Why Is There Hydromorphone In My Patient’s Urine?
Drug testing commonly is used in clinical, criminal, and workplace settings. Unexpected results can be misinterpreted, leading to a host of negative outcomes including premature termination of patients from practice, compromised patient-physician trust, suboptimal outcomes, denied legitimate medical access, possible inappropriate employment termination, and/or unjust exclusion from sporting events.
Monitoring for opiate compliance is mandated in multiple states and is considered the standard of care for patients taking chronic opioid therapy. The most common method of monitoring for opiate compliance is urine drug screening (UDS). The drug test typically will screen for morphine as well as codeine, hydrocodone, hydromorphone, oxycodone, oxymorphone, norhydrocodone, and noroxycodone. Interpretation of the UDS results may not always be as straightforward as it appears and relies heavily on knowledge of drug metabolism.
One of the more perplexing situations is when a patient who is prescribed morphine has a positive UDS for the prescribed morphine and for hydromorphone. One may think this only is seen when the morphine test result is very high, but, in fact, it is the ratio of the hydromorphone to the morphine that is important. In Figure 1, we see an example of this situation in a 58-year-old male who is prescribed 100 mg of MS Contin (controlled-release morphine) to be taken every 6 hours for chronic pain. The quantitated morphine (by LC-MS/MS) at 8,891 ng/mL is not a high value for urine, given that results >50,000 ng/mL are not uncommon. Thus, hydromorphone at a urine level of 168 ng/mL, as this patient had, would be considered a low value.
How Morphine Is Metabolized
Morphine is one of several opiates prescribed for pain. Morphine is an alkaloid derived from the poppy plant. It is used to treat moderate to severe pain and is available in both short-acting and extended-release formulations. Morphine undergoes complex metabolism through which the majority of the drug is inactivated to morphine-3-glucuronide. Other metabolites include normorphine, morphine-6-glucuronide, morphine-3-ethereal sulfate, and morphine-3,6-diglucuronide.1 In some individuals, morphine will also metabolize into hydromorphone.2,3
When a patient who is prescribed morphine tests positive for hydromorphone, the first conclusion may be that the patient is using a drug such as Dilaudid (hydromorphone) or Exalgo (hydromorphone) in addition to their prescribed medication. Another possible explanation is that the patient may be taking hydrocodone, because hydromorphone is a metabolite of hydrocodone. Is there a way to sort through the information and come to a logical conclusion as to the source of the hydromorphone?
Mining the Information
There are many pieces of information in the laboratory report that can help the clinician identify the source of the hydromorphone. First, looking at the combination of the test results related to hydrocodone, hydromorphone, and norhydrocodone can provide valuable information. In the example provided, both hydrocodone and norhydrocodone are negative. When a patient uses hydrocodone, the UDS report will often be positive for hydrocodone, hydromorphone, and norhydrocodone. Finding just hydromorphone is unusual.
Another important piece of information is the actual quantity (ng/mL) of hydromorphone found in the urine. In the example, hydromorphone has a very low value relative to the morphine value (all quantitative values obtained from LC-MS/MS). Cone determined that the hydromorphone:morphine ratio ranged between 0.2%-2.2% when the morphine was the source of the hydromorphone.2 Other reports also support the idea that morphine should produce less than approximately 3% of hydromorphone as a byproduct, and a urine hydromorphone concentration exceeding 5% of the morphine concentration is suggestive of concurrent hydromorphone use.3
In our example, hydromorphone values equaled 168 ng/mL, while morphine values equaled 8,891 ng/mL. Therefore, the ratio of hydromorphone to morphine is 168/8,891=0.0189, or 1.9%, which falls into the range from the Cone study. Taking it one step further and applying the range (0.2% and 2.2%) from the Cone study to our example [(0.002)(8,891)=17.8 and (0.022)(8,891)=195.6] gives a hydromorphone (as a likely metabolite of morphine) range of 18-196 ng/mL (Table 1). In this case, it appears that morphine was the likely source of the hydromorphone in the urine.
In conclusion, some patients on morphine may have detectable amounts of hydromorphone in the UDS. The clinician will need to determine drug protocol compliance based not only on the presence of hydromorphone, but also by examining the report to see if the hydromorphone in each specific case is possibly from the prescribed morphine and not another drug. Hydromorphone:morphine ratios that exceed 5% may suggest possible concomitant drug use. Because the metabolic pathway from morphine to hydromorphone has yet to be elucidated,1,3 knowing the relationship between morphine and hydromorphone and their relative concentrations in the urine is critical for accurate interpretation of the results.
When interpreting the results of an assay for a particular drug of interest, clinicians are concerned about inconsistent findings or unexpected results and how the results relate to patient behaviors. Careful review of all the information contained in the test report, as we have seen in our hydromorphone example, will help guide the clinician in the interpretation of the UDS result. Clinically relevant testing combined with accurate result interpretation becomes a robust tool as part of the patient assessment in the continuum of care. It can also enhance the trust between patients and clinicians, and, most importantly, optimize clinical outcomes.