of the two or more versions of a gene. An individual inherits two alleles for each gene, one from his father and the other one from his mother. Alleles are in the same position inside of the homologous chromosomes. If both alleles are identical, the individual is homozygous for this gene. On the contrary, if alleles are different, the individual is heterozygous, heterozygotic, for this gene (44).

POLYMORPHISM:  Polymorphism implies one of two or more variants in a particular DNA sequence (45).

SNP: Single-nucleotide polymorphisms (SNP) are a type of polymorphism which produce variation in just a base pair (46).

INDEL: Insertions and deletions (InDel is the contraction of “insertion-deletion”) are a type of mutations consisting in the elimination or insertion of nucleotide bases in particular DNA regions (47).

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Accessed Jun 23, 2022  

ACKOWLEDGEMENTS

I want to express my gratitude to Angel Carracedo for giving to me  his permit to take part in this work.

To Olalla Maroñas and Almudena for keeping me company, instructing me and providing me with their help during this project.

Finally, to my parents and my friends for always listening and supporting me. 

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