Negative urine opioid screening caused by rifampin-mediated induction of oxycodone hepatic metabolism

Abstract

Introduction

Oxycodone has become widely used in the clinic for the treatment of chronic pain. This reflects its favorable pharmacokinetics and side effect profiles.

Case report

We report a 60-y-old man who had a clinically significant drug interaction between rifampin and oxycodone, resulting in 3 consecutive negative urine oxycodone screens in a 2-month period, suggesting non-adherence. A combination of urine opioid metabolite quantification by GC/MS and CYP genotyping confirmed that he was compliant with his oxycodone therapy. Determination of the complete oxycodone metabolite profile and the CYP3A4/5 and 2D6 genotype allowed the physician to be confident that the patient was compliant with the medication (and not diverting it) and to increase his oxycodone dose to optimize his pain control.

Conclusion

This case demonstrates how the combination of analytical toxicology and pharmacogenetic analyses enhances a physician's ability to personalize drug therapy in patients with chronic pain syndromes.

Introduction

Opioid analgesics are one of the most important therapeutic components in the treatment of moderate to severe pain according to the World Health Organization (WHO) pain ladder. The choice of potency of opioid and its dose should be optimized for individual patient analgesic requirements [1]. Oxycodone is a semi-synthetic opioid analgesic that has been used clinically since 1917 [2]. It has a lower incidence of nausea and hallucinations compared to morphine, thus oxycodone has become one of the most commonly prescribed opioids in the U.S. [3]. The bioavailability of immediate-release oxycodone ranges from 60% to 87% [4], [5] and the relative analgesic potency of oral oxycodone is between 1.5 and 2 times that of oral morphine [6]. Immediate-release oxycodone has a duration of analgesic action of 4 h [7] whereas the controlled-release formulation of oxycodone (OxyContin®) provides pain relieve for up to 12 h [8].

Oxycodone undergoes extensive hepatic Cytochrome P450 (CYP450) mediated metabolism, while only 10% of a dose of oxycodone is excreted unchanged in the urine [8]. CYP450 metabolism of oxycodone catalyzes N-demethylation at the 17-position to produce noroxycodone, a major metabolite, which exhibits only modest analgesic potency [9]. This metabolic conversion is catalyzed by CYP3A4 and 3A5 [8]. Oxycodone also undergoes a CYP2D6-catalyzed O-demethylation at the 3-position to yield oxymorphone, which is a minor metabolite, but has an analgesic potency approximately 10 times that of morphine after parenteral administration [10]. Oxycodone and oxymorphone undergo conjugation by uridine diphosphate glucuronosyl transferase enzymes (UGTs) to yield glucuronides, [11] which are renally excreted (Fig. 1). Oxycodone metabolism is highly dependent on CYP450 enzymes. Therefore, concurrent administration of inhibitors or inducers of hepatic drug metabolizing enzymes have the potential to cause clinically significant changes in oxycodone disposition [12], [13], [14].

Patients receiving chronic opioid analgesic therapy are often subjected to surveillance of compliance to ensure that they are not diverting or abusing the drug. The most commonly used drug surveillance process is to perform random urine screenings for the opioid that the patient is taking and also detect any additional intake of other drugs of abuse [15]. Both immunoassay and gas chromatography–mass spectrometry (GC/MS) techniques have been extensively used in the random screening of opioids in urine samples. However, the widely available and often routinely used immunoassays are subject to analytical interferences from commonly prescribed drugs (e.g., venlafaxine, fluoroquinolone antibiotics) [16]; in addition, immunoassays are generally less analytically sensitive than GC/MS [17]. In one case report, a patient was mistakenly suspected of diverting from his oxycodone treatment and nearly was refused opioid prescription when his urine immunoassay screen was negative for oxycodone. Repeated analysis using GC/MS found that the oxycodone concentration in the patient's urine was appropriate [18].

In this report, we describe a patient who had 3 consecutive negative urine oxycodone screens determined by GC/MS while he was reportedly taking a combination of immediate and controlled-release oxycodone for chronic pain. We investigated a combination of potential contributory factors causing repeated negative urine oxycodone results, and it was determined that the patient was complying with his oxycodone therapy, but the drug was not detected in his urine by these routine analytical screens because of increased metabolism of the drug.