Predictive Genomics for Response Variability to Opioids in Third Molar Patients. the Clinical Trend for Personalizing Analgesia

Predictive Genomics for Response Variability to Opioids in Third Molar Patients. The Clinical Trend for Personalizing Analgesia.

Krishnan, Deepak G. DDS; White, Gregory D. DDS; Senthilkumar, Sadhasivam MD; Abdallah, Yasmine BS; Uribe Rivera, Armando DDS; Goodwin, William DDS

  

Opioid medications are commonly used to treat post-operative surgical pain. Despite opioid medication efficacy, they have significant variability in patient response and central adverse effects. Hydrocodone is a semi-synthetic derivative commonly prescribed by oral and maxillofacial surgeons.  Previous studies have shown that the CYP2D6 oxidase system is the main pathway involved in the metabolism of hydrocodone among other semi-synthetic derivatives.

The purpose of this study is to prospectively determine factors associated with hydrocodone’s adverse effects in a homogenous population of patients undergoing outpatient third molar extractions in an effort to develop personalized effective, safe and tailored therapies for all types of surgical patients.

40 patients greater than 17 years of age and ASA I or II, presenting for extraction of at least one impacted third molar requiring osteotomy were enrolled in the prospective, genotype blinded, clinical observational study. Patients underwent surgery with a standardized anesthetic technique. Blood samples were collected at the time of IV catheter insertion and submitted for genetic analysis to determine CYP2D6 phenotype. Patients then completed questionnaires at home regarding their postoperative course days 0-3. Outcome measures included therapeutic effects and adverse drug reactions.

The patient cohort was divided into CYP2D6 phenotypes following genetic testing: ultra-rapid metabolizers, extensive metabolizers, intermediate metabolizers and poor metabolizers. The genotype-predicted phenotypes were consistent with previous reports. Significant differences were found between total narcotic requirements, with poor metabolizers requiring higher doses than extensive metabolizers for adequate analgesia. Sixty minutes following administration of the narcotic, the extensive metabolizer group had a higher drop in pain level compared to the poor metabolizer group. Adverse drug reactions were common among all groups with 52% reporting at least one adverse drug reaction.  75% of poor metabolizers experienced adverse drug reactions compared to 43% of extensive metabolizers.

The CYP2D6 oxidase system is known to be the main pathway involved in the metabolism of hydrocodone to its active metabolite hydromorphone. The variability in gene phenotypes may play an important role in the effectiveness of hydrocodone in controlling postoperative pain as well as experiencing adverse drug reactions. It is predicted that partial, and to a lesser extent, intermediate metabolizers will experience inadequate pain control with standard doses of hydrocodone and expected to have a greater incidence of adverse drug reactions. Even with the limited statistically significant results of this pilot study, there are predictive differences among the phenotypes that follow the expected trends. Expanding the enrolled number of patients with this pilot study will help lead to a greater understanding of pharmacogenetics; ultimately leading to personalized medicine for the surgical patient including tailored medication regimens or recommendation of alternative medications within the physicians’ armamentarium.

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