By Swan Lin, PharmD Candidate, and Valerie Fishbeck, PharmD

 

A patient walks up to the pharmacy counter with two new prescriptions for the opioid oxycodone, also known as Oxycontin.

One is for a long acting form of the medication while the other is for a short-acting form; prescribing both is common pain management strategy. The patient had previously been taking Vicodin and Lidoderm patches.

Such a situation probably doesn’t surprise most pharmacists anymore. But given the potency of oxycodone, these prescriptions are still enough to raise eyebrows.

In the U.S., more people are affected by issues of chronic pain than cancer, cardiovascular diseases and diabetes combined. According to the National Institutes of Health, chronic pain is cited as the most common reason Americans access the health care system. Approximately 76.2 million Americans, or one in every four, have suffered from pain that lasts longer than 24 hours.

Ethical Dilemma of Opioid Prescribing

Opioid painkillers are widely prescribed and are effective in treating patients with acute and chronic pain. Unfortunately, opioid misuse and abuse is a potential problem that poses an ethical dilemma for prescribing and dispensing practitioners.

On one hand, it would be unethical to deny pain medications to a patient who needs them. On the other, prescribers and pharmacists can face severe legal consequences by inadvertently enabling opioid abuse through overprescribing opioids or over filling opioid prescriptions.

In the pharmacy, there are checkpoints in place to help determine whether prescriptions for controlled substances such as opioids should be filled. Policy and legal interventions exist to help identify fraudulent prescriptions, and some states have controlled substance registries to help check for patterns of abuse. Other strategies used to combat opioid abuse, addiction and diversion include: setting up patient-physician pain contracts, developing drug monitoring and compliance guidelines in clinics, and patient participation in addiction management programs.

Pharmacogenetics and Opioid Prescribing

Although many interventions currently exist, pharmacogenetic testing remains an underutilized tool in opioid pain medication abuse and diversion.

There is a wealth of evidence surrounding genetic variations of cytochrome P450 enzymes, specifically CYP2D6 polymorphisms, and patients’ response to opioid medications. The enzyme CYP2D6 is responsible for converting many of the opioid medications to their active forms. These opioids include: codeine, tramadol, hydrocodone and oxycodone.

Patients can be CYP2D6 poor metabolizers, intermediate metabolizers, normal metabolizers or ultrarapid metabolizers. Patients who are CYP2D6 ultrarapid metabolizers have increased CYP2D6 enzyme activity, and therefore higher levels of active metabolites. CYP2D6 ultrarapid metabolizers may be at higher risk of experiencing side effects and opioid toxicity. Conversely, patients who are CYP2D6 intermediate or poor metabolizers with less than normal or impaired CYP2D6 enzyme activity may not receive the full benefits of opioid analgesics due to lower active metabolite drug levels.

Urine Drug Screening Interpretation

Urine drug testing (UDT) is method of measuring parent drug and metabolite levels. It is a tool that physicians often use to determine whether patients are taking their opioid medications as prescribed or whether medications are being abused or diverted. Correct interpretation of UDT results is essential for therapeutic decision making and establishing patient-provider trust and relationship.

Opioid metabolism contributes greatly to what is detected from UDT. As codeine and heroin are both metabolized by CYP2D6 to morphine, UDT detects morphine in patients taking either codeine or heroin. Similarly, hydrocodone and oxycodone are metabolized (respectively) by CYP2D6 to hydromorphone and oxymorphone, which are compounds that are detected by UDT.

To complicate interpretation of UDT further, morphine, hydromorphone, and oxymorphone are prescription medications themselves available as MS Contin, Dilaudid, and Opana, respectively. Detection of these metabolites can easily be misinterpreted as a patient taking an opioid medication they were not prescribed, especially if they have CYP2D6 genetic variations that result in increased or decreased levels. On the other hand, major compounds detected via UDT for morphine, hydromorphone and oxymorphone are not other prescription medications, and thus UDT interpretation for these medications is more straightforward.

 

Prescribed Drug	Half-Life (Hours)	Major Metabolites in UDT
Morphine	1.5-6.5	Normorphine
Codeine	1-4	Morphine, norcodeine
Oxycodone	4-12	Oxymorphone, noroxycodone
Hydrocodone	3.5-9	Hydromorphone, norhydrocodone, dihydrocodeine
Hydromorphone	3-9	Hydromorphol

Table Source

 

What This Means for the Patient

Let’s go back to our patient with prescriptions for oxycodone.

This patient’s initial urine opiate screen comes back as negative. Concerned that this is a false-negative result, the patient’s doctor orders a confirmatory test. This test is positive for oxycodone and oxymorphone which leads to a frequently asked question: “Why is oxymorphone showing up when that wasn’t the medication prescribed?”

As we’ve discussed, the patient is likely adherent and this is just the metabolite of the prescribed drug oxycodone. However, if this patient’s provider is not aware that oxymorphone is a metabolite of oxycodone, he or she may wind up falsely accusing the patient of abusing oxymorphone (Opana).

Let’s discuss another possible outcome. What does it mean if only oxycodone is detected by UDT? Is the patient trying to outsmart the system by shaving bits of an oxycodone tablet into the urine sample? Or could it be decreased metabolism of oxycodone to oxymorphone because the patient is a CYP2D6 poor metabolizer?

And what does it mean if the confirmatory tests are negative for both oxycodone and oxymorphone? As health practitioners, our professional licenses are always under scrutiny; therefore, diversion is often one of the first assumptions made. This could lead to inappropriate pain management, poor clinical outcomes and distrust between the patient and provider.

Alternatively, perhaps the negative test results could be explained by the patient running out of his medication early because of uncontrolled pain. Or maybe this patient was taking less oxycodone because his pain has improved.

As you can see, it is imperative that we know how to correctly interpret UDT results to avoid jumping to conclusions and adversely affecting the patient-provider relationship.

Benefits of Pharmacogenetic Testing

Pharmacogenetic testing and application of CYP2D6 polymorphisms in opioid prescribing and management can be a powerful tool. Numerous case reports and clinical studies have resulted in dosing and management recommendations for codeine and other opioids for patients with CYP2D6 polymorphisms. These guidelines come from expert organizations such as the U.S. Food and Drug Administration, the Clinical Pharmacogenomics Implementation Consortium and the Dutch Pharmacogenetics Working Group. However, CYP2D6 polymorphisms can also play a role in explaining UDT results and clarifying potential opioid abuse behaviors, in addition to safety and effectiveness considerations.

Unfortunately, lack of awareness and training hinders the broader application of pharmacogenetic testing in the clinical setting. Instead of constantly raising eyebrows, denying pain medications or turning a blind eye, using pharmacogenetic testing in concert with other safeguards against opioid misuse and abuse has the potential to improve treatment regimens and patient-provider relationships.

 

Swan Lin is a PharmD candidate at the University of Michigan. She earned her bachelor’s degree in Molecular and Cell Biology from the University of California, Berkeley.

Valerie Fishbeck, PharmD, is a certified geriatric pharmacist who has worked at Genelex as a personalized prescribing clinical pharmacist for a year and a half. She received her Doctor of Pharmacy degree from Butler University in Indianapolis, Indiana.