An Evaluation of the Clinical Tools Used to Monitor Illicit Methamphetamine Use Among Chronic Pain Patients: A Cross Sectional Retrospective Study

Abstract

Purpose: Illicit drug use continues to be a concern for adults on opioid therapy for chronic pain. Prescribers use tools such as urine screening and confirmatory testing with mass spectrometry to monitor adherence to chronic opioid therapy contracts. Design: A cross sectional retrospective study was conducted using electronic medical records. Methods: Data was analyzed from 6558 urine samples of adult outpatients receiving opioid therapy at an urban pain specialty clinic who consented to urine drug tests. Results: From October 18, 2021, to October 21, 2022, 569 were positive amphetamine with immunoassay testing. 310 (54%) of those samples were absent amphetamine with or without methamphetamine while 259 (45.5%) were true positive amphetamine proven by confirmation testing. Analysis of confirmatory testing results identified 281 samples positive for amphetamine with or without methamphetamine. 71 samples confirmed positive for methamphetamine with or without amphetamine. 37 (52.1%) of those methamphetamine samples screened positive for amphetamine and 34 (47.9%) samples screened negative for amphetamine. 48 of the methamphetamine samples were sent for chiral confirmation testing. 45 (93.8%) samples were positive for D-methamphetamine while 3 (6.2%) samples were positive for L-methamphetamine. Only 5 (11.1%) of the 45 patients whose samples were positive for d-methamphetamine reported the use of illicit drugs before their urine sample was tested. Discussion: Confirmatory testing with mass spectrometry can detect illicit drugs, such as methamphetamine, with high sensitivity and specificity and should be used with all samples given the low sensitivity of screening immunoassay. It is of utmost importance that opioid pain medicine prescribers know the many possible interpretations of these results so that they are equipped to make appropriate clinical decisions to ensure the safety of the patient, prescriber, and practice.

Background/Rationale

In 2019, 16 167 drug overdose deaths involved psychostimulants in the United States, and 53.5% of these deaths involved an opioid. The rate of drug overdose deaths involving psychostimulants with and without involvement of opioids increased from 2012 (0.3, 0.3) to 2019 (2.8, 2.3). ¹ The risk of illicit drug use, specifically psychostimulants, is prevalent among adults with chronic pain being treated with opiate therapy. A back pain survey conducted among 5103 adults (20-69 years) identified 700 with chronic low back pain (cLBP). Among those with cLBP, 9% used methamphetamine versus 5% of those surveyed without cLBP. ² In a study done by Guevara et al, ³ 600 000 urine drug specimens were analyzed from January 1, 2015 to September 30, 2021. It was concluded that among the 347 092 patients who were prescribed opiates, those with an inconsistent urine were 2.5 times more likely to test positive for methamphetamines than the consistent urine group. ³ The researchers defined consistent as positive for their prescribed opiates and inconsistent as negative for their prescribed opiate.

One of the most common ways to monitor illicit drug use and adherence to a controlled substance agreement is by conducting regular, random urine drug tests (UDT), which include both urine drug screens and confirmatory drug tests. The immunoassay (IA) drug test, or urine drug screen, is the first test conducted on urine specimens because it is fast, results instantly or within 1 to 2 business days, ⁴ and cost-effective, $250 according to billing and coding guidelines for L35724—Lab: Controlled Substances Monitoring and Drugs of Abuse. ⁵ The immunoassay test uses antibodies to detect the presence of a drug and drug metabolites at predetermined thresholds. ⁶ The most common drug classes that are tested for are amphetamine, cannabinoid, opiates, benzodiazepines, cocaine, buprenorphine, oxycodone, and methadone. Urine drug screen results are considered presumptive due to their reputation of being easily manipulated, either unintentionally or intentionally, so a confirmatory drug test should always follow a drug screen.

Interferences with urine drug screen tests can lead to false negative or false positive results. False negative results arise due to the immunoassay test’s detection limit, dilution, adulteration, or substitution of the urine sample. Most toxicology laboratories can detect dilution, adulteration, or substitution with specimen validity testing including pH, specific gravity, and creatinine. Whether intentional or not, if the drug concentration is too low for the immunoassay test to detect then it will appear as negative and may not be flagged for further confirmation testing. False positive results are quite common with urine drug screens because drugs with similar chemical structures to those being targeted with immunoassay can cause cross-reactivity. Prescribed and over-the-counter drugs that may cause a false positive amphetamine result include bupropion, ⁷ dimethylamylamine (DMAA), ⁸ fenofibrate, ⁹ labetalol, ¹⁰ metabolites of chlorpromazine and brompheniramine, ¹¹ phenylephrine, ¹² promethazine metabolite(s), ¹³ pseudoephedrine, ¹⁴ and the trazadone metabolite, meta-chlorophenylpiperazine (m-CPP). ¹⁵ The immunoassay drug test is prone to misleading results and should be followed up by a confirmatory drug test.

Confirmation testing is conducted through gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS). These tests are used to confirm the use, misuse, or nonuse of prescribed, non-prescribed, or illicit substances. It can identify specific drugs, their metabolites, and their concentrations with high sensitivity and specificity which cannot be done by immunoassay testing. Secondly, confirmation drug tests have a much lower limit of detection for specific drugs in comparison to immunoassay testing. Finally, confirmation tests are not subject to false positive results caused by cross reactivity of other structurally similar drugs. The disadvantages of confirmation drug testing are that it is far more expensive, ranging from $235.50 to $507.74, ⁵ and has a longer turnaround time, 2 to 3 business days for negative results and 4 to 6 business days for non-negative and positive results, ⁴ than immunoassay drug testing. Also, it cannot differentiate between chiral isomers. An isomer is a pair of molecules that share the same atomic makeup but have different spatial arrangements. Chirality refers to isomers that are non-superimposable mirror images of one another. The chiral confirmations, d-methamphetamine, and l-methamphetamine are metabolites of prescription and over-the-counter medications including selegiline, ¹⁶ Desoxyn, ¹⁷ Vicks Vapor Inhaler containing l-methamphetamine,^18,19 and benzphetamine ²⁰ (Table 1). Vicks Vapor Inhaler contains l-methamphetamine, selegiline is metabolized into l-methamphetamine while Desoxyn and Didrex contain or are metabolized into d-methamphetamine, respectively. The metabolite of the illicit form of methamphetamine is d-methamphetamine. Due to a multitude of reasons a patient can be positive for methamphetamine on a confirmatory test, further clinical action and chirality testing are needed.

Table 1.

Prescription and Over-the-Counter Methamphetamine Derivative Medications.

Brand name/generic name	Summary	Metabolites	DEA classification	d/l-methamphetamine
Ensam, Zelapar/selegiline	Monoamine oxidase type B inhibitor.	Desmethylselegiline and l-methamphetamine.	Not a scheduled medication.	l-methamphetamine.
Desoxyn/metamfetamine	Sympathomimetic agent.	Norephedrine, 4-hydroxyamphetamine, 4-hydroxymethamphetamine, 4-hydroxynorephedrine, d-methamphetamine.	Schedule II.	d-methamphetamine.
Vicks Vapor Inhaler containing l-methamphetamine/levmetamfetamine	Sympathomimetic vasoconstrictor.	l-methamphetamine.	Over the counter medication.	l-methamphetamine.
Didrex/benzphetamine	Sympathomimetic agent.	Amphetamine, d-methamphetamine.	Schedule III.	d-methamphetamine.

This retrospective study’s primary objective was to demonstrate the importance of certain testing when monitoring for illicit substance use and suggest an appropriate clinical course of action when interpreting methamphetamine urine drug tests. There are many explanations for a positive methamphetamine urine sample and this algorithm is a tool to empower opioid pain medication prescribers with the information needed to make accurate clinical decisions. Specifically, aim 1 was to examine the effectiveness of the amphetamine immunoassay urine drug screen in identifying methamphetamine in urine specimens. Immunoassay drug screens are cost-effective and fast but are prone to false negative and positive results. The use of prescription and over-the-counter drugs that are chemically and structurally like amphetamine/methamphetamine and the amount of amphetamine/methamphetamine that is present can lead to misleading immunoassay results. This study demonstrates that the immunoassay drug screen is not sensitive enough to accurately identify illicit methamphetamine users. Aim 2 was to highlight the interpretation and aid decision making of positive methamphetamine LC-MS/MS and GC-MS results. Many opioid pain medicine prescribers make easily avoidable mistakes when interpreting these results due to incomplete understanding of possible false positive results from metabolites or over-the-counter medications. Since the likelihood of patient admittance to illicit methamphetamine use is low, and there are other medications that can cause positive methamphetamine results on LC-MS/MS and GC-MS testing, it is important to understand the relevant pharmacology described in this paper to analyze the clinical situation and appropriately and accurately identify illicit methamphetamine use among patients managed with chronic opioid therapy. LC-MS/MS or GC-MS is the only way to specifically detect methamphetamine while chiral testing combined with prescription drug monitoring reports can confirm the use of illicit methamphetamine versus prescribed/over-the-counter alternatives.

Methods

A cross sectional study was conducted using electronic medical records. Patients of an urban pain specialty clinic had previously consented to clinical monitoring with random urine drug tests per a controlled substance agreement. The results of urine drug screens and LC-MS/MS confirmation tests of chronic pain patients were stored within electronic medical records. The urinalysis tests conducted from October 18, 2021, to October 21, 2022, were de-identified and their results were evaluated.

Inclusion and Exclusion Criteria

There were no exclusionary criteria. All urine drug tests within the specified time were evaluated.

Urine Sample Collection and Handling

Patients acknowledged and signed a sticker with their last name, first name, date of service, and date of birth which was attached to the urine cup. The patients were instructed to submit their urine sample to qualified medical personnel within 5 minutes. Once obtained, medical personnel ensured the sample was properly labeled and ordered. Medical personnel attached a lab requisition form to the appropriate urine sample and brought the samples to the lab. The lab technologist reviewed the requisition form and barcode order to ensure the identifying information matches and is identical to the urine sample then the sample is aliquoted and analyzed.

Clinical Laboratory Assessment

All urine samples underwent specimen validity tests, immunoassay urine tests, and LC-MS/MS confirmation tests for all available drugs and their metabolites (Table 2).

Table 2.

Every Urine Sample Is Tested for Specimen Validity, All 8 Drug Classes, and All 48 Drugs and Their Metabolites.

Test type	Testing metrics
Immunoassay urine drug test	Amphetamine (AMP), buprenorphine (BUP), benzodiazepine (BZO), methadone (MTD), opiates (OPI), oxycodone (OXY), cocaine (COC), and cannabinoid (THC).
Specimen validity test	pH and urine creatinine (UCRE) levels.
LC-MS/MS confirmation test	Amphetamine, methamphetamine, phenylcyclohexyl piperidine (PCP), benzoylecgonine, acetylmorphine, codeine, morphine, hydrocodone, hydromorphone, norhydrocodone, oxycodone, oxymorphone, noroxycodone, fentanyl, norfentanyl, meperidine, normeperidine, mitragynine, buprenorphine, norbuprenorphine, alprazolam, alpha hydroxyalprazolam, 7-aminoclonazepam, diazepam, oxazepam, temazepam, lorazepam, 3,4-methylenedioxy-methamphetamine (MDMA), methylone, methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), methylphenidate, carisoprodol, meprobamate, baclofen, cyclobenzaprine, phentermine, gabapentin, pregabalin, tapentadol, tramadol, O-desmethyltramadol, zolpidem, amobarbital, phenobarbital, tetrahydrocannabinol carboxylic acid (THC-COOH), ethyl sulfate (EtS), and ethyl glucuronide (EtG).

Immunoassay AMP test results were recorded as either positive or negative and the cutoff level of detection for amphetamine immunoassay testing is 500 ng/ml. The cutoff level of detection for LC-MS/MS of amphetamine and methamphetamine are 100 ng/ml. Urine samples at or above that cutoff were reported as positive for amphetamine or methamphetamine.

Methamphetamine Chirality Testing

If methamphetamine was detected at or above 50 ng/ml but below 100 ng/ml, the provider was notified of this finding and the sample was sent for further confirmation via chirality testing at an outside laboratory. The cutoff level of detection for chiral d/l methamphetamine confirmation testing is 50 ng/ml. The test results were reported as a percentage of d-methamphetamine, with a result greater than 20% d-methamphetamine consistent with Didrex, Desoxyn, or illicit methamphetamine usage. ²¹ Urine samples that were positive for methamphetamine and had previous chirality testing done did not have chirality testing performed again if a subsequent urine sample from the same patient confirmed positive for methamphetamine.

Patient Questioning

Patient responses to illicit drug use questioning by their provider were documented on the day of collection of the urine sample and subsequently analyzed if that sample was positive for methamphetamine upon LC-MS/MS and/or chirality testing.

Sensitivity and Specificity

Sensitivity and specificity were calculated using MedCalc Software Ltd. Diagnostic test evaluation calculator, version 20.116. ²² Table 3 contains definitions of the parameters used to calculate the sensitivity and specificity for amphetamine and methamphetamine.

Table 3.

The AMP Immunoassay Test Is Not Specific for Amphetamine and Methamphetamine So the LC-MS/MS Is Used to Determine Diagnostic Accuracy.

	Amphetamine	Methamphetamine
True positive	Positive AMP immunoassay test and positive amphetamine with LC-MS/MS test.	Positive AMP immunoassay test and positive methamphetamine with LC-MS/MS test.
False positive	Positive AMP immunoassay test and negative amphetamine with LC-MS/MS test	Positive AMP immunoassay test and negative methamphetamine with LC-MS/MS test
True negative	Negative AMP immunoassay test and negative amphetamine with LC-MS/MS test.	Negative AMP immunoassay test and negative methamphetamine with LC-MS/MS test.
False negative	Negative AMP immunoassay test and positive amphetamine with LC-MS/MS test.	Negative AMP immunoassay test and positive methamphetamine with LC-MS/MS test.

All procedures were reviewed and considered exempt research by the Washington State University Institutional Review Board. The certification number is 19237-001 and the review category is exempt—45 CFR 46.104 (d)(4).

Results

6558 urine samples of chronic pain patients at an urban pain specialty clinic from October 18, 2021, to October 21, 2022, were examined. 281 (8.68%) samples were confirmed positive for amphetamine with or without methamphetamine and 71 (1.1%) samples were positive for methamphetamine with or without amphetamine. 48 out of the 71 samples that confirmed positive for methamphetamine were sent to an outside lab for chirality testing. Among the samples tested for d- or l-methamphetamine, 3/48 (6.2%) did not confirm greater than 20% d-methamphetamine while 45/48 (93.8%) confirmed greater than 20% d-methamphetamine. Of the 3 urine samples not confirmed to be greater than 20% d-methamphetamine, one patient had documented use of selegiline while the other 2 patients reported use of Vicks Vapor Inhaler several days before the urine sample was collected. The 45 urine samples that were greater than 20% d-methamphetamine had no documented prescription of Desoxyn or Didrex. A small proportion of patients, with urine samples that confirmed positive for d-methamphetamine, reported use of illicit drugs, 5/45 or 11.1%, at the appointment the urine sample was collected. 40 of the 45 (88.9%) denied the use of illicit drugs within the last 2 weeks and/or reported that they did not have a history of illegal drug misuse at the appointment the urine sample was collected.

569 urine samples screened positive for AMP with the amphetamine immunoassay test from the defined period. 310 of the 569 urine samples (54%) were false positive for amphetamine by immunoassay AMP test due to the lack of confirmation of amphetamine with LC-MS/MS testing (Figure 1). 259 of the 569 urine samples (46%) were true positive immunoassay AMP tests with confirmation of amphetamine upon LC-MS/MS testing. Of the 71 patients confirmed positive for methamphetamine with LC-MS/MS or chirality testing, the AMP immunoassay test identified 37/71 (52%) of the samples (Figure 1). 34/71 (48%) of the methamphetamine urine samples were false negative AMP with immunoassay testing.

Figure 1.

Immunoassay and LC-MS/MS testing results for amphetamine and methamphetamine.

Sensitivity and specificity calculations were done to assess the diagnostic accuracy of the amphetamine immunoassay urine drug screen for detecting amphetamine and methamphetamine. The sensitivity for amphetamine and methamphetamine was 92.17% (88.39%-95.03%) and 52.11% (39.92%-64.12%), respectively (Table 4). The specificity for amphetamine and methamphetamine was 95.06% (94.50%-95.58%) and 91.80% (91.10%-92.46%), respectively.

Table 4.

Summary of Sensitivity and Specificity Calculations for Amphetamine and Methamphetamines.

	True positive	False positive	True negative	False negative	Sensitivity (%)	Specificity (%)
Amphetamines	259	310	5967	22	92.17	95.06
Methamphetamines	37	532	5955	34	52.11	91.80

Discussion

When looking at the entire population of 6558 urine samples, only 8.68% of those screened positive for AMP and even less, 4.28%, were positive for amphetamine with or without methamphetamine with LC-MS/MS testing. 22 out of 281 LC-MS/MS confirmed samples were false negative with the immunoassay AMP test. The immunoassay AMP test is sensitive (92.17%) and specific (95.06%) for amphetamine, but this does not factor in the likelihood of false positive results. Out of the 569 samples that screened positive for AMP, the amphetamine immunoassay urine drug screen test accurately identified amphetamine with or without methamphetamine in less than half of those samples, proven by LC-MS/MS testing. More than half of those samples were false positive. A similar study looking at the frequency of false positive amphetamine screens found that among 362 urine samples that screened positive for amphetamine, 35% or 128 urine samples were false positive results. ¹⁰ The proportion of false positives by the immunoassay AMP test shows the importance of LC-MS/MS confirmation testing. The confirmation test can definitively rule out false positives and allow providers to make appropriate decisions when prescribing opioids.

The positive LC-MS/MS methamphetamines with or without amphetamine were 1.1% of the entire population of urine samples but the sensitivity of the immunoassay AMP test was low. The sensitivity was 52.11% in this study, meaning there is only a 52.11% probability that the immunoassay AMP test would detect methamphetamine when it is present in the urine. A study that evaluated the accuracy of immunoassay tests reported similar sensitivity (40.0%) and specificity (98.8%) for methamphetamine detection. ²³ Without subsequent LC-MS/MS confirmation testing, about half of the urine samples with methamphetamine would have been missed. The clinical advantages of the AMP immunoassay test are limited to being fast and cost effective while the disadvantages are numerous. The immunoassay AMP test has a cutoff level of detection that is 5× higher than LC-MS/MS which can lead to false negative results. Also, the test is subject to cross-reactivity thus false positives. The results of the immunoassay test should only be seen through a presumptive lens and LC-MS/MS or GC-MS testing should follow immunoassay testing regardless of the results. Due to the high number of false positives for amphetamine with or without methamphetamine and false negatives for methamphetamine with or without amphetamine, LC-MS/MS testing is necessary to make appropriate clinical decisions regarding prescription opioid medications. The results suggest that the immunoassay AMP test is not sensitive enough to monitor methamphetamine use among chronic pain patients.

LC-MS/MS or GC-MS confirmation testing can detect methamphetamine in a urine sample with high sensitivity and specificity but cannot determine the ratio of chiral forms, d- and l-methamphetamine. There are multiple explanations for methamphetamine in a urine sample that do not involve illicit drug use and chiral testing is a tool that can be used to confirm illicit methamphetamine use versus over the counter or prescription drugs containing methamphetamine. Out of the 48 urine samples sent for chirality testing, 3 did not confirm <20% d-methamphetamine indicating that l-methamphetamine was the main source of methamphetamine in the urine sample. 45 of the urine samples confirmed >20% d-methamphetamine and there was no documentation or evidence of prescription d-methamphetamine, suggesting that the main source of methamphetamine in the urine sample is from the illicit drug. Only 5 of those samples admitted to illicit drug use before the urine sample was collected indicating that the likelihood of patient self-admittance to illicit drug use among chronic pain patients receiving opioid medications is low. It is important to conduct multiple tests and use various clinical tools to monitor adherence to a pain agreement and illicit drug use. Alone, conducting patient interviews is not an effective tool to monitor illicit drug use due to a lower likelihood of self-admittance. The prescription monitoring program (PMP) could explain the source of methamphetamine with evidence of prescriptions such as Desoxyn or Didrex but if it does not indicate the use of these medications then chiral testing should be performed. A chiral confirmation test is a necessary and accurate clinical tool when the patient denies the use of illicit methamphetamine and there is no indication of Desoxyn or Didrex prescriptions.

This study demonstrates the low sensitivity of the amphetamine immunoassay urine drug screen and frequent false positive and negative results, which highlights the importance of LC-MS/MS and chirality testing for monitoring chronic opioid therapy patients (Figure 2). This is especially applicable to providers who prescribe opioids working in populations with higher methamphetamine use. A recent Canadian population study found that within a group of 7460 people, those who used both opioids and stimulants risk of fatal overdose was twice more likely than those using opioids only. ²⁴ According to the U.S. Department of Health and Human Services, since 1999 to 2021, there has been a 59-fold increase of overdose deaths due to psychostimulants, primarily methamphetamine. ²⁵ As methamphetamine use in the United States and Canada increases, the need for safer opioid prescribing practices becomes more evident. It is important that opioid pain medicine prescribers can not only have continued access to tools such as LC-MS/MS and chiral testing but also be able to confidently interpret those results. Although immunoassay urine drug screens are cost-effective and thus more attractive to insurance companies endorsing cost conservation, the research supports that they are inadequate at monitoring patient adherence.

Figure 2.

Suggested prescriber action based on testing results, prescription monitoring program results, medication lists, and subjective patient reports.

*If initial chiral testing is consistent, repeated chiral testing on subsequent positive methamphetamine is unnecessary within 12 months.