CAN MY DRUG SCREEN BE WRONG?

CAN MY DRUG SCREEN BE WRONG? Drug screens performed for compliance monitoring or as an initial step before prescribing opioids can have several sources of errors. One of the most frequent sources of error is physician lack of knowledge about false positives and false negatives for the specific drug screen they use. Some manufacturers will include these in documentation about the drug screens while others omit this information, but in either case the physician usually has not studied the data provided to determine the accuracy of the drug screen. As federal guidelines continue to target physicians who prescribe high dose opioids and states are targeting physicians prescribing opioids to a large number of patients, doctors that may have never tested patients with drug screens or confirmatory tests are now doing so. Many do not have the experience necessary to interpret the results properly. Drug screens, if the results are aberrant, should always be checked with a LC/MS or GC/MS method that is called a confirmation test. The confirmation tests are virtually 100% accurate in the drugs and metabolites in the body, but the physician may not be aware certain drugs may be metabolized into other drugs that would trigger both a urine drug screen as being positive and the confirmation test as being positive. TYPES OF SCREENING TESTS USED: 1. Urine immunoassay enzyme based testing. The cloned enzyme donor immunoassay, enzyme-multiplied immunoassay technique (EMIT), fluorescence polarization immunoassay (FPIA), immunoturbidimetric assay, and radioimmunoassay (RIA) are different methods to detect drugs in urine. However, the simple dipstick method uses one of the first two techniques. Some doctors have more advanced techniques (FPIA or immuno-turbidimetric) machines and charge significant amounts for these tests. They are more accurate than the dipstick methods, but are much less accurate than the confirmatory testing LC/MS or GC/MS. The immunoassay tests cannot be used as definitive proof of

substance abuse by the patient: if the patient states the test results are incorrect, then the sample must be sent for confirmation. However, if the patient confesses to have used some substance that would create a positive in the test for drugs not prescribed or in cases where an expected drug does not show up and the patient states they have not taken the medication in x number of days, then it may not be necessary for a confirmation test. 2. LC/MS or GC/MS. These confirmatory tests are performed outside of the office in a reference lab. Their findings are essentially 100% correct with no false positives or false negatives on testing. However, there may be unrecognized metabolites that would be expected to show a positive for a specific drug if the physician knew these drugs were being taken or knew enough about metabolism to make this connection. Frequently physicians lack this knowledge, causing them to erroneously accuse patients of engaging in substance abuse. LC stands for liquid chromatography. This technique uses a liquid flowing through a column of absorbent to separate out the different components of the urine, saliva, or blood. The sample then passes through a MS or mass spectrometer, that identifies each drug by hitting the drug

with a beam of electrons, causing the drug to both fragment and become positively charged. The drug passes through a vacuum with magnets in a quadripole configuration, causing the positively charged drug to bend in its course. As it strikes the collector at a certain point, the pattern of the positively charged parent and fragments are collected and displayed with a computer model used to identify the drug from its relative mass to charge ratios. The GC stands for gas chromatography- instead of the urine sample being dissolved in a liquid, intsead it is injected into a gas passing through a column under low pressure to separate out the components, then pass through the mass spectrometer. There are extremely few false positives or negatives, and unlike immunoassay that a low sensitivity, the LC/MS or GC/MS has a very high sensitivity and is very accurate. The sample may consist of urine, saliva, blood, or hair, each with its own longevity of detection of drugs. For instance, a urine drug sample collected first thing in the morning concentrates the drugs and makes them easier to detect. For instance, an opioid in the blood may be undetectable in 6 hours whereas in saliva it is 21 hours, urine 4 days, and hair 1 year. Marijuana is undetectable in 6 hours after use in blood, 12 hours in saliva, 30 days (usually) in urine, and a year in hair. But the appearance of the drugs also vary depending on the specimen. For instance, opioids appear within 10 minutes in the blood, 1 hour in saliva, 2-5 hours in urine, and 5-7 days in hair. Length of Time Drugs of Abuse Can Be Detected in Urine: Alcohol 7-12 h, Amphetamine 48 h, Methamphetamine 48 h, Barbiturate Short-acting (eg, pentobarbital) 24 h, Long-acting (eg, phenobarbital) 3 wk, Benzodiazepine Short-acting (eg, lorazepam) 3 d, Long-acting (eg, diazepam) 30 d, Cocaine metabolites 2-4 d, Marijuana Single use 3 d, Moderate use (4 times/wk) 5-7 d, Daily use 10-15 d Long-term heavy smoker >30 d, Codeine 48 h, Heroin (morphine) 48 h, Hydromorphone 2-4 d, Methadone 3 d, Morphine 48-72 h, Oxycodone 2-4 d, Phencyclidine 8 d

Immunoassay techniques are most accurate for urine since the specimen is concentrated. For blood and saliva, usually GC/MS or LC/MS are used but occasionally immunoassays are performed as a screening test for saliva. Each immunoassay test technique has a cutoff value that is set high enough to avoid most false positives. For instance poppy seeds are known to contain small amounts of morphine. Therefore the DHHS (Department of Health and Human Services) has set the cutoff values for work related testing very high. Opioids are set at 2000ng/ml to be positive. This means the test is relatively insensitive for opioids, opioid pain killers, heroin, etc. that may show up as negative even if you are taking the medication several times a day. These is the same for the Department of Transportation in order to maintain or obtain the CDLs for driving. Immuno-testing cups in doctors offices may use more specific testing for different drugs. For instance, doctors frequently test for oxycodone and methadone and sometimes buprenorphine instead of simply testing for Opioids. These three medications are usually not picked up on federal testing cups and are rarely positive. The testing cups are with built in or separate testing (dip stick) strips, the number of strips chosen by the practice. Each strip usually shows one drug.

FALSE POSITIVE TESTING IMMUNOASSAY TECHNQUES While this varies from one manufacturer to another and the percentage of false positives vary, the following may trigger false positive urine drug screens: Cannabinoids (Marijuana): dronabinol (Marinol), efavirenz (Sustiva), ketoprofen (NSAID), naproxen (Aleve), pantoprazole (Protonix), ibuprofen (Advil), promethazine (Phenergan), riboflavin, tolmetin (NSAID), Niflumic acid (NSAID), some bath soaps Opioids: diphenhydramine (Benadryl), poppy seeds (Poppy seed dressing, hamburger buns), chlorpromazine (Thorazine), rifampin, dextromethorphan (found in several cough syrups), quinine (tonic water, antimalarial drug), ofloxacin (Floxin), papaverine (Pavabid) Amphetamines: DMAA (energy supplement), benzphetamine (Didrex), chlorpromazine (Thorazine), clobenzorex (Asenlix, Greenies ), isometheptene (Amidrine), isoxsuprine (Vasodilan), phentermine (Adipex), phenylpropanolamine (Dexatrim), promethazine (Phenergan), ritodrine (Yutopar), thioridazine (Mellaril), trazodone (Desyrel), trimethobenzamide (Tigan), trimipramine (Surmontil), ephedrine, methylphenidate (Ritalin, Concerta), pseudoephedrine (Sudafed), desipramine (Norpramin), bupropion (Welbutrin), fenfluramine (Pondimin), propranolol (Inderal), labetalol (Normodyne), mexiletine (Mexitil), selegiline (Eldepryl), tyramine amantadine (Symmetrel), ranitidine (Zantac), phenylephrine (Sudafed PE), vapor sprays (Vick s) PCP: doxylamine (Unisom), ibuprofen, (Advil, Motrin), imipramine (Tofranil), ketamine (Ketolar), meperidine (Demerol), mesoridazine (Serentil), tramadol (Ultram), chlorpromazine (Thorazine), thioridazine (Mellaril), dextromethorphan (cough syrup), diphenhydramine (Benadryl), venlafaxine (Effexor), synthetic cathinones (Bath Salts) Benzodiazepines: flunitrazepam (Rohypnol),oxaprozin (Daypro), sertraline (Zoloft), some herbal agents including valerian, EFV (efavirenz) Ethanol: asthma inhalers, diabetics with lactic acidosis or with elevated blood sugars and the sample is not analyzed within 12 hours Tricyclic Antidepressants: quetiapine (Seroquel), cyclobenzaprine (Flexeril), carbamazepine (Tegretol) Buprenorphine: heroin, morphine, methadone, dihydrocodeine Methadone: quetiapine (Seroquel) LSD: sertraline (Zoloft), ambroxol, Amitriptyline, benzphetamine, bupropion, buspirone, cephradine, chlorpromazine, desipramine, diltiazem, doxepin, fentanyl, fluoxetine, haloperidol, imipramine, labetalol, metoclopramide, prochlorperazine, risperidone, sertraline, thioridazine, trazodone and verapamil, Ergonovine, lysergol, brompheniramine maleate, imipramine HCl and methylphenidate HCl

FALSE POSITIVES GC/MS or LC/MS Technically there are no false positives for these tests since they measure the actual molecule in the body, unless there is some gross error in laboratory equipment or calibration. Most drugs are metabolized to other drugs in the body that may then be detected on GC/MS or LC/MS. The metabolites are important clues as to the presence or absence of a drug in the body. For instance, if a person tries to adulterate the urine with a small amount of the drug that is to be taken (the patient forgot for the past 4 days to take the medication), then there will be no metabolite but only the parent drug. Benzodiazepines: Diazepam (Valium) is metabolized in the body to both temazepam (Restoril) and oxazepam (Serax). A patient being prescribed Valium will therefore show up with all three drugs in their system. This is not a false positive, but is a metabolic process that is normal. Many physicians are unaware of these pathways. Chlordiazepoxide (Librium) is metabolized into nordiazepam (a metabolite of Valium) and oxazepam (Serax). Temazepam (Restoril) is metabolized into oxazepam (Serax) Hydromorphone: Hydromorphone (Dilaudid) is metabolized into morphine in 2/3 of patients. Morphine is found in a ratio of no more than 2% of the concentration of hydromorphone. Codeine: Codeine is metabolized into morphine and a small amount of hydrocodone. Morphine and its metabolites are expected normal for those taking codeine as well as a small amount of hydrocodone. Hydrocodone: Hydrocodone is metabolized into hydromorphone via the CYP2D6 liver metabolic pathway. In urine drug testing, the concentration of hydromorphone may be greater than that of hydromorphone. Oxycodone: Oxycodone is metabolized in part to oxymorphone via the CYP2D6 liver pathway. Heroin: Heroin is very rapidly metabolized into morphine. Heroin itself is rarely seen in urine drug testing due to this rapid metabolism. Amphetamine/Methamphetamine: This drug may show up on confirmation testing even if the person is not taking methamphetamine or any amphetamine containing drug. A sophisticated urine drug testing unit can ferret out the probability of the person consuming an illegal drug, but not entirely. Street methamphetamine (crystal meth) is a mixture of the d and l isomer of methamphetamine but has more than 20% as the d-isomer

Desoxyn is the prescription form of pure d-methamphetamine Benzphetamine (Didrex) is a Schedule III drug used to treat obesity and has d-methamphetamine as a primary metabolite. Vicks vapor rub is metabolized primarily into the l-isomer of methamphetamine Selegiline (Eldepryl) is a Parkinson s disease treatment that is metabolized into the l-isomer of methamphetamine. Amphetamines are a metabolite of methamphetamine but is also a prescription drug (Adderall). THEREFORE: A person with methamphetamine in the UDS is using crystal meth, Didrex (prescription), Desoxyn (prescription), Selegiline (prescription) or Vicks vapor rub (over the counter). Further testing for the d-isomer would be positive for crystal meth, Didrex, Desoxyn, or Selegiline. Testing of the d:l ratio would show 100% for Desoxyn and less than this (but more than 20%) for methamphetaime, Didrex, or Selegiline. A patient having <20% d isomer is presumed positive for Vicks vapor rub. The patient would have a prescription for Didrex, Desoxyn, or Selegiline. FALSELY ELEVATED OR FALSELY LOW LEVELS OF DRUG Some confirmation reference labs will try to calculate how much drug a person should have in their system based on the specific gravity (concentration) of the urine. These have not been confirmed in chronic pain patients taking opioids and there are many things that can affect this value. Some doctors will accuse their patients not taking the medication as prescribed due to a value that is either too high or too low compared with the calculated values. However these calculated values do not take into account the known liver enzyme inducers and inhibitors that are known to elevate or suppress the level of the drug in the body. For instance drugs that are metabolized by the CYP2D6 pathway (codeine, hydrocodone, hydromorphone) may have elevated values if the patient is also taking chlorpheniramine (found in cough and cold medicines and allergy medicines), cimetidine (Tagamet), ranitidine (Zantac), celexicob (Celebrex), amiodarone, chlorpromazine, haloperidol, duloxetine, citalopram, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, bupropion, moclobemide, doxorubicin, ritonavir, terbinafine. Additionally, 1-7% of Caucasians

lack the gene to use the CYP2D6 pathway, therefore codeine and hydrocodone measured values in urine drug tests may be elevated in these patients. Ironically, those with this genetic defect derive very little benefit from codeine or hydrocodone since they function as prodrugs that are metabolized into the more active morphine and hydromorphone respectively. On the other hand, drugs metabolized by this pathway may have falsely low values if the patient is also taking the antibiotic rifampin or the steroid dexamethasone (oral or injected) Other medications such as tramadol are affected by the 3CA pathway that may be inhibited by antidepressant drugs, especially the tricyclic antidepressants (e.g. Elavil, amitriptyline, Flexeril, cyclobenzaprine, nortriptyline, trimipramine, doxepin, desipramine, amoxapine, protriptyline). The levels of tramadol may become very high when taking these medications, to the point of causing seizures. There are also other metabolic pathways for morphine, hydromorphone, and oxymorphone that can be influenced by other medications, but the influence is not as clear as it is with the previously discussed medications. OTHER WAYS THE URINE DRUG SCREENS CAN BE INCORRECT 1. Incorrect labeling. In a busy medical practice, urine drug specimens may be collected and analyzed on-site using a drug analyzer. These medical practices use the least expensive cups possible, frequently without any labeling on them, and may collect them in a box connected to the restroom. If the cup has no label on it with an identifier, your specimen may be comingled with many other specimens in the same box. This system is fraught with potential inaccuracy, and may result in a specimen that is not your urine being attributed to you. ALWAYS CHECK THE URINE CUP FOR A LABEL WITH A UNIQUE IDENTIFYING NUMBER THAT IS LINKED TO YOUR NAME. Initials written on the cup are inadequate for documentation of identity and is a failure in the chain of custody of the sample. 2. Spillage of a specimen. If your sample is partially spilled in transit to a confirmatory lab, it is possible other specimens spilled, leading to mixing of the urine specimens. Not infrequently with some companies, the top is loosened or dislodged causing spillage, or the top of the container is improperly sealed.

3. Failure to divulge all medications being taken at the time of the specimen collection. This may result in a metabolite giving a positive result, and without your accurate medication list may cause issues with your prescribing physician 4. Placing opioid tablets or capsules in a bottle with other opioids no longer taken. Mixing the medications in the same bottle may lead to one medication rubbing off on another resulting in a drug screen positive for both medications. 5. Pill counts by physician s staff or pharmacies not using a clean counting surface. A surface that is not freshly clean may result in contamination of pills being counted on that surface. This is a very low likelihood occurrence. 6. Adulterants. Some patients will try to fool the drug test by adding adulterants such as bleach, but many immunoassay strips now have adulterant detection panels that show if the patient tried adding something to the urine to fool the urine drug test. 7. Incorrect report viewed by the doctor. If the physician s staff places the wrong report on a patient s chart, it may cause confusion and chaos for the patient. Ask to see the report if it has data that you know is incorrect. 8. Failure of the confirmation lab to wait long enough before all the drug from the last test was off the high pressure chromatography column. Failure to wait long enough will result in overlap of the samples, and a false positive result. This is very rare. OTHER SOURCE FALSE POSITIVES/NEGATIVES If the specimen was blood, there is only a very short window of time to collect and analyze the specimen. If saliva, the window is much less than for urine, and there may be not enough sample in the specimen to analyze. WHAT NOT TO DO 1. Failure (refusal) to take a urine drug test will automatically place a red flag in your file, and many physicians will not give any further controlled substances after this point, ever. If you can t give a specimen immediately, stay in the office and drink nonstop until you can.

2. Do not try to fool the test by bringing in powdered urine from the internet to mix on site. There are several ways to detect this behavior. 3. Do not try to claim your UDS is positive for THC (marijuana) because you were hanging around friends in a car. This has been shown to be non-sensical, and has been tested. 4. Do not expect to be given a second chance on a failed urine drug test that was confirmed with GC/MS or LC/MS. If the results are incorrect, use this guide to figure out why, then discuss it with your physician. REFERENCES: Saitman et. al J Anal Tox Sept 2014;38(7), 387-96 Moeller Mayo Clin Proc Jan 2008: 83(1):66-76 23rd Annual Meeting of the American Academy of Pain Medicine, February 2007: Abstract 152. DeGeorge, Jr. Practical Pain Management Nov 2012 Methamphetamine Urine Toxicology Pain Physician Journal: Opioid Special Issue July 2012;15:ES119-S133