Pharmacogenetic Testing and Opioids

Tennille Collins, PharmD Candidate; Diane Nykamp, PharmD

US Pharmacist. 2015;40(3):23-26.

Abstract and Introduction

Abstract

A majority of medications are metabolized by the liver's CYP450 system. Metabolism of specific pain medications differs among individuals due to pharmacogenetic variation. CYP450 genotyping displays the type of metabolizer a patient is, in order to determine drug appropriateness, dosage, and dosing interval. Results of pharmacogenetic tests allow patients to be dosed appropriately and avoid experiencing dose-dependent side effects or lack of drug efficacy. Pharmacists can play a role in providing information to patients on selecting opioids where genetic testing may be useful.

Introduction

Patients with CYP450 pharmacogenetic variations may respond differently to opioids, ranging from drug unresponsiveness to toxicity with elevated serum levels. The administration of opioids may be associated with adverse drug reactions including sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance, and respiratory depression.^[1] By performing pharmacogenetic testing, patients can be dosed appropriately to avoid experiencing dose-dependent side effects or lack of drug efficacy.

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Table 1. Metabolizer Status and Selected CYP2D6 Genotypes
Metabolizer Status	Examples of Allele Combinations
Ultra-rapid (UM)	CYP2D61/1XN, CYP2D61/2XN
Extensive (EM)	CYP2D61/1, CYP2D62/3
Intermediate (IM)	CYP2D64/10, CYP2D69/10
Poor (PM)	CYP2D63/6, CYP2D619/38

* Denotes allele number. 1 is usually normal version of allele. Each individual has at least 2 copies for a gene, in multiple combinations.
XN denotes more than two copies of alleles.
Source: Reference 4.

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Case Studies

Case 1. Codeine

JM, a 4-year-old (27.6 kg) male, was discharged from the hospital after an overnight stay post adenotonsillectomy for treatment of recurrent tonsillitis and pediatric obstructive sleep apnea syndrome. Patient was receiving liquid codeine at age-appropriate dose (8 mg up to 5 doses a day as needed) inpatient, which was continued after discharge. Two days post discharge, after four doses, the child was brought to the hospital without vital signs. Postmortem morphine serum concentration was 17.6 ng/mL (therapeutic range 4.5 +/- 2.1 ng/mL). Blood codeine range was within the expected range with no other medications detected. Postmortem genotyping results revealed a CYP2D6 genotype (CYP2D6*1/*2XN ). CYP2D6 status resulted in supratherapeutic morphine levels leading to respiratory arrest. Cause of death was determined to be bilateral acute bronchopneumonia; a consequence of codeine and morphine toxicity post adenotonsillectomy.²¹

Case 2. Fentanyl

BC, a 50-year-old male, presents to his physician with the complaint of inadequate pain control while taking a total daily dose of oxycodone 70 mg. After consulting the dose conversion guidelines, the physician gave BC a prescription for fentanyl patch 50 mcg/h to apply one patch every 72 hours. BC's wife contacted his physician's office 24 hours after the first patch application stating that her husband was heavily sedated and having difficulty breathing. After pharmacogenetic testing (PGT), BC learned that he is a slow CYP3A4 metabolizer, which caused decreased metabolism of fentanyl to its inactive metabolites. Based on clinical evaluation in this case, a 50% dose reduction to 25 mcg/h provided BC with adequate pain control and minimal adverse drug effects.

Case 3. Oxycodone

After elective outpatient surgery, AN, a 26-year-old female, was given a prescription for oxycodone 5-mg tablets to be used every 4 hours as needed for pain. The next day, after six doses within a 24-hour period, AN called her surgeon stating that she was receiving minimal pain relief from her medications, causing her to get very little or no sleep. Her husband stated that she has complained about minimal pain relief since her operative pain medications wore off. If PGT had been performed prior to surgery, it would have revealed that AN is a poor CYP2D6 metabolizer (CYP2D6*19/*38 ). AN's CYP2D6 status resulted in subtherapeutic oxymorphone levels, leaving the patient without pain relief. Alternative therapy, such as morphine or hydromorphone, might have provided the patient with adequate pain control.