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Arroyo Seguí et al. J Transl Genet Genom 2020;4:263-77 I http://dx.doi.org/10.20517/jtgg.2020.35 Page 265

studies evaluate genotypic-phenotypic associations and their potential impact on pharmacokinetic (e.g.,
metabolic function, dosing requirements) and pharmacodynamic (e.g., receptor activity, treatment efficacy)
parameters. In recent years, pharmacogenomic research for OUD has accelerated.

To date, the majority of pharmacogenomic studies for OUD treatment have focused on methadone use,
where a number of relevant pharmacogenes have been identified. Methadone is a full agonist at the
[20]
μ-opioid receptor, with antagonistic activity at the N-methyl-D-aspartate (NMDA) receptor . This NMDA
antagonism can potentially cause cardiac toxicity, especially in patients with an elevated QTc interval.
Regarding pharmacogenes, CYP2B6 variants (e.g., *4, *6, *9 alleles) have been associated with alterations
in metabolic rate and plasma methadone concentrations, which could determine dosing requirements [32-34] .
OPRD1 variants (e.g., rs678849) have been shown to impact treatment outcomes in African American
patients, while OPRM1 variants (e.g., rs10485058, rs3192723) may impact efficacy in European and
Asian patients [31,35] . UGT2B7 variants (e.g., rs6600879, rs4554144) may also determine severity of opioid
[36]
withdrawal in some populations . The evidence related to the pharmacogenomics of methadone has
recently been reviewed elsewhere and, therefore, will not be further discussed here [37,38] .

[20]
Buprenorphine is a high-affinity, μ-receptor partial agonist . It also possesses antagonistic activity on
κ-receptors, and weak agonist activity on δ1-receptors. Partial agonism leads to effective analgesic effects
and abatement of withdrawal symptoms while reducing the risk of respiratory depression observed with
[20]
methadone and other opioids . Additionally, due to its effects on κ-receptors, clinical data have suggested
that buprenorphine may possess antidepressant benefits, potentially representing a better option for
patients with comorbid depression [39,40] . Buprenorphine has also been co-formulated with naloxone as a
sublingual film or tablet to discourage intravenous administration, which results in the immediate onset
of euphoric effects . Naloxone is a high-affinity μ-receptor antagonist that displaces other opioid ligands,
[20]
essentially blocking and reducing their pharmacological effects (e.g., euphoria, respiratory depression).
With easier dosing protocols (compared to the more complex dosing required of methadone due to its long
and variable half-life) and fewer prescribing limitations (may be prescribed outside the setting of federally
[21]
approved clinics), the increase in buprenorphine use has been dramatic in recent years . The number
of patients receiving therapy from non-OTP facilities increased from 1,670 in 2004 to 54,488 in 2015, an
increase of three thousand percent. However, pharmacogenomic studies including buprenorphine have
lagged behind those of methadone. Understanding how to tailor drug treatment in OUD is essential to
reducing opioid misuse, improving treatment adherence, and saving healthcare resources. This review will
cover the available pharmacogenomic data for the use of buprenorphine in the management of OUDs.

PHARMACOGENES: OPIOID RECEPTORS
Activity on all three G-protein coupled receptors of the opioid receptor family (μ, δ and κ), differentiates
[41]
buprenorphine from other opioid-based medications . These receptors are structurally and functionally
[42]
related, but exhibit variations in ligand affinity and cellular distribution . The main effects of opioids (i.e.,
analgesia, reward, adverse effects) are mediated through μ-receptor binding, while δ- and κ-receptors help
modulate these effects via different biological mechanisms. Alterations in opioid receptor expression and
function (i.e., genetics), may impact substance dependence risk and influence treatment response [31,42] .

μ-Opioid receptor gene (OPRM1 )
As the primary target in opioid therapeutics, it is reasonable to assume that activity on μ-receptors plays
a crucial role in opioid dependence, and that variations in the genes encoding these receptors may impact
clinical outcomes. Although OPRM1 variants (e.g., rs9479757G>A) have been associated with heroin
dependence risk, pharmacogenomic analyses of OPRM1 variants have demonstrated conflicting results in
[43]
OUD treatment response .