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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 271

and skin redness (P = 0.003), while the AA genotype was associated with a higher incidence of vomiting (P
= 0.003). Patients with the TT genotype at the ARRB2 variant rs1045280 were less likely to experience loss
of libido (P = 0.021) and dry skin (P = 0.024) than CC/CT genotypes. No significant differences were found
with ABCB1 variants.

Discussion
[68]
To date, the study by Muriel et al. provides the only evidence on pharmacogenomic determinants
of adverse events for patients with OUD treated with buprenorphine. Several factors, however, make
interpretation of the study difficult. One key limitation in understanding the specific relation to
buprenorphine is the inclusion of other opioids. The deprescription process included opioid tapering with
the addition of tramadol, plus some patients were transitioned to fentanyl patches instead of buprenorphine
(the authors do not report what percentage of patients were treated with buprenorphine patches compared
to fentanyl patches). In addition, there were conflicting results between genotypes and the frequency of
adverse events, when comparing baseline and final visits. For example, the AG genotype at COMT variant
rs4680 was associated with less skin redness at baseline, but significantly more (than AA/GG genotypes)
at the end of the program (P = 0.007). In summary, individual genotypes have the potential to contribute
toward the rate and intensity of adverse events in OUD patients treated with buprenorphine. However,
more research is needed to better understand the influence of genetic variants on adverse effects.

CONCLUSION
The prevalence of OUD has reached unparalleled numbers in the last decades, increasing the rates of
[4]
overdose fatalities and socioeconomic burden. Most of these patients do not receive proper treatment , and
furthermore, the lack of guidelines for individualized pharmacotherapy may limit the therapeutic benefits
of medication-assisted treatment. Patient-specific factors can influence treatment response, but to date,
clinicians are not equipped to use this data for therapy optimization. Understanding the pharmacogenomic
variables that predict reductions in illicit opioid use, treatment adherence, and incidence of withdrawal
symptoms would enhance clinical decisions.

For many years, methadone has been the primary option for medication-assisted treatment for OUD.
However, buprenorphine may present a safer and more effective alternative for some patients based on
comorbidities (e.g., mental health disorders) and genetic profile. Even though pharmacogenomic studies
have accelerated in recent years, research involving PGx-guided strategies for OUD treatment has been
limited, especially with buprenorphine. Nonetheless, the available data suggests significant relationships
[69]
between some pharmacogenes and buprenorphine response [Table 1] . Evidence is strongest for variants
in opioid receptor pharmacogenes (OPRD1) and metabolic pharmacogenes (CYP3A4), but still limited with
regards to dopaminergic pharmacogenes. Of particular clinical value might be genetic markers with ability
to potentially direct treatment by identifying patients who may respond favorably to buprenorphine, but
poorly to methadone and vice versa.

In conclusion, further research is needed to better understand how pharmacogenomic factors may be
proactively used to improve treatment outcomes. As the vast majority of data that currently exists regarding
pharmacogenomic determinants of buprenorphine response has been observational, the benefits of
incorporating these factors into clinical treatment decisions remain theoretical. Thus, to date, there are no
FDA-approved or Clinical Pharmacogenetics Implementation Consortium (CPIC®) recommendations for
directing OUD therapy on the basis of pharmacogenomic testing. Hopefully, prospective clinical trials will
better elucidate the role of PGx-guided treatment strategies. Additional research opportunities also exist
in larger genome-wide association studies to identify novel genetic variants, investigating other potentially
relevant candidate pharmacogenes (e.g., perhaps those affecting the ORL-1/NOP receptors), and research
to better understand how other clinical factors such as treatment adherence interact with and mediate