The medical community struggles to balance the need for pain medication against the use of addictive and potentially deadly opioid pain relievers. Ironically, while the sale of opioid pain relievers has quadrupled in the last 20 years, 40% of patients report inadequate treatment of their pain. With the increased use of opioid pain relievers, there has been an increase in medical treatment costs, decreases in productivity, and an increase in opioid-related fatalities. A new high-resolution targeted opioid screening test from Mayo Medical Laboratories offers improved sensitivity and specificity for use in the monitoring and management of patients who are prescribed opioid pain relieving medication.
Presenters and Credentials:
Paul Jannetto, Ph.D., is an Assistant Professor of Laboratory Medicine and Pathology and Consultant in the Clinical Biochemistry & Immunology at Mayo Clinic in Rochester, Minnesota.
Our speaker for this program is Dr. Paul Jannetto, an Assistant Professor of Laboratory Medicine and Pathology at Mayo Clinic, as well as the Director of the Clinical and Forensic Toxicology Lab, the Clinical Mass Spectrometry Lab, and the Metals Lab. Dr. Jannetto provides an overview of a new high-resolution targeted opioid screening test for use in management of prescription opioid use.Welcome to Mayo Medical Laboratories Hot Topics. These presentations provide short discussion of current topics and may be helpful to you in your practice.
I have nothing to disclose.
As you view this presentation, consider the following important points regarding the use of qualitative and/or quantitative urine opiate tests for determining compliance in pain management patients.
- First of all, traditional laboratory-based or point-of-care qualitative urine immunoassays have limited sensitivity and specificity.
- Secondly, urine opiate immunoassays only report out as a class not individual drugs, requiring additional definitive (eg, mass spectrometry-based) testing, which increases the cost and turnaround time for results.
- While quantitative opioid testing in urine can be useful in select situations to identify variant drug metabolism, and detect pharmaceutical impurities or metabolism through minor routes, it can’t be used to evaluate adherence to a prescribed dosage regiment. Concentrations in urine don’t correlate back to dosage.
- Finally, the high-resolution, targeted opioid screen is designed to be a comprehensive test that can detect and identify 33 different opioids and/or their metabolites using LC- tandem mass spectrometry and has an enhanced report with interpretative comments.
The objectives of my talk are to:
- Describe the clinical utility and limitations of traditional opiate immunoassays and mass spectrometry-based screening assays used to support pain management/monitoring of controlled substances.
- Secondly, to define the metabolic profiles of opioids commonly used in pain management and discuss how to interpret screening and definitive test results.
Opiate Crisis in America
The United States is currently experiencing an epidemic of prescription opioid misuse and overdose. Increased prescribing and sales of opioids—a quadrupling since 1999—helped create and fuel this epidemic.
In fact, enough opioid pain relievers were prescribed to medicate every adult American around the clock giving them 1 pill every 4 hours for a month.
Yet despite the use of potent narcotics to manage pain, 40% of patients still report being inadequately treated for pain.
Medical examiner reports also continue to show an increase in opioid related fatalities
In the end, chronic pain is a major contributor to healthcare costs, which is estimated at over $635 billion dollars per year in medical treatment and lost productivity.
Do Clinicians Use Urine Drug Tests (UDT) to Monitor Opioids?
Why do physicians use urine drug tests to monitor pain management patients? Currently, there are numerous clinical practice guidelines published that support the use of laboratory tests to monitor compliance in pain patients.
For example, the American Society of Interventional Pain Physicians have a guideline that states that urine drug testing must be implemented from initiation along with subsequent adherence monitoring to decrease prescription drug abuse or illicit drug use when patients are in chronic pain management therapy. The purpose of urine drug testing is to verify adherence to prescribed medications, identify undisclosed drugs, and discourage drug misuse, abuse, and diversion.
The actual use of urine drug tests as part of adherence monitoring has been associated with a 49% reduction in opioid abuse according to a publication by Manchikanti.
2016 CDC Recommendation for UDT
In March 2016, the CDC also issued new recommendations for prescribing opioid medications for chronic pain as part of the urgent response to the epidemic of overdose deaths. The new guideline aims to improve the safety of prescribing and curtail the harms associated with opioids, including opioid use disorder and overdose.
In regards to urine drug testing, the CDC specifically recommended that when prescribing opioids for chronic pain, clinicians should use urine drug testing before starting opioid therapy and consider urine drug testing at least annually to assess for prescribed medications, as well as other controlled prescription drugs and illicit drugs.
Why Do Clinicians Use Urine Drug Tests (UDT) to Monitor Opioids?
There are also financial reasons to use urine drug tests to monitor pain management patients.
For example, it has been shown that nonadherence to opioid therapy leads to increased healthcare utilization and cost. Furthermore, the early monitoring of opioid adherence using urine drug tests may provide substantial cost savings associated with healthcare issues incurred in nonadherent chronic pain patients.
Why Do Clinicians Use Urine Drug Tests (UDT) to Monitor Opioids?
Finally, there is also the fear of regulatory scrutiny and both state and federal regulations that cause physicians to use urine drug tests to monitor pain management patients.
Currently, most states have specific regulations, guidelines, or policy statements for prescribing opioid analgesics for pain management. Some states actually discourage or prohibit physicians from prescribing opioids to patients whom they know or should know are using controlled substances for nontherapeutic purposes. On the other hand, the federal regulations do not prohibit the use of opioids to treat pain if a patient is abusing controlled substances.
Types of UDTs
So what types of urine opiate tests are being used by physicians to determine compliance to opioid pain management therapy? Routinely, physicians may use qualitative or screening assays, or definitive assays. Screening assays typically identify the drug and/or drug metabolite with variable specificity and often only by drug class. These are commonly immunoassay-based, offer quick turnaround time on automated platforms, and have higher cutoffs. Alternatively, physicians may use definitive tests where they can identify and/or quantify an individual drug or drug metabolite with high specificity and better sensitivity. These tests are commonly performed using mass spectrometry-based methods.
Point-of-care tests have the advantage of having the fastest turnaround time, so the physicians can get an immediate result, which is good for patients who have a high risk for abuse or reside far from care. Laboratory-based immunoassays typically have a larger test menu and are more economical. However, all immunoassays suffer from higher cutoffs, limited sensitivity and specificity. On the other hand, targeted screens have better sensitivity and specificity, but aren’t widely available at all local laboratories.
Cross-Reactivity Issues with Immunoassays
Cross-reactivity with immunoassays is a big issue that needs to be considered when interpreting screening test results. For example, in the urine opiate immunoassay the antibody used in most manufacturer kits is directed against morphine. It has limited-to-no cross-reactivity with all of the other opioids used in pain management. As you can see, a standard urine opiate immunoassay has a pretty good cross-reactivity with codeine, and the metabolite of heroin (6-acetyl morphine).1 However, a patient’s urine sample would need to have a much higher concentration (higher than the 300 ng/mL cutoff) of oxycodone and/or oxymorphone to get a “positive” result using this assay. In addition, you will notice that other opioids like methadone, tramadol, fentanyl, or tapentadol are absent from this list since they do not cross-react at all with this assay and you will get a “negative” result even if these drugs are present in the patient’s urine.
Limitations of Immunoassays
The following slide demonstrates how a patient may test “negative” on a urine immunoassay, which has a higher cutoff and varying degrees of cross-reactivity to all opioids compared to a liquid chromatography-tandem mass spectrometry-based method (LC-MS/MS). In this study, Mikel and colleagues took the urine of pain management patients and tested it both using an immunoassay and an LC-tandem mass spectrometry assay. The urine opiate immunoassay had a cutoff of 300 ng/mL, while the LC-tandem mass spectrometry-based assay had a cutoff or detection limit of 50 ng/mL.
If you look at the hydromorphone results, you can see that approximately 69% of patients who were prescribed and taking hydromorphone tested “positive” or had detectable concentrations on the LC-tandem mass spectrometry method, but tested “negative” on the immunoassay due to the higher cutoff and poor cross-reactivity of the immunoassay antibody with hydromorphone.
High-Resolution Targeted Opioid Screen: TOPSU / Targeted Opioid Screen, Urine
The features and benefits of the new high-resolution targeted opioid screen, TOPSU, include:
- It uses high-resolution accurate mass spectrometry to identify 33 different opioids and/or metabolites where immunoassays are not adequate
- It also has lower detection limits (improved sensitivity) compared with traditional immunoassays
Drugs Detected in the High-Resolution Targeted Opioid Screen
Here is the complete list of the 33 opioids and metabolites along with the cutoffs or concentration required to give a positive or “present” result. This one test will allow clinician’s to not have to remember which opioid does or does not cross-react with the urine opiate immunoassay, or have to order multiple different immunoassays and/or confirmatory tests to look for all of the different opioids like buprenorphine, fentanyl, methadone, tramadol, and tapentadol.
High-Resolution Targeted Opioid Screen: TOPSU / Targeted Opioid Screen, Urine
The high-resolution targeted opioid screen also will improve test utilization without compromising turnaround times.
It will reduce the need for confirmatory testing that is required with traditional immunoassays since they don’t specifically identify which opioid is present.
Because it detects both parent and metabolite of an opioid, we can identify spiked samples where patients crush-up pills and then add them into the urine instead of ingesting them.
Lastly, this new test comes with an enhanced PDF report that has interpretative comments to aid the clinician with the interpretation of the test results.
Example of Enhanced Report
Here is an example of an enhanced report. All positive results are pulled into the top section of the report so the clinician can immediately see what was present or detected. It also provides some additional information regarding brand names or if something is a metabolite or possibly impurity of another drug.
The next section is the interpretation section where a comment is given providing guidance regarding the test results.
The last section shows all the analytes tested for that were negative or not detected.
Clinical Case Study
Now let’s look at one clinical case study comparing a traditional approach using immunoassay screens with reflex to confirmatory testing compared to the new high-resolution targeted opioid screen.
In this case, we have a 38-year-old male with chronic back pain who is taking hydrocodone (10 mg twice a day) along with a rescue pain medication (tramadol), which is taken as needed for breakthrough pain. The ordering physician sees the patient is improving based on the visual analog scale (originally 6/10, and now 3/10), but orders a urine drug test (pain management panel) that uses a variety of immunoassays to screen for drugs of abuse and opiates and reflexes to confirmatory testing if positive.
The purpose of the urine drug test is to check for adherence to the prescribed medications (hydrocodone and tramadol). The screening results come back “presumptive positive” for opiates, but we don’t know which opiate may or may not be present. As a result, the opiate confirmation test is automatically performed and shows both hydrocodone (2,153 ng/mL) and hydromorphone (1,780 ng/mL).
As a result, how should the physician interpret these results? The patient is prescribed hydrocodone and tramadol and admits taking both of these medications daily (the last dose in the morning prior to collection of the urine sample). However, the test only shows hydrocodone and hydromorphone.
As a result, the physician wants to know where the hydromorphone came from since it can be a separate prescribable drug (brand name = Dilaudid)
Where did the Hydromorphone Come From?
As you can see from this simplified figure showing the endogenous metabolism of some opioids, hydrocodone is metabolized to hydromorphone by the cytochrome P450 system (specifically CYP2D6).
Clinical Case Study Continued
Based on the concentrations and the metabolic ratio of hydrocodone to hydromorphone, these results are most likely consistent with hydromorphone being a metabolite of hydrocodone.
As a result, the patient has taken the hydrocodone at least in the past 3 days.
However, the physician still wants to know where is the tramadol? In this case, the physician has to order an additional confirmatory test for tramadol and its metabolite, which does come back positive or detectable. Unfortunately, this resulted in additional testing, expense, and a delay in the final results.
Now let's look at this same case study, but use the new high-resolution targeted opioid screening test. Alternatively, this new test will also be incorporated into a new pain management panel in place of the opiate, oxycodone, and methadone immunoassay, if a physician also wants to look for other drugs of abuse or medications.
In this case, the physician just ordered the targeted opioid test on the urine sample and got the following results back:
Hydrocodone, norhydrocodone, dihydrocodeine, hydromorphone, tramadol, and o-desmethyltramadol were all present.
Based on the pattern of analytes, the interpretation stated that the test detected the presence of hydrocodone and several of its metabolites (hydromorphone, dihydrocodeine, and norhydrocodone). Suspect use of hydrocodone within the past 3 days.
Also, the test detected the presence of tramadol and its metabolite (O-desmethyltramadol). Suspect use of tramadol within the past 3 days.
These results are consistent with the patients prescribed medications and no additional tests need to be ordered.
In summary, objective measures like laboratory tests are needed to identify and evaluate adherence or misuse or abuse of controlled substances.
The new high-resolution targeted opioid assay can:
- Identify 33 different opioids and/or metabolites where immunoassays are not adequate (improved specificity)
- Has lower detection limits (improved sensitivity)
- Reduces need for confirmatory testing required with traditional immunoassay screens
- Improves test utilization
- Available with enhanced reports and interpretative comments
In the end, all urine drug test results must be interpreted in the context of the test, drugs prescribed, specimen type, time since last dose and sample collection, specimen validity test results, and the patient. Unexpected or unexplained results should be discussed with the patient and laboratory, and additional testing performed if needed.
Thank you for your attention. I hope you found this presentation useful. If you have any questions, please contact Mayo Medical Laboratories.