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Page 270 Arroyo Seguí et al. J Transl Genet Genom 2020;4:263-77 I http://dx.doi.org/10.20517/jtgg.2020.35

unauthorized substances (i.e., urine drug screens), and dosing comparisons between standard-of-care (SOC)
and PGx guided treatment. With PGx-guided dosing (that allowed for higher dosing), carriers of the *1B
allele (homozygous or heterozygous) had significantly less withdrawal symptoms compared to patients on
SOC dosing (P = 0.0294). No significant differences were observed with CYP3A5 genetic variants or the use
of unauthorized substances. The researchers concluded that CYP3A4 genetic variants can impact clinical
outcomes, and therefore, PGx-guided dosing should be implemented in buprenorphine therapeutics,
especially for African American patients.

Using a sample from the previously mentioned START trial (n = 764/1,267) composed of European
Americans (n = 599), African Americans (n = 79), and other ethnicities (n = 96), a different study evaluated
variants in six pharmacokinetic genes (i.e., CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP2D6 and CYP3A4)
[29]
on dropout rate and mean dose . No significant associations were identified for any variants of these
genes in either the buprenorphine or methadone treatment arm.

[45]
Blanco et al. examined the effects of both the UGT2B7 802C>T (rs7439366) polymorphism and the
CYP3A4 290A>G (rs2740574) polymorphism on analgesic response to buprenorphine. As previously
mentioned, the study included 93 patients with critical limb ischemia who were treated with transdermal
buprenorphine for pain. In this study, patients who were AA homozygotes for the CYP3A4 gene showed
the best response to analgesic treatment (P = 0.003), but no association was identified between the UGT2B7
polymorphism and analgesic response to buprenorphine.

Discussion
Buprenorphine dose adjustments based on CYP3A4 functional status are the only PGx-guided
interventions that have been implemented and evaluated to date. Findings from Ettienne et al. [65,67] suggest
that dosing patients by CYP3A4 phenotype can improve treatment outcomes. Patients with an increased
metabolic rate (i.e., EM and UM) may need higher doses to prevent withdrawal symptoms and maintain
opioid abstinence. However, to date, these improvements have only been observed in African Americans.
The sample from the START trial was mostly composed of European Americans (n = 599/764) and did
not show significant associations between any metabolic gene variant and mean dose or dropout rate. Of
note, results did trend towards a potential association between CYP3A4 status and dropout rate, when the
buprenorphine and methadone groups were combined. The authors hypothesized that a possible reason
for the lack of significance was the low frequency of patients with PM or IM phenotypes in their study
population with Western European ancestry. Again, further research with larger and more diverse patient
populations is needed to assess the clinical benefits of CYP3A4-guided dosing (or other metabolic genes)
for buprenorphine OUD treatment.

PHARMACOGENES: ADVERSE EFFECTS
Genetic variations can not only influence treatment efficacy, dosing requirements and withdrawal incidence
but adverse effects as well. Multiple studies involving methadone-treated patients have found associations
[38]
between the rate and intensity of adverse effects with several pharmacogenes . However, only one study
has included buprenorphine in their evaluation of genetic variants and adverse effects. A prospective study
analyzed variants in OPRM1, OPRD1, COMT, ARRB2 and ABCB1 on patients participating in an opioid
[68]
deprescription program with buprenorphine patches . The patient population was composed of Europeans
with non-cancer chronic pain (n = 88, 64% females), who had been taking prescription opioids for more
than 6 months, and were diagnosed with OUD at the start of the study. AA genotype at the OPRM1 variant
s1799971 was associated with a higher incidence of nausea (P = 0.034) and gastrointestinal adverse events (P
= 0.031) when compared with AG/GG genotypes combined. Patients with the CT genotype at the OPRD1
variant rs2234918 experienced less sexual dysfunction than TT/CC genotypes combined (P = 0.001). At the
COMT variant rs4680, the AG genotype was associated with a lower incidence of loss of libido (P = 0.003)