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Hot Topic: Interpretation of Qualitative and Quantitative Urine Opiate Tests for Pain Management Patients



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Summary

Published: February 2014

Pain is one of the most common reasons people seek medical care. Current published clinical practice guidelines support the use of opioids in certain patients to manage moderate to severe pain. However, these medications pose a high risk of abuse and misuse, so monitoring for compliance or lack of, is commonplace. Various laboratory tests provide objective measures to effectively manage pain patients, assess adherence, and detect diversion. Appropriate test utilization and interpretation of laboratory results can be confusing. Dr. Jannetto discusses the use of qualitative urine screening assays and quantitative confirmatory testing to determine compliance in pain management patients.

Presenter: Paul J. Jannetto, PhD, DABCC, FACB

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Welcome to Mayo Medical Laboratories Hot Topics.  These presentations provide short discussion of current  topics and may be helpful to you in your practice.  Our speaker for this program is Dr. Paul J Jannetto, Co- Director of the Toxicology and Drug Monitoring  Laboratory at Mayo Clinic, Rochester, Minnesota. Dr. Jannetto discusses the interpretation of qualitative and  quantitative urine opiate tests for pain management patients.  Thank you, Dr. Jannetto, for presenting with us today. Thank you for that introduction. I have nothing to  disclose.

Utilization Message

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, with any qualitative urine immunoassay you  have to ask yourself what drugs will actually test  “positive” in that assay. You want to make sure that the  right test was ordered to detect the medication that the  patient is currently taking. Secondly, you also need to remember to consider the  limitations of each urine immunoassay when interpreting  the test results. These tests are not 100% sensitive and  specific,  so you can get false-positive and false-negative results. Lastly, for quantitative or confirmatory urine opioid tests,  review the metabolic profiles of the prescribed pain  medication(s) and don’t overlook the possibility of  detecting  pharmaceutical impurities when interpreting  the test results

Pain is a major public health issue.

In fact, pain is cited as the most common reason  Americans access the healthcare system. Pain affects more Americans than diabetes,  heart disease, and cancer combined. According to the National Center for Health Statistics, 1 out of every 4 Americans have reported that they  suffered from pain that lasted greater than 24 hours and  millions more suffer from acute pain. As a result, pain is a major contributor to healthcare  costs which is estimated at over  $635 billion dollars per year in medical treatment and  lost productivity. Between 1999 and 2010, the sale of opioid pain relievers used to manage pain has actually risen over 4-fold.

In 2010, enough opioid pain relievers were prescribed to  medicate every adult in America around the clock  taking 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.

Why do physicians use urine drug tests to monitor pain management patients? 

Currently, there are numerous clinical practice  guidelines published which support the use of laboratory tests to monitor compliance in pain patients. For example, the American Society of Interventional Pain  Physicians have a guideline which 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.

The abuse potential for opioids is very high. According  to the results from the 2011 National Survey on Drug  Use and Health, approximately 13% of Americans age  12 or older have admitted to using a pain reliever for  non-medical reasons at least once in their lifetime. Approximately 11 million Americans age 12 or older  have admitted to using a pain reliever non-medically at least once in the past year. In 2011, pain relievers had the second highest level of  past year dependence or abuse after marijuana.

There are also financial reasons to use urine drug tests  to monitor pain management patients.  For example, it has been shown that non-adherence 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 non-adherent chronic pain patients.  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 non-therapeutic  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 Urine Opiate Tests

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 screening assays. These tests typically  identify the drug and/or drug metabolite with variable  specificity and often only by drug class.  Alternatively, physicians may use quantitative or more  confirmatory assays where they can identify and  quantify the individual drug and/or drug metabolite with  high specificity and better sensitivity.

Screening Assays

However, physicians are primarily using screening  assays with or without confirmatory assays to verify  adherence in pain management patients. There are 2  types of screening assays.  Traditional screening assays that use antibodies  directed against a drug or drug metabolite.  These immunoassays may be in a point-of-care format  so the test can be done right in the physician’s office or  clinic; or they can be commercially based immunoassays  run in CLIA-certified laboratories.  Alternatively, new targeted laboratory-developed  screening assays using mass spectrometry have also  started to emerge as a screening tool. Each of these  types of assays has advantages and disadvantages.  Point-of-care tests have the advantage of having the  fastest turnaround time, so the physician can get an  immediate result which is good for patients that 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 laboratories.

Cross-Reactivity Issues with Immunoassays

Cross-reactivity with immunoassays is a big issue that  needs to be considered when interpreting 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 opioids used in pain management.  As you can see from this package insert from the  Siemens EMIT urine opiate assay, it has a pretty good  cross-reactivity with codeine, hydrocodone, and the  metabolite of heroin (6-acetyl morphine).  However, a patient’s urine sample would need to have a  much higher concentration (higher than the 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.

What Does a Positive Urine Drug Screen (Immunoassay) Result Really Mean?

As a result, what does a “positive” urine drug test result  on an immunoassay actually mean? It could mean that the patient was compliant and took  the prescribed drug as directed.  However, it could also mean the patient was only  partially compliant and just took 1 dose prior to  collection. Alternatively, the patient could have directly  spiked/added the drug into the urine sample after  collection. Other possible explanations include that the  patient took another medication that cross-reacted with  the immunoassay causing a false-positive result.

Limitations of Immunoassays

False-positive results are one of the limitations of using  an immunoassay. Shown here is a partial list of other  medications that can give a “positive” result in various  screening immunoassays. In the case of amphetamine,  you will see that other over-the-counter medications like  pseudoephedrine can result in a “positive” result.

What Does a Negative Urine Drug Screen (Immunoassay) Result Really Mean?

Alternatively, what does a “negative” urine drug test  result on an immunoassay really mean?  It could mean the patient is not compliant with their  prescribed medication. It could also mean they were  partially compliant and maybe missed a few doses, or  took less medication.  Maybe the patient is well hydrated and the urine is dilute  or possibly adulterated.  Alternatively, the wrong test might have been ordered  and the test may not cross-react with the patient’s  medications. However, another explanation is that the  drug may actually be present, but it is below the cutoff or  detection limit of the assay leading to a false-negative  result.

False-negative results can happen as easily as a false- positive result with immunoassays.  Therefore, it is important to look at the assay cutoff or  detection limit when interpreting test results.  A call to the laboratory can determine the cross- reactivity of the patients medication  with the assay ordered. Other information that is  important and should be considered is the timing  between when the patient last took their medication and  when the urine sample was collected.  For most opiates, you typically have a 1 to 3 day window  of detection, but if the patient stopped taking their  medication several days ago, you might get a “negative”  result.  Specimen validity testing can also be used to help  determine the integrity and quality of the patient’s  sample. For example, if the creatinine is <20 mg/dL and  the specific gravity is between 1.001 and 1.002,  the patient’s urine sample is unusually dilute. Therefore,  the drug may actually be present,  but below the detection limit of the assay which will give  a negative result.

The following slide demonstrates how a patient may test  “negative” on a urine immunoassay which has a higher  cutoff or detection limit compared to a liquid  chromatography tandem mass spectrometry-based  assay (LC-MS/MS). In this study, Mikel and colleagues  took the urine of pain management patients and tested it  using both an immunoassay and a LC- tandem mass  spec assay.  The urine opiate immunoassay had a cutoff of 300  ng/mL while the LC- tandem mass spec 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 spec  assay, but tested “negative” on the immunoassay due to  the higher cutoff and poor cross-reactivity with the  antibody used in the immunoassay.

Clinical Case Studies

Now let’s look at 2 clinical case studies. In these  examples, patient #1 and #2 are both prescribed and  taking 20 mg/day of oxycodone. The ordering physician  orders a urine opiate immunoassay screen with a  300 ng/mL cutoff to determine if both patients are  compliant. Patient #1 test results come back “negative”. The ordering physician now wonders if patient #1 is  noncompliant. Or is this just a false-negative result? Since the ordering physician knows the urine opiate  screening assay is not 100% sensitive or specific for  oxycodone, they order a urine opiate confirmatory test.  The results of the confirmatory test come back positive  for oxycodone at a concentration of 1,235 ng/mL  and oxymorphone at a concentration of 746 ng/mL.

Where Did the Oxymorphone (Opana ®, Numorphan ® ) Come From?

As a result, the physician now wants to know why is  oxymorphone present since it is another opioid  medication under the brand names of Opana or  Numorphan which can be prescribed for pain.  However, oxymorphone is also a metabolite of  oxycodone as you can see from this slide.  Oxycodone is metabolized endogenously to  noroxycodone and oxymorphone by the  cytochrome P450 system. Based on the concentrations  and the metabolic ratio of oxycodone to oxymorphone,  patient #1 results are most consistent with the  oxymorphone being a metabolite of oxycodone.

Why was the Urine Opiate Immunoassay Negative?

However, the physician wants to know why was the urine  opiate immunoassay originally “negative”  while the confirmatory LC-tandem mass spec assay  result came back as “positive”.  To explain these results, we must first go back to the  cross-reactivity of the urine opiate immunoassay. As you can see, if you use a 300 ng/mL cutoff on the  urine immunoassay, the concentration of oxycodone  must be greater than or at least equal to 1,500 ng/mL to  cause a “positive” result. In this case, the oxycodone concentration in the  patient’s urine was only 1,235 ng/mL which resulted in a  “negative” result. The confirmatory test had a lower  detection limit of 100 ng/mL  and specifically can identify oxycodone. Therefore, the final interpretation in this case is that  patient #1 is likely compliant  and taking their prescribed oxycodone.

For patient #2, the original urine opiate immunoassay  was “positive.”  However, the physician wanted to know if this meant the  patient was compliant or could they be taking another  opiate which is causing the “positive” test result?  As a result, the physician decides to order the urine  opiate confirmatory test. In this case, the LC-tandem  mass spec test comes back positive for hydrocodone at  a concentration of 2,504 ng/mL,  hydromorphone at a concentration of 2,013 ng/mL,  oxycodone at a concentration of 2,407 ng/mL,  and oxymorphone at a concentration of 1,836 ng/mL.  Similar to patient #1, the physician was expecting  oxycodone and its metabolite oxymorphone.  However, the physician was surprised by the  hydrocodone and hydromorphone results.

Where did the Hydrocodone/Hydromorphone Come From?

Now, the physician wanted to know where did the  hydrocodone and hydromorphone come from?  Are those compounds also metabolites of oxycodone?  Are they false-positive results?  The answer to both of these questions is “no”.  Hydrocodone and hydromorphone are not metabolites  of oxycodone  and the LC-tandem mass spec confirmatory assay can  specifically identify both of these compounds.  As a result, you can see from the following slide the  metabolic pathway of opioids is rather complex. Both hydrocodone and hydromorphone are available as  individually prescribable medications,  but they can also be minor metabolites of codeine and  morphine, respectively.  Since the morphine and codeine were not detected in  the confirmatory LC-tandem mass spec assay,  it is unlikely that the hydrocodone and hydromorphone  represent minor metabolites of these drugs.  From the metabolic pathway, you can also see that  hydromorphone is a metabolite of hydrocodone  similar to how oxymorphone is a metabolite of  oxycodone.  As a result, the hydrocodone and hydromorphone  results are most consistent with the use of hydrocodone.

Nevertheless, the ordering physician also knows that  prescription medications aren’t 100% pure  and maybe these unexpected results are due to  pharmaceutical impurities.  Prescription medications can contain a small amount of  an allowable process impurity. In the case of oxycodone, you can find up to 1% present  as hydrocodone. Therefore, if you have a case with  In the case of oxycodone, you can find up to 1% present  as hydrocodone. Therefore, if you have a case with  really high concentrations of oxycodone, you could see  detectable levels of hydrocodone.  For example, if the oxycodone concentration was  approximately 10,000 ng/mL, you could see  hydrocodone concentrations up to 100 ng/mL.

However, the concentration of oxycodone in this case  was only 2,407 ng/mL and the hydrocodone  concentration was actually slightly higher at 2,504 ng/mL  which is not consistent with being a minor impurity.  As a result, the final interpretation in this case is that the  patient is most likely taking both the oxycodone which  was prescribed and hydrocodone which was not  prescribed.

Summary

In summary, the interpretation of qualitative and/or  quantitative urine opiate tests in pain management  patients to determine compliance is challenging.  You need to select and interpret the qualitative tests  based on the limitations of each assay. In addition, you need to remember metabolic pathways  and possible pharmaceutical impurities  when interpreting quantitative test results.  Lastly, if you have any questions or get unexpected or  unexplained results, you should discuss these with the  patient  and/or laboratory to determine if any additional  testing is needed.

Thank you for your attention.  I hope you found this presentation useful.  If you have any questions, please contact Mayo Medical  Laboratories. 


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