High-resolution targeted stimulant and phencyclidine (PCP) screen
Expires: April 5, 2024
Paul Jannetto, Ph.D.
Director, Clinical and Forensic Toxicology, Clinical Mass Spectrometry Lab
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic, Rochester, Minnesota
Hello, my name is Dr. Paul Jannetto. I am an associate professor in the Department of Laboratory Medicine and Pathology at Mayo Clinic. I am also the director of the Forensic Toxicology Laboratory.
I have nothing to disclose.
The objectives of my talk today are to:
- Describe the clinical utility of prescription stimulant drugs
- Identify the advantages and limitations of traditional laboratory or point-of-care-based immunoassays and mass spectrometry-based screening assays used to monitor amphetamine-type stimulants
- Compare the effectiveness of various types of screening assays to identify phencyclidine (PCP) abuse
- Lastly, differentiate how Mayo Clinic’s targeted stimulant and PCP test, as well as the controlled substance monitoring panel, helps clinicians correctly interpret test results
Central nervous system (CNS) stimulants
CNS, or central nervous system, stimulants are a large class of drugs. While some of these are legal and others are illicit, they all enhance the activity of the brain chemicals dopamine and norepinephrine. Dopamine is involved in the reinforcement of rewarding behaviors while norepinephrine affects blood vessels, blood pressure, heart rate, blood sugar, and breathing.
Most prescription stimulants come in tablet, capsule, or liquid form, which a person takes orally. When misusing a prescription stimulant, a person can swallow, snort, smoke, or inject the drug.
The effects of CNS stimulants include:
- Increased alertness, attention, and energy
- Increased blood pressure and heart rate
- Increased blood glucose
- Opens up breathing passages and increases respiration
In toxicity or overdose situations, patients can experience:
- Irregular heartbeat, heart disease, or even a heart attack
- Seizures, psychosis, or paranoia
- Dangerously elevated body temperatures
Examples of CNS stimulants
Some examples of CNS stimulants include:
- Prescription drugs like amphetamine (brand names Adderall and Vyvanse) or methylphenidate (brand names Ritalin and Concerta)
- Diet aids like phentermine (brand names Adipex-P and Fastin)
- Illicit drugs like methamphetamine (street names speed, uppers, crank, and meth) and MDMA, commonly known as ecstasy
According to a 2018 news release by scientists at the U.S. Department of Health and Human Services, approximately 16 million U.S. adults use prescription stimulants.
While most adults use them properly, approximately 5 million misused prescription stimulants at least once and approximately 0.4 million had prescription stimulant use disorders.
However, stimulant misuse doesn’t only affect adults, but also children. According to the 2020 Monitoring the Future drug survey results, the percentage of eighth graders who self-reported amphetamine misuse rose from 3.5% in 2016 to 5.3% in 2020.
CNS stimulants (prescription/Rx)
As mentioned previously, many CNS stimulants are available by prescription. These medications include amphetamine, methamphetamine, and methylphenidate, which are all FDA approved for use in treating attention deficit hyperactivity disorder, or ADHD, in adults and children. Amphetamine is also approved for narcolepsy and obesity.
Stimulants (Rx and/or over-the-counter)
Other stimulants may be available without a prescription, which is commonly referred to as an over-the-counter product. While they are available without a prescription, they are still located behind the pharmacy counter. For example, ephedrine and pseudoephedrine are available without a prescription and are used as a bronchodilator or for nasal and sinus congestion, respectively.
I also wanted to discuss the dissociative anesthetic phencyclidine, or PCP. It is an illegal drug often abused for its hallucinogenic effects. It has several street names, such as angel dust, embalming fluid, or rocket fuel. It can cause:
- Distortion of sights, sounds, colors, and environment
- Numbness of extremities, slurred speech, and lose of coordination
- A sense of strength or invulnerability, acute anxiety, paranoia, or hostility
PCP abuse is highly regional
PCP abuse is a highly regional phenomenon. Washington D.C. has some of the highest reported cases in emergency room databases, followed by Los Angeles, Chicago, St Louis, New York, and San Francisco.
Laboratory testing for CNS stimulant use/misuse and PCP abuse
So let’s talk about the types of laboratory tests used to detect CNS stimulant use/misuse and PCP abuse in urine.
Screening assays for CNS stimulants and PCP
Physicians may use screening assays or definitive assays. However, physicians are primarily using screening assays with or without confirmatory tests to verify adherence to prescribed stimulants.
There are two types of screening assays. One type includes traditional immunoassays 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 a commercially based immunoassay run in a CLIA-certified laboratory. Alternatively, new targeted laboratory-developed screening assays using mass spectrometry have also started to emerge as a screening tool, like the new targeted stimulant and PCP assay I am talking to you about today. 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 physicians can receive an immediate result, which is good for patients who have a high risk for abuse or reside far from care. Laboratory-based immunoassays typically 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 they aren’t widely available at all local laboratories.
Amphetamine immunoassays and cross-reactivity issues
Let’s look at the specificity and cross-reactivity of a commercially available amphetamine immunoassay that is commonly utilized by many hospital and clinical laboratories worldwide. Cross-reactivity with immunoassays is a key issue that needs to be considered when interpreting screening results.
For example, most commercial urine amphetamine immunoassays are calibrated with d-methamphetamine.
These assays generally have great cross-reactivity with amphetamine. They can also pick up MDMA (ecstasy), MDA, and MDEA. Unfortunately, they also have some cross-reactivity to pseudoephedrine which is a commonly used over-the-counter product for sinus congestion.
Clinical case study #1
Now, let’s look at a clinical case study which uses a traditional immunoassay approach with reflexing to confirmatory testing when positive.
In this case, we have a 16-year-old male with attention-deficit hyperactivity disorder who is being prescribed methylphenidate (a CNS stimulant). However, the patient also presents with a cough and chest congestion of which he reports using an over-the-counter cough and cold medicine. The patient’s ADHD is well-controlled. But per institutional guidelines, the physician wants to order a urine drug test that uses several different immunoassays to screen for the adherence to the controlled substance, as well as commonly abused drugs.
The purpose of the urine drug tests is to check for adherence to the prescribed medication and make sure the patient isn’t abusing other medications. However, you can see the immunoassay screening results all came back negative, except for PCP which was presumptive positive.
Is the patient compliant based on the urine test results?
As a result, how should the physician interpret these results? Is the patient compliant?
- The patient was prescribed methylphenidate and admits taking this medication as prescribed daily. (The last dose was taken in the morning prior to collection of the urine sample).
- However, the physician is concerned that the amphetamine/methamphetamine immunoassay test result was “negative” and the PCP immunoassay was presumptive positive.
- In this case, it is important that the physician remember and understand the limitations of the immunoassays. The doctor should contact the laboratory to determine the cross-reactivity of the various immunoassays used with the prescribed medication.
- In this case, the amphetamine/methamphetamine immunoassay does NOT cross-react (trip positive) to methylphenidate even at concentrations of 1 mg/mL in the urine.
- The clinician must also understand that most methylphenidate appears in the urine as the metabolite (ritalinic acid), and this immunoassay also does NOT cross-react to the metabolite. In fact, <1% of the parent drug is excreted unchanged in the urine and ~60-81% of methylphenidate is excreted as the metabolite (ritalinic acid).
Therefore, the physician adds on another confirmation test that is specific for methylphenidate and its metabolite. As you can see, the patient’s urine showed detectable levels of both methylphenidate and its metabolite which is consistent with the patient taking the prescribed drug within the past three days.
What about the “positive” PCP test result?
However, what about the presumptive positive PCP test result. PCP is an illicit drug.
Since a PCP immunoassay was used, one of the key things that should be considered is the cross-reactivity of this assay and the possibility of a false-positive result. As you can see, there are other prescription and over-the-counter medications which have been reported to give a positive result in various PCP immunoassays. For example, dextromethorphan, an antitussive agent used to temporarily relive coughs, can give a positive result. It is also used in several over-the-counter cough and cold medications, including the brand this patient was taking.
As a result, a PCP confirmation test was ordered and was negative.
In the end, the patient was compliant and taking the prescribed methylphenidate, and the PCP was only a false-positive screening result. However, two additional confirmation tests had to be ordered to get all the information to make the correct interpretation.
Mayo Clinic’s new high-resolution targeted stimulant and PCP screen (TSPU)
Now, let’s look at Mayo Clinic’s new high-resolution targeted stimulant and PCP screen (TSPU).
2017 AACC Academy LMPG evidence-based recommendations: Definitive testing
The use of mass spectrometry-based technologies to screen for stimulants is consistent with the evidence-based laboratory medicine practice guideline entitled, “Using Clinical Laboratory Tests to Monitor Drug Therapy in Pain-Management Patients,” that was published in January 2018 in the Journal of Applied Laboratory Medicine.
One of the recommendations was that qualitative definitive tests should be used instead of immunoassays since they are more effective at identifying prescribed medications and illicit substances in pain-management patients.
High-resolution targeted stimulant and PCP screen (TSPU)
The features and benefits of the new high-resolution targeted stimulant and PCP screen, TSPU, include:
- It uses high-resolution accurate mass spectrometry to identify 10 different stimulants and metabolites, along with PCP, where immunoassays are not adequate. In other words, it has improved specificity to eliminate false-positive screening results.
- It also has lower detection limits (improved sensitivity) compared with traditional immunoassays.
Drugs detected in the high-resolution targeted stimulant and PCP screen
On this slide is the complete list of the 11 analytes along with the cutoffs or concentration required to give a positive or present result. This one test will enable clinicians so that they don’t have to remember which amphetamine-like stimulants do or do not cross-react with the urine amphetamine/methamphetamine immunoassay or have to order an additional costly confirmation tests to detect methylphenidate and its metabolite.
High-resolution targeted stimulant and PCP screen (TSPU)
The high-resolution targeted stimulant screen will also improve test utilization without compromising turnaround times.
It will also significantly reduce the need for confirmatory testing that is required with traditional immunoassays since ~90% of the presumptive positive PCP tests and ~20% of presumptive positive amphetamine/methamphetamine immunoassays are false-positives, meaning they are really negative when follow-up definitive testing is performed. As a result, the targeted screen reduces the need for extra testing, added expense, and delayed turnaround times.
Common false-positive results reported with immunoassays
Shown here is a list of common prescriptions and over-the-counter drugs that can contribute to those high false positive rates in amphetamine/methamphetamine and PCP immunoassays. For example, both pseudoephedrine and ranitidine are available without a prescription and can give a false-positive amphetamine test result.
High-resolution targeted stimulant and PCP screen (TSPU)
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 for case study #1
On this slide is an example of an enhanced report for our patient in case study #1.
As you can see, if the ordering provider includes the prescribed stimulant, it is listed at the top of the report.
The next section is the interpretation section where a comment is given providing guidance regarding the test results. In this case, it says that “the test detected the presence of methylphenidate and its metabolite (ritalinic acid). Suspect use of methylphenidate within the past three days.” Since the patient was prescribed methylphenidate, this is consistent with the prescribed therapy.
This last section shows all the analytes tested, along with some additional information regarding brand names or if something is a metabolite of another drug. For example, it states that ritalinic acid is a metabolite of methylphenidate.
Controlled substance monitoring panel (CSMPU)
In addition to being a separate orderable test, the high-resolution targeted stimulant screen (TSPU) will also be available as part of the new controlled substance monitoring panel (CSMPU).
This controlled substance monitoring panel starts with adulterant testing looking at the creatinine, specific gravity, pH, and oxidants. It includes the high-resolution targeted opioid, stimulant, and benzodiazepine screening assays along with a few traditional immunoassays for common drugs of abuse (e.g. barbiturates, cocaine metabolite, and carboxy-THC).
2021 Mayo CSMPU algorithm
This slide shows the algorithm for the CSMPU where adulteration or specimen validity testing is performed first. If the sample is adulterated, testing stops and no charge is issued to the client/patient. If the sample is not adulterated, testing then resumes with the targeted screens for opioids, stimulants, and benzodiazepines, along with a few traditional immunoassays. In the end, an enhanced PDF report is available with interpretation.
In summary, objective measures like laboratory tests are needed to identify and evaluate adherence, misuse, or abuse of controlled substances.
The new high-resolution targeted simulant and PCP assay:
- Identifies 10 different stimulants and PCP where traditional immunoassays are not adequate (improved specificity)
- Has lower detection limits (improved sensitivity)
- Reduces need for confirmatory testing required with traditional immunoassay screens, which have high false-positive rates
- Improves test utilization
- Is 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 should be performed if needed.
Thank you for your attention. I hope you found this presentation useful. If you have any questions, please contact Mayo Clinic Laboratories.
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