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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 267

genotypes (RR = 1.69, P = 0.021). This analysis was unable to confirm the previously identified association
between the C-allele and treatment success in the methadone group. Of note, the methadone group in this
cohort was relatively small with only 22 participants.

In addition to the OPRD1 variant rs678849, two other intronic SNPs have been identified as clinically
relevant in buprenorphine therapeutics. Using the European American sample from the START trial, a
[49]
pharmacogenomic analysis was conducted to evaluate sex-specific differences on clinical outcomes .
OPRD1 variants were compared between males and females undergoing methadone or buprenorphine/
naloxone treatment. No significant interactions were observed for males on either treatment, nor females
on methadone. However, in females treated with buprenorphine (n = 81), genotypes at rs581111 and
rs529520 predicted therapeutic response. During the 24-week treatment period, females with a GG
genotype at rs581111 were more likely to have opioid-positive tests than AA/AG genotypes combined (RR
= 1.72, P = 0.031). At rs529520, females with the AA genotype were more likely to have opioid-positive tests
than females with the CC genotype (RR = 1.65, P = 0.025). Outcomes in carriers of the AC genotype were
not significantly different from those with the AA genotype. The researchers concluded that genotypes at
these two OPRD1 variants may be useful when considering OUD pharmacotherapy for females, but further
validation is warranted. Interestingly, sex and gender differences have previously been shown to impact
OUD outcomes, as well as buprenorphine pharmacokinetic and pharmacodynamic parameters [4,24,50-52] .

κ-Opioid receptor gene (OPRK1 )
κ-Opioid receptors may play an important role in buprenorphine therapeutics, especially for patients with
comorbid depression. The antidepressant effects displayed by buprenorphine are related to its antagonistic
activity at these receptors [39,40] . Uncontrolled psychiatric illnesses can negatively impact OUD treatment
outcomes, and thus, a medication that could potentially provide benefits for both disorders would be
clinically advantageous [53,54] . To date, one study has evaluated OPRK1 genetic variants on buprenorphine
[55]
response . The patient population was composed of Western Europeans (n = 107, 81% male) who had a
history of heroin-dependence for 4-7 years. Buprenorphine was administered for a 6-month period, and
participants were classified as responders or non-responders on the basis of their clinical outcomes (e.g.,
relapse, treatment completion). Genotypes at the OPRK1 36G>T SNP (rs1051660) were compared between
response groups, but no significant differences were observed. Of note, due to the low numbers of TT and
GT genotypes observed in the study population, the two genotypes were collapsed, and the comparison
was made between GG versus GT/TT (i.e., dominant genetic model). In addition, the small number of
patients affected by mental health comorbidities precluded an analysis of the association between gene
variants and psychiatric illnesses. Despite the negative finding of this small study, further investigations of
this variant in other populations and of other genetic variants influencing the function of the κ-opioid
system, are needed to assess the effects of OPRK1 genetic variants on OUD treatment outcomes. Of note,
[55]
this study by Gerra et al. did find a significant association with a dopamine-related pharmacogene, which
will be discussed later.

Discussion
Preliminary evidence suggests that some opioid receptor genetic variants may be associated with
buprenorphine treatment outcomes in OUD. The strongest evidence to date shows an association with
variants in intronic OPRD1 SNPs and treatment efficacy, but race and sex may modulate these effects. The
rs678849 variant in particular shows promise as a potential clinical variable that could be useful to direct
individuals toward buprenorphine (carriers of CT/TT genotypes) or methadone (carriers of CC genotype)
in African Americans. Additionally, the rs581111 and rs529520 variants have the potential for utility among
females of European ancestry, especially given the differences observed in the opioid system between sexes.
Nonetheless, further research is needed with larger and more diverse populations to better understand the
role of these variants and other opioid receptor variants in pharmacogenomics-guided treatments.