Case Presentation

A 54-year-old male presented to the pain medicine center for evaluation of chronic neck pain and transfer of medication management. He was taking oxymorphone extended-release (ER) tablets 10 mg twice a day and one to two tablets of oxycodone 10 mg per day. The state prescription monitoring program confirmed his prescriptions of 60 tablets of oxymorphone ER 10 mg and 150 tablets of oxycodone 10 mg, filled monthly. His last prescription was filled 25 days prior. When asked about how much remaining oxycodone he has, he replied that he only had a few tabs left. He added that he had taken one tab of oxymorphone and one tab of oxycodone in the morning prior to his arrival at the clinic. A urine sample was taken, and the results are reported in the Table.

He is MOST likely taking which of the following?

1. He is taking oxymorphone and oxycodone.
2. He is taking oxymorphone, oxycodone, and morphine.
3. He is taking oxymorphone, oxycodone, and heroin.
4. He is taking oxymorphone.

“A great man once said that the true symbol of the United States is not the bald eagle. It is the pendulum. And when the pendulum swings too far in one direction, it will go back.”– Ruth Bader Ginsberg

Nearly one-third of the American population has experienced or is living in chronic pain, defined as pain that is persistent and lasts more than 3 to 6 months. Over the past several decades, the development of opioid medications for the treatment of pain has increased dramatically. With this increase, we have seen yearly prescriptions of opioids catapult from 76 million to greater than 250 million over a 20-year period,^[1] which, unfortunately, is directly correlated with an increase in opioid abuse.^[2] In response to this increase in opioid maintenance, dependence, and addiction, the Centers for Disease Control and Prevention (CDC) published guidelines for the prescribing of opioids for chronic pain in March 2016.^[3]

With the growing epidemic, providers must effectively monitor the use of prescription opioids to identify misuse, addiction, and diversion. Some examples of the tools available include state prescription drug monitoring programs and urine drug testing. There are two fundamental questions that lead a clinician to order a urine drug screen (UDS): (1) Is the patient taking the prescribed medication, and (2) is the patient abstaining from the use of nonprescribed controlled and illicit substances? The CDC suggests obtaining a UDS before the initiation of opioid treatment and to consider screening at least annually. However, the interpretation of drug testing is far less straightforward than expected, yet the ramifications can be significant. Occasionally, it can be difficult to interpret a result as normal or abnormal based on opioid compounds found in the urine. Misinterpreting results can lead to false reassurance or incorrect conclusions about medication use and abuse.

“With the growing epidemic, providers must effectively monitor the use of prescription opioids to identify misuse, addiction, and diversion.”

Accurate interpretation of a UDS requires knowledge of urine metabolites, specificities and sensitivities of the assay, and detection times. Some opioids produce metabolites chemically identical to another opioid, which may complicate the interpretation of the UDS. A common example is codeine, a prodrug that metabolizes to morphine in approximately 90% of Caucasian patients.^[4] Interestingly, in a 2007 survey of physicians who routinely order UDSs, only 29% knew that morphine is a metabolite of codeine and should be expected on UDSs in patients taking codeine.^[5] In a more recent study of knowledge and confidence in UDS interpretation of internal medicine residents, less than 30% correctly answered what the expected metabolites would be in a patient prescribed acetaminophen/codeine.^[6] Unfortunately, many were confident in their incorrect response.

Incorrect conclusions may also be drawn from ordering inappropriate tests. UDSs are most commonly performed using immunoassays or mass-spectrometry. Opiate immunoassays are relatively inexpensive (Medicare midpoint of $20.22–$107.85),^[7] whereas confirmatory mass-spectrometry–based methods have a higher analytical sensitivity and specificity, incurring much higher costs (Medicare midpoint of $158.98–$343.07).^[7] Clinicians must know which drugs are tested in the particular panel ordered.

In fact, the term “drug screen” is a misnomer because it suggests that it detects all drugs in a given class. For example, the common immunoassay for the detection of opiates uses an antiopioid antibody that detects morphine and will show positive if a patient is taking morphine, codeine, or heroin. The test may or may not detect semisynthetic opioids (such as hydrocodone and oxycodone) and will not detect synthetic opioids (such as buprenorphine and fentanyl). Hydrocodone is the most commonly prescribed opioid in the United States, yet the opiate screen may be considerably less sensitive for this drug. In a review of urine specimens with unexpected negative opiate immunoassay results in hydrocodone users, 72.3% were found to be positive for hydrocodone or its metabolite using confirmatory testing.^[8]

For the patient presented, the mass-spectrometry screen was positive for oxymorphone and negative for oxycodone. Oxymorphone is a metabolite of oxycodone and is expected in the UDS of a patient taking oxycodone, although the opposite is not true; that is, this patient is taking oxymorphone and not taking the oxycodone as he stated. He was prescribed 150 tabs per month, states he takes one to two per day, and has only a few tabs left. The numbers and the UDS do not add up, raising the suspicion for misuse or diversion. In addition, the morphine screen is positive. The common reflex is to assume he is taking nonprescribed or illicit substances; the level of morphine detected is consistent with the use of morphine, heroin, or ingestion of poppy seeds. In this case, accusing the patient of using nonprescribed or illicit substances may be wrong—unfortunately, there is no way to differentiate. Because of the oxycodone discrepancy, the clinical decision was to wean opioids.

For the same patient, if a basic opiate immunoassay screen were done, the interpretation of the results may have resulted in a very different outcome. The benefit of the opiate immunoassay is that it is rapid, sensitive, widely available, and relatively inexpensive. A major disadvantage is that semisynthetic opioids may not be detected, making the interpretation of compliance nearly impossible. The opiate immunoassays perform very well when compared to confirmatory screens in evaluating morphine; however, the cross-reactivity varies among manufacturers for oxycodone and oxymorphone.^[9]

In this case, the opiate may have been positive because of the presence of morphine or because of the minor cross-reactivity with the semisynthetic medications. The test would have come back as positive, giving no insight that the patient was not taking oxycodone. There are immunoassays designed to detect specific semisynthetic opioids, but those are not typically included in the basic screens. The immunoassay specifically for oxycodone and its metabolite, oxymorphone, has a sensitivity and specificity of approximately 99%.^[9]

In the United States, we are enveloped in a crisis where overdose from opioids is the leading cause of accidental death.^[10] Although we hope to see a decrease in prescribing opioids, it is important that we do not let the pendulum swing back to the practice of reserving opioids for end-of-life care. It is essential for physicians who prescribe opioids to monitor their patients closely and identify signs and symptoms of misuse and abuse. UDSs give unbiased and reproducible objective data and are an important tool in the setting of addiction and pain management. Although numerous guidelines recommend UDSs for pain management patients as a tool to monitor compliance, there is a lack of specific recommendations for which to order and at what frequency. Therefore, clinicians must understand the capabilities and limitations of assays performed to prevent incorrect interpretation. Answer: D

References

1. Volkow ND. America's addiction to opioids: heroin and prescription drug abuse. The National Institute on Drug Abuse: Senate Caucus on International Narcotics Control. Available at: https://www.drugabuse.gov/about-nida/legislativeactivities/testimony-to-congress/2016/americas-addiction-to-opioids-heroinprescription-drug-abuse. Published May 14, 2014. Accessed September 8, 2017.
2. Chen KY, Chen L, Mao J. Buprenorphine-naloxone therapy in pain management. Anesthesiology 2014;120(5):1262–1274. doi: 10.1097/ALN.0000000000000170
3. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. JAMA 2016;315(15):1624–1645. doi:10.1001/jama.2016.1464 4. Tenore P. Advanced urine toxicology testing. Journal of Addictive Diseases 2010;29(4):436–448. doi: 10.1080/10550887.2010.509277
4. Reisfield G, Bertholf R, Barkin R, Webb F, Wilson G. Urine drug test interpretation: what do physicians know? J Opioid Manag 2007;3(2):80–86.
5. Starrels JL, Fox AD, Kunins HV, Cunningham CO. They don't know what they don't know: internal medicine residents' knowledge and confidence in urine drug test interpretation for patients with chronic pain. J Gen Intern Med 2012;27(11):1521–1527. doi: 10.1007/s11606-012-2165-7
6. Centers for Medicare and Medicaid Services. Clinical laboratory fee schedule. Available at: https://www.cms.gov/Medicare/Medicare-Fee-for-ServicePayment/ClinicalLabFeeSched/index.html. Accessed June 15, 2017.
7. Bertholf R, Johannsen L, Reisfield G. Sensitivity of an opiate immunoassay for detecting hydrocodone and hydromorphone in urine from a clinical population: analysis of subthreshold results. J Anal Toxicol 2015;39(1):24–28. doi: 10.1093/ jat/bku109
8. National Academy of Clinical Biochemistry. Laboratory Medicine Practice Guidelines. Using clinical laboratory tests to monitor drug therapy in pain management patients. Available at: https://www.aacc.org/~/media/practiceguidelines/pain-management/rough-draft-pain-management-lmpg-v6aacc.pdf. Accessed June 7, 2017.
9. Centers for Disease Control and Prevention, National Center for Health Statistics. Multiple cause of death 1999–2015. Available at: https://wonder.cdc.gov/ wonder/help/mcd.html. Accessed September 8, 2017.