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Page 266 Arroyo Seguí et al. J Transl Genet Genom 2020;4:263-77 I http://dx.doi.org/10.20517/jtgg.2020.35

Data from the randomized clinical trial Starting Treatment With Agonist Replacement Therapies
[44]
(START), has been used to perform several pharmacogenomic analyses of OUD treatment outcomes .
Genotypic information was available for 60% (n = 764/1,267) of the patient population, which was
primarily composed of European Americans (n = 599), with few African Americans (n = 79) and other
[29]
ethnicities (n = 96) . Over a 24-week period, participants treated with methadone (n = 364, 66% male)
or buprenorphine/naloxone (n = 410, 71% males) were submitted to weekly urine drug screens. From
the several pharmacogenomic studies conducted from this trial, only two evaluated OPRM1 variants [29,30] .
No significant results were observed between variants and buprenorphine response in either study. One
study compared the genotypes of all participants at the OPRM1 variant rs1799971, with dropout rate and
dosing requirements . The other used a sample of European Americans (n = 582) and analyzed the effects
[29]
of single-nucleotide polymorphisms (SNPs) in an untranslated region (3’) of OPRM1, on the number of
opioid-positive urine tests . Although no differences were found with buprenorphine, this second study
[30]
did show an association between the OPRM1 variant rs10485058 and methadone-treated patients. AA
genotypes at this locus were less likely to have opioid-positive urine tests than carriers of the G-allele (RR =
0.76, P = 0.0064).

In addition to OUD trials, one study evaluated the effect of the OPRM1 118A>G (rs1799971) polymorphism
on the analgesic effect of buprenorphine . The study was conducted in a Spanish population (n = 93, 77%
[45]
male) with critical limb ischemia who were hospitalized for revascularization and treated with transdermal
buprenorphine for pain. No significant association was found between rs1799971 and the analgesic effect
of buprenorphine, although significant findings were observed with other pharmacogenomic variables,
which will be discussed later in this review. On the other hand, a study evaluating an individualized opioid
deprescription program with buprenorphine, did show a significant association between the same OPRM1
[46]
variant rs1799971 and morphine equivalent daily dose (MEDD) requirements . Participants included
patients of European ancestry (n = 88, 64% female) with chronic non-cancer pain, who were using opioids
long-term (> 6 months) and were diagnosed with prescription opioid dependence. Interventions involved a
slow-tapering process, with a 30% reduction in opioid dose and rotation to buprenorphine and/or tramadol.
Carriers of the rs1799971 variant required significantly higher MEDD (P < 0.05) for analgesic control and
prevention of withdrawal symptoms. No associations were found between OPRM1 and program response.

δ-Opioid receptor gene (OPRD1 )
Multiple studies have demonstrated the impact of δ-Opioid receptor gene (OPRD1) genetic variants
on substance dependence risk [42,47] . As for OUD treatment, a series of SNPs located on intron 1, may be
predictive of outcomes in some patient populations receiving buprenorphine. A patient cohort from the
START trial was used to evaluate the effects of OPRD1 variants on opioid abstinence, which was measured
[31]
by urine drug screens . This sample was primarily composed of European Americans (n = 566, 68% male)
and some African Americans (n = 77, 69% male). Although no significant differences were observed in the
amount of opioid-positive tests when comparing methadone and buprenorphine, the rs678849 variant of
OPRD1 was significantly associated with treatment outcomes in African Americans for both medications.
In the buprenorphine group, African Americans with the CC genotype (n = 24) were more likely to have
opioid-positive drug screens than CT/TT genotypes (n = 17, RR = 2.17, P = 0.008). The opposite was
observed for the methadone group, as African Americans with the CC genotype (n = 21) were less likely to
have opioid-positive drug screens than carriers of the T-allele (n = 15) (R = 0.52, P = 0.001). No significant
results were shown in European Americans for any OPRD1 genetic variant. The researchers concluded that
for African Americans, matching rs678849-related genotypes to pharmacotherapy could improve treatment
efficacy overall . Estimates have indicated that half of all African Americans may possess the CC
[31]
[37]
genotype . A follow-up analysis was performed to replicate the results of this study using an independent
cohort of African Americans . This replication study confirmed that the rs678849 genotypes were related
[48]
to buprenorphine outcomes: CC genotype was more likely to have opioid-positive tests than CT/TT