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New Report of a High-Dose Morphine Metabolite

A previously unreported metabolite of high-dose morphine treatment, hydromorphone, has recently been discovered by a select few laboratories.

Recently, a toxicologist at our laboratory received a frantic phone call from a patient participating in high-dose morphine therapy. The reason for his call? He’d just been discharged from his pain clinic. The reason for his dismissal? He tested positive for morphine and hydromorphone, the latter being a known metabolite of hydrocodone, a commonly prescribed opioid narcotic also frequently sold on the street. The treating physician assumed the patient was taking hydrocodone and dismissed him from the practice.

What that physician didn’t realize was that hydromorphone is on its way to becoming a recognized metabolite of morphine. A little research on his part would have not only prevented him from humiliating a patient but, more importantly, exposed him to crucial facts that a select few laboratories have only recently discovered. This story is just one of many examples why it’s so critical for practitioners to understand that as treatment for chronic pain continues to increase, so will the appearance of unusual metabolic pathways.

However, before we talk about where opioid metabolism is headed, it will be helpful to briefly review traditional patterns.

Classical Patterns of Opioid Metabolism

In order for the body to excrete opioids in the urine, they must be converted to a water-soluble form, a conversion that primarily occurs in the liver through either non-synthetic oxidation or reduction mechanisms or synthetic conjugation mechanisms such as glucuronidation. Figure 1 shows the classic opioid metabolic pathways.1

Figure 1. Classic Opioid Metabolic Pathways

In the last several years, opioids have taken over as the most commonly prescribed regimen for chronic pain. As a result, patients have developed a high tolerance to high levels of opioids whereas, for the average person who usually cures ailments with ibuprofen and the occasional antibiotic, the daily dosage required to control severe pain would be enough to kill.

AIT laboratory, as well as other life-science facilities, has recently begun observing metabolites of prescription opioids that have previously gone unreported. Shown in Figure 2 are metabolites that AIT has encountered since initiating monitoring of chronic-pain patients for medication compliance.

Figure 2. Observations at AIT Laboratories

In routine experience, the morphine-to-hydromorphone conversion is commonly observed, while the hydromorphone-to-oxymorphone conversion is observed only in rare instances.

  Case 1* Case 2*
Age 52 39
Demographic Female Female
Illness Congenital Hip Dysplasia with Implants Fibromyalgia
Duration of Opioid Therapy 15 years 6 years
Daily Morphine Dose 180 mg 500 mg
Morphine Urine Level 38,438 ng/mL 193,848 ng/mL
Hydromorphone Urine Level 260 ng/mL 2,190 ng/mL
*Dosages were witnessed by physician as well as family validation of compliance

Explanation for New Observations

Until recently, pain treatment with opioids was usually targeted at acute pain patients requiring low-dose, short-term administration. The emerging movement to adequately treat severe chronic-pain cases has created a subset of patients who require high daily doses and have thus developed considerable opioid tolerance. Such metabolic tolerance to opioids may develop as a result of induction of liver enzymes and perhaps other enzymes in the body. Consequently, metabolites of morphine that have not been reported previously are now showing up in tests that monitor therapeutic compliance. The suspicion is that these metabolites are present as a result of chronic high-dose therapy and enzyme induction.

Clinical Importance

Since clinical testing for compliance and detection of possible diversion is becoming commonplace practice, physicians will most likely encounter laboratory results similar to those reported above. It is essential to know that the presence of these metabolites is not always an indicator of non-compliance or diversion of prescription drugs. On the contrary, these findings appear to mean the patient is likely complying with their high-dose therapy. Above all, physicians must not jump to false conclusions, make accusations, or discharge a patient who demonstrates unusual opioid metabolites. Physicians who treat pain patients with opioids need to be aware of possible metabolites of the common opioid morphine, lest patients be unfairly accused of taking non-prescribed medications.

Consultation with Laboratories

Because the research is new and updated frequently, physicians who have a question about opioid metabolites should contact a laboratory that specializes in pain treatment and toxicology to discuss concerns about questionable test results from their patients. In addition to the information presented here, it is likely that other metabolites may be found in patients taking high-dose opioids over the course of their lifetime.

Case Studies

As an example of observations, AIT has worked with several physicians who have documented and/or directly observed a select group of patients to ensure their morphine regimen has been followed as prescribed. The table below shows two representative cases.

In general, when hydromorphone is present in a patient using high-dose morphine, the concentration of hydromorphone is less than two percent of the concentration of morphine in the urine. In the rare cases when oxymorphone is also present, the concentration of oxymorphone is also very low compared with the morphine concentration.


The treating physician mentioned in the article’s introduction wasn’t a bad doctor. The prescription of powerful opioids and their increased availability is reason enough to test every patient who walks into someone’s office. His mistake wasn’t performing the test; rather, it was his unwillingness to investigate other explanations for the test result of a patient—who previously showed no signs of misuse—that proved faulty. In chronic-pain therapy, nothing can be taken for granted.

Last updated on: December 20, 2011
First published on: January 1, 2006