Personalized medicine and opioid use disorder

Abstract

Opioid use disorder (OUD) is a major public health problem affecting millions of people worldwide. Although OUD is a chronic and relapsing disorder, a variety of pharmacological and non-pharmacological interventions are available. Medication-assisted treatment of OUD generally relies on competition for opioid receptors against the addictive substance. The mechanisms of this competition are to block or inactivate the opioid receptor or activate the receptor with a substance that is intermittent or long acting. Methadone and buprenorphine are two United States Food and Drug Administration-approved medications that have long-term positive effects on the health of opioid-dependent individuals. Although clinical studies of drugs generally demonstrate efficacy in thousands of people and toxicity is excluded, it cannot be predicted whether the given drug will cause side effects in one of the patients at the treatment dose. Individual differences can be explained by many biological and environmental factors. Variations in genes encoding drug metabolism or cellular drug targets significantly explain the variability in drug response between individuals. Therefore, for the effects of candidate genes to be accepted and included in individual treatment protocols, it is important to repeat studies on individuals of different ethnic backgrounds and prove a similar effect.

Key Words: Opioid use disorder; Genetic vulnerability; Treatment failures; Personalized medicine; Pharmacogenetics

Core Tip: Although maintenance treatment with methadone or buprenorphine is effective for treating opioid use disorder, the rate of treatment failure is high among patients, which leads to significant costs to society in terms of healthcare and justice. Thus, it is important to understand the genetic information of patients to increase treatment effectiveness. There has been evidence showing the interaction between genetic variants and the rate of metabolism, the mechanism of action and transport of drugs. Therefore, patient-tailored treatment would be a good approach to facilitate longer periods of abstinence in addicts who are at high risk of treatment failure.

INTRODUCTION

Opioids are active ingredients of drugs used to treat pain for centuries[1]. However, nonmedical opioid use has spread and become a severe public health concern worldwide because opioids are responsible for causing abuse, addiction, and tolerance[2]. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), opioid use disorder (OUD) is defined as a “problematic pattern of opioid use leading to clinically significant impairment or distress, as manifested by at least two of eleven criteria”[3]. Illegal opioid use triggers participation in criminal activities, poor living standards, and exposure to violence, accidents, injuries, and suicide, leading to an increased risk of death due to regular illegal opioid use. Thus, the effectiveness of pharmacological interventions for OUD should be improved. For pharmacological (maintenance) treatment of OUD, methadone and buprenorphine are commonly used United States Food and Drug Administration (FDA)-approved drugs[4]. Naltrexone, an opioid receptor antagonist, was also developed for the treatment of OUD. In 2008, Mattick et al[5] reported that these medications are successful in treating OUD in a meta-analysis. However, most of the patients with OUD continue to use illegal opioids, leading to a higher rate of treatment failure. Furthermore, in 2013, Laib et al[6] demonstrated that only patients with OUD receiving maintenance treatment with buprenorphine exhibited plasma buprenorphine levels within the therapeutic reference range (0.7 ng/mL to 1.6 ng/mL). One of the reasons for this higher rate of treatment failure could be the genetic information of patients.

OPIOID MAINTENANCE TREATMENT

OUD is a chronic and relapsing brain disorder; therefore, its treatment can take a very long time, even throughout life. Detoxification can be considered a first stage of OUD treatment since the aim is to manage of only opioid withdrawal symptoms and should be followed by maintenance treatment to increase successful treatment rates. Additionally, maintenance treatment consists of both pharmacological interventions (naltrexone, buprenorphine, and methadone) and psychosocial interventions[7]. Medication-assisted treatment of OUD generally relies on competition for opioid receptors with opioids. Methadone and buprenorphine are mu-opioid receptor (MOR) agonists, whereas naltrexone is a MOR antagonist[8].

Methadone is an FDA-approved drug. It is marketed as a solid tablet since its oral bioavailability is high (about 80%). This average bioavailability can change due to interindividual differences (a range between 41% and 95%). Its half-life is long (22 hours) and thus it takes several days to reach a steady state concentration in the blood. In the liver, methadone is metabolized primarily by cytochrome P450 3A4 (CYP3A4), but other CYP450 enzymes such as CYP2B6 and CYP2D6 contribute to biotransformation of methadone. Both methadone and its metabolite (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine) are eliminated through the kidneys and, to a lesser extent, through feces. Methadone exerts its effects including analgesia, miosis, and sedation by binding primarily to MORs[9].

Naltrexone, a competitive opioid receptor antagonist, was approved by the FDA to manage the treatment of opioid and alcohol use disorder. However, its clinical efficiency is not as high as expected for opioid maintenance treatment and, thus, it is used as an adjunctive medication in order to shorten detoxification. Naltrexone can be administered orally, via implant, through sustained release injection[10].

Until 1996, methadone and naltrexone were the main prescribed pharmacologic agents to treat OUD. Since the late 1990’s, buprenorphine has also been used as an FDA-approved medication with (Suboxone) and without (Subutex) naloxone. Unlike methadone, the oral bioavailability of buprenorphine is low due to the first-pass effect of the liver, and thus it is administered sublingually. Similar to methadone, buprenorphine is metabolized by CYP3A4. Its major metabolite is norbuprenorphine. The glucuronide conjugates of both buprenorphine and norbuprenorphine are excreted in urine. Most of the unconjugated buprenorphine and norbuprenorphine are excreted though feces. The advantage of buprenorphine over other medications used to treat OUD is that buprenorphine acts a partial MOR agonist at lower doses and a MOR antagonist at higher doses. This agonist-antagonist property of buprenorphine allows for a ceiling effect and thus makes buprenorphine safer compared to full MOR agonists. Buprenorphine is also a kappa- and delta-opioid receptor antagonist[11].

INDIVIDUAL VARIABILITY IN OPIOID MAINTENANCE TREATMENT

Both methadone and buprenorphine are efficacious interventions to treat OUD. However, when they are administered, the treatment responses can be quite diverse between patients with OUD, ranging from good treatment responses with no severe adverse effects to poor treatment response with severe adverse effects. There are a number of potential reasons for discrepancies in treatment responses between individuals. For instance, psychosocial determinants such as accessibility, availability and affordability of the treatment modality and co-morbid medical conditions can impact the selection of an appropriate treatment plan. Nevertheless, the primary focus of this paper is to highlight the role of an individual's genetic background in influencing treatment responses. Hence, the subsequent section will examine the impact of single-nucleotide polymorphisms (SNPs) within gene sequences. Inherited genetic variations can also affect treatment response variability by altering the function and structure of opioid metabolism enzymes, opioid receptors, and/or transport proteins[12].

SNPs are a kind of genetic variations in the human genome. DNA has four types of nitrogenous bases (A: Adenine, G: Guanine, C: Cytosine and T: Thymine). The substitution of one nitrogenous base with another nitrogenous base in the DNA sequence is called SNP. A single base change in DNA sequence can result in two allelic forms: major and minor alleles. The frequency of minor allele is at least > 1% in the population. A SNP with two alleles has three genotypes: homozygous wild type, heterozygous, and homozygous variant[13]. The influence of SNP's varies depending on their location. A SNP in the coding region of a gene: (1) Can alter the amino acid sequence of a protein; (2) cannot alter the amino acid sequence of a protein; or (3) can shorten the length of the protein due to the occurrence of stop codon. Conversely, a SNP in the non-coding region of a gene can affect the quantity or mRNA stability of the related protein[14]. Due to these effects of SNPs on protein products: (1) The metabolism of buprenorphine or methadone can be increased or decreased; (2) the affinity of opioid receptors to buprenorphine or methadone could be increased or decreased; and (3) the transport of buprenorphine or methadone across cell membranes can be increased or decreased. All these scenarios can result in individual variability in plasma levels of buprenorphine or methadone, which influences the occupancy of MORs and thus the efficacy of opioid maintenance treatment[15]. Therefore, opioid maintenance treatment interventions should be personalized based on patients’ biological factors including genetic information.

Ettienne et al[16] showed that a patient with OUD receiving a daily dose of 24 mg buprenorphine experience multiple relapses. After it was determined in the pharmacogenetic test that this individual had the CYP3A4*1/*1B genotype (ultrarapid metabolizer phenotype), the daily buprenorphine dose was increased to 32 mg, and it was reported that the number of relapses was reduced. The study results were later confirmed by the same research group with a greater number of participants[4]. Furthermore, several studies from different populations (reviewed in 17 and 18 in detail) have showed that the efficacy of buprenorphine and methadone is not equal for all individuals receiving opioid maintenance treatment due to SNPs in genes involved in the metabolism (CYP450 and UDP-glucuronosyltransferase [UGT] enzymes), transportation (P-glycoprotein), and mechanism action (opioid receptors) of buprenorphine and/or methadone[4,17,18].

CONCLUSION

Previous pharmacogenetic studies have consistently emphasized the importance of pharmacogenetic testing for better OUD management. Therefore, the key message for clinicians is that the paradigm “right drug to right patient at right dose” can limit treatment failures and enhance treatment efficacy, and that personalized treatment rather than the trial-and-error method should improve the prognosis of OUD, especially in patients who are at high risk of treatment failure.