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The Toxicology Laboratory's Role in Pain Management


Author: Kevin F. Foley, PhD, DABCC, MT, SC Reviewer: Robert E. Moore, MLS(ASCP)C M, SCC M, TC(NRCC)

Course Instructions
Please proceed through the course by clicking on the blue arrows or text links. Use the table of contents to monitor your progress. Your progress will be saved automatically as you proceed through the course, and you may later continue where you left off even if you use a different computer. You may encounter practice questions within the course, which are not graded or recorded.

Course Info
This course carries the following continuing education credits:
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P.A.C.E. Contact Hours: 2.00 hour(s) Course Number: 578-018-13 Florida Board of Clinical Laboratory Science CE - General (Clinical Chemistry/UA/Toxicology): 2.00 hour(s)

Laboratory Testing Methods For Drugs of Abuse

Course Introduction
Toxicology is the study of adverse effects of chemicals on living organisms. General toxicology is typically associated with environmental toxins and poisons such as ethylene glycol, heavy metals, pesticides, and carbon monoxide. However, drugs of abuse (DOA) are usually considered part of the clinical toxicology laboratory's test menu as they are chemicals that have adverse effects on humans. This course will focus on DOA testing in the clinical laboratory and specifically in the context of pain management. DOA testing in non-medical settings, including employment testing and legal testing is not within the scope of this course.

Laboratory Testing Methods For Drugs of Abuse

Drugs of Abuse (DOA) Screening Tests


A DOA screen provides simple positive or negative results; it is qualitative, not quantitative testing. DOA testing usually starts with a screen and moves toward confirmation of specific drugs, only if the screen is positive. Drug screening:
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Is fast Is qualitative, not quantitative Is generally performed on urine Can be done as a point-of-care (POC) test Often requires confirmatory testing for positive samples

A variety of devices are currently available from several manufacturers for rapid urine DOA screening. Several examples are shown in the image on the right. Most laboratories will screen for at least the following DOA:
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Cocaine THC (Marijuana) Barbiturates Benzodiazepines Amphetamine and methamphetamine Opiates Oxycodone/oxymorphone Methadone

Some labs may also screen for tricyclic antidepressants, PCP, and propoxyphene.

Laboratory Testing Methods For Drugs of Abuse

Drugs of Abuse (DOA) Screening Tests, continued


A DOA screen can be done quickly using an immunoassay method. Immunoassays use antibodies directed against specific

prototype chemical structures associated with specific drugs. They are ideal for screening since they can often pick up several different drugs within the same class. For example, an immunoassay screen for benzodiazepines will likely pick up diazepam, oxazepam, lorazapem, etc. All of these are benzodiazepines and so it is expected that the immunoassay will be positive in the presence of any of them. In general, screening tests like DOA immunoassays have adequate sensitivity but are not usually highly specific for a given drug. The low specificity of DOA immunoassays, which is helpful for detecting the presence of any drug within the same class, is not helpful when the screen is being used to detect drugs used for pain management. An immunoassay can tell you that an opiate is present but it cannot tell you which opiate is present. In pain management, it is not enough to know simply that a class of drugs was detected. Rather, we need to know specifically which pain drugs are present (ie, is it morphine, hydrocodone, etc.?)

Laboratory Testing Methods For Drugs of Abuse

Cutoff Concentrations for DOA Screening Tests


Drug screens use cutoff concentrations to distinguish between negative and positive samples. For a qualitative test like a urine drug screen it is important to consider that some arbitrary threshold has to be met for the assay to be positive. The cutoff points for drugs of abuse on screening panels are usually determined by the immunoassay manufacturer. However, they can be adjusted by the laboratory, if the laboratory prefers a higher or lower cutoff. Clinicians may over-interpret cutoffs and should be reminded that a negative result on a screening test does not necessarily mean that the drug is not present in the sample, only that it is less than the cutoff concentration established by the manufacturer or laboratory for that drug. For example, if a sample screens negative for oxycodone, there may be oxycodone present in the sample, but the concentration could be less than the laboratory's cutoff, eg, 100 ng/mL. Cutoff concentrations should be posted with all laboratory screening results. Below are some typical cutoff concentrations for DOA screens:

Drug Amphetamine Barbiturates THC Cocaine/BE Oxycodone/Oxymorphone Opiates Methadone Benzodiazepines

Typical Cutoff Concentration 500 ng/mL 200 ng/mL 50 ng/mL 300 ng/mL 100 ng/mL 300 ng/mL 300 ng/mL 200 ng/mL

Laboratory Testing Methods For Drugs of Abuse

Confirmation of Positives
A confirmatory test is often ordered or reflexed when a positive drug screen is encountered, but not all positive DOA screens need to be confirmed. For example, if a patient admits to using THC and the urine THC test is positive, the clinician can stop there; there is no need to spend time and money confirming something that is not deemed suspicious. However, when a screen gives an unexpected result or when we need to know which particular drugs are present, as in the case of pain

management, confirmatory testing is necessary. Confirmatory testing is always performed using gas chromatography and mass spectrometry (GC/MS) or liquid chromatography with tandem mass spectrometry (LC-MS/MS). Unlike immunoassays, a GC-MS or LC-MS/MS instrument looks for specific chemical compounds. Mass spectrometry techniques can produce quantitative results, although not all laboratories report quantitative results. In most cases, the clinician is only looking for the identity of the drug and not the quantity.

Laboratory Testing Methods For Drugs of Abuse

Mass Spectrometry (MS)


A thorough description of MS is outside the scope of this course, but a simple explanation may be useful. To analyze specimens with mass spectrometry, drugs first need to be extracted from urine samples using a series of organic solvents. The elutions are then injected into a chromatography system. Chromatography refers to a filtration type of process in which samples are passed over a stationary phase that contains some chemical substrate, which will retain molecules in the sample in varying degrees. In the case of gas chromatographymass spectrometry (GC-MS), the sample is evaporated into a gas and carried through a long thin chromatography tube known as the column. Different drugs in the sample will pass through the column at different speeds, depending on their affinity for the column (how polar or non-polar they are relative to the column's stationary phase). There are many different types of columns that can be used to separate out compounds. In liquid chromatography with tandem mass spectrometry (LC-MS/MS) methods the sample is carried by a solvent and through a column that contains a gel-like liquid, which retains molecules in the samples in various degrees. The purpose of chromatography is to get the molecules (in our case drugs) in the sample to come through the column one by one. Imagine that you are asked to name and count all the different kinds of candy present in a giant bin containing many different types and pieces of candy. It would be very hard to analyze all the different types of candy in the bin by just looking into the bin. But if we could get each piece of candy to pass by our eye one at a time, in single file, we could easily analyze and count each piece. This is the purpose of the initial chromatography step; it allows a myriad of compounds to be injected but will retain compounds in various degrees and they will (if the method is designed well), elute off the column and enter the MS instrument one by one. The drug molecules that are slowed or retained by the column will eventually continue through to the mass spectrometer. This device fragments the molecule into charged ions. The ions are then pulled through a vacuum based on their charge. Their trajectory through the vacuum can be controlled using magnetic and radio frequency adjustments that will allow only ions of a certain mass to hit the detector. The amount of ions that hit the detector is directly proportional to the amount of drug in the sample. A technologist then must interpret, or at least review, the results from the instrument. Chromatography with MS is highly specific and can tell us which drugs are present and at what concentrations. Labs can develop and validate methods that can detect a given drug or metabolite with a specificity of >99.99%. The reason for this high degree of

specificity is that a compound must have very specific qualities to be detected. If we are looking for morphine, for example, we know that our GC-MS instrument will only identify morphine if:

1. The compound has the exact retention time as morphine on our chromatography column. 2. The compound fragments into the specific ions with the exact mass/charge found for morphine. 3. The ratios of those specific ion fragments to each other must match those found with morphine.

The odds that any drug other than morphine will meet these criteria is very low. One disadvantage to MS methods is they are not highly automated.

Laboratory Testing Methods For Drugs of Abuse

False-Positive Opiate Results


Although confirmation methods should never produce false-positive results, the initial drug screens for opiates can sometimes be falsely positive. Falsepositive results for opiate after ingestion of poppy seeds can occur with urine drug screens. Poppy seeds contain the alkaloids morphine, and to a lesser extent, codeine. Ingestion of foods with poppy seeds usually causes only trace (very low) amounts of morphine in the urine (usually less than 500 ng/mL). Quantitating opiates with mass spectroscopy is often useful to help clinicians determine whether a positive opiate screen could have been due to poppy seeds (a low amount is seen) or prescription opiates (which would usually give higher concentrations). However there is no sure way to know, and no rule to apply in order to determine definitively whether a positive opiate result is due to poppy seeds or drug use. Cough suppressants containing codeine and some quilolone drugs can also cause false-positive opiate results with some brands of immunoassays. Since many drugs of the opiate class can cross-react in drug screens, confirmation that an opiate is present and identification of the opiate that is present is important, especially for pain management.

Laboratory Testing Methods For Drugs of Abuse

Laboratory Samples for DOA


One might initially think that serum would be the preferred sample for DOA testing. After all, serum is a highly-controlled, homeostatic fluid that reflects the exact metabolic state of the patient. Furthermore, it's easy to substitute or tamper with a urine sample, since individuals being tested need to collect the urine themselves. It would be much harder to tamper with a serum sample. So why don't we use serum for routine DOA testing? The reason is that urine actually gives us a better window into the patient's history. Serum will contain traces of any ingested drugs but the liver and other tissues quickly clear the blood of drugs. Although each drug has a different half-life or kinetic in the blood, most are cleared fairly rapidly, within hours. Urine, on the other hand, tends to concentrate drugs. This is due to the simple fact that urine is a small amount of volume

compared to the total fluid in the body. As drugs are cleared by the kidneys, the urine becomes more and more concentrated with the drugs that were once present in the serum. As an example, consider the opiate codeine. In the serum, an appropriate concentration of codeine would be around 13-35 ng/mL. However, due to the concentrating effect of urine, we don't even call a patient's urine positive for codeine until the concentration reaches 150 ng/mL. This is greater than 10-times more concentrated than serum! Other advantages to urine as samples for DOA testing are:

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The samples are readily preserved by freezing. Drugs are stable in urine (Generally no cells present to further metabolize the drugs). It is easier to obtain (although this also means it is easier to tamper with or adulterate).

Laboratory Testing Methods For Drugs of Abuse

Adulterants
In reference to urine testing for drugs of abuse (DOA), adulteration of a sample means the addition of some agent (salts, acids, oxidizers or even water) to one's urine sample to produce a falsely negative result. Adulteration is done to trick the clinician into thinking the patient has no drug use in the recent past. Adulterants are simple chemical solutions that change the pH of the urine, oxidize or reduce proteins, or change the ionic environment such that the detection antibodies don't effectively bind the drugs that are present or the chemicals inactivate the antibody-linked detection systems. Some adulterants that are used include:
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Klear (KNO )
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Whizzies (potassium nitrate) Urine Aid (glutaraldehyde) Synthetic urine Water dilution

Individuals have also added bleach, handsoap, vinegar, or other common household items to their sample to interfere with the screen. To combat adulteration of samples, laboratory professionals should be aware of strange-smell or strange appearance of specimens. Ideally, the sample should be assessed by the collector within four minutes so that normal color, odor, foaming, the presence of any precipitates, and the temperature can be checked. The temperature should be between 90-100 F (32-38 C). The pH should be between 4-11. There are urine dipsticks available, such as the example shown on the right, that test for the presence of adulterants. Some laboratories may choose to use these dipsticks to test pain management urine samples. The most important tests for adulteration are a simple urine creatinine and specific gravity. If the sample has a specific gravity of less than 1.005 or the urine creatinine is less than 20 mg/dL, adulteration of the sample should be suspected. Since it is so easy for a patient to simply replace or dilute a specimen with tap water or toilet water, a creatinine value <20 should be considered an invalid specimen. The sensitivity of a drug screen on a sample with a value <20 mg/dL is very low.

Laboratory Testing Methods For Drugs of Abuse

Ungraded Practice Question


Adulteration of a urine sample collected for drugs of abuse testing refers to: Please select the single best answer j Submitting another person's sample in place of your own. k l m n j Adding something to the sample to cause interference and elicit a negative result. k l m n j Concentrating one's sample to increase the chance of detecting a drug. k l m n j Combining or using older samples over time to change the perceived time that someone took a drug. k l m n

Laboratory Testing Methods For Drugs of Abuse

Ungraded Practice Question


Adulteration of a urine sample collected for drugs of abuse testing refers to: Please select the single best answer j Submitting another person's sample in place of your own. k l m n j Adding something to the sample to cause interference and elicit a negative result. k l m n j Concentrating one's sample to increase the chance of detecting a drug. k l m n j Combining or using older samples over time to change the perceived time that someone took a drug. k l m n

Feedback Adulteration of a sample for drugs of abuse testing refers to the addition of some agent (salts, acids, oxidizers or even water) to one's urine sample in order to obtain a falsely negative result. Adulteration is done to trick the clinician into thinking the patient has no drug use in the recent past.

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Pain Management Contracts


When patients see a clinician to manage their pain they are, by simple definition, pain management patients. The practice of pain management is more involved than simply prescribing analgesics. We will discuss the goals of pain management in coming sections. The concept of a "pain management contract," or an "opiate therapy plan" is important to mention. When a patient's pain is going to be managed with opiates or other prescription analgesics the patient and clinician must agree to the terms of this treatment.

Opiates are narcotics. A narcotic can refer to any drug derived from opium or opium-like compounds. These drugs have potent analgesic effects and can cause alterations in mood and behavior. Narcotics also have the potential for dependence and tolerance with repeated administrations. Since these are strong drugs, an agreement is usually signed between the clinician and patient. This agreement, or contract has these provisions:

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Patient will not seek medications from other providers Patient will only use medications that are provided to him/her Patient will not sell or give his/her medications to others

These contracts are important to establish trust and expectations between the clinician and the patient. These contracts will often also specify the requirements for routine urine drug testing.

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Opiates
Opiates define a large class of drugs with structural similarity to morphine (a major analgesic found in opium extract from the poppy flower). The term opioid is often used interchangeably with the term opiate. However, the term opiate more properly refers to the natural narcotic compounds (alkaloids) found in the resin of the opium poppy (Papaver somniferum). Use of the term "opioid" should be reserved for semi-synthetic substances that are derived from the opium poppy or made completely in the lab. Opiates/opioids include the following drugs:

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Morphine: Contin, Oramorph, Roxanol Oxycodone: Oxycontin, Percoset Hydrocodone: Codan, Hycodan, Hydromet Hydromorphone: Dilaudid Loperamide: Imodium Methadone: Dolophin

Opiates activate opiate receptors found in the central nervous system (CNS). The endogenous ligands for these receptors are endorphins and endorphin-like peptides. Interestingly, opiates do not alter the pain threshold of nerve endings nor do they affect the conductance of nerve impulses (like anesthetics do). Instead, analgesia is mediated through changes in the perception of pain at the spinal cord and higher levels in the CNS. There is no ceiling effect of analgesia for opiates. The emotional response to pain is also altered with opiate use. Opiates are often referred to as euphoric medications since they can elevate mood. They also can induce physical and emotional dependence and addiction.

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Opiates, continued
Opiates/opioids are used predominantly for pain. However opiates such as codeine can be used as antitussives (to reduce coughing). A well-known effect of opiates is that they decrease GI motility. Opiate-induced constipation is a common side effect of opiates. This side effect is exploited in the drug loperimide (sold as Imodium). Loperimide is used to treat diarrhea. However loperimide does not cross into the brain so it does not have abuse potential. Opiates are Schedule 2 drugs, meaning they require a prescription and have abuse potential. Clinical uses for opiates include:
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diarrhea migraine moderate pain myalgia severe pain antitussives

Many newer analogs of morphine have been created that have increased potency (such as sufentanil and fentanyl). Many opiates undergo metabolism to compounds that also have significant activity. For example, the drugs codeine and heroin, which have effects at opiate receptors, both get metabolized to morphine, which is also an active compound (see figure). Opiates can cause:
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miosis (pinpoint pupils) and thus blurred vision confusion constipation drowsiness euphoria hypotension nausea/vomiting physiological dependence / tolerance respiratory depression syncope

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Opiate Abuse
Although opiates are prescribed for pain they are also used illicitly. Opiates can cause euphoria. This trait means that opiates have value on the street. Prescription opiate abuse is a tremendous problem in the United States and other countries. Abuse of non-prescription opiates centers around the use of heroin. Heroin is simply morphine with two additional acetyl-groups. Heroin is a very potent opiate that is taken intravenously and causes intense euphoria and narcosis. When heroin is metabolized in the body it will

initially lose one acetyl group. The resulting compound is 6-acetyl-morphine (abbreviated 6AM). The finding of 6-AM is conclusive for heroin use. However 6-AM is rapidly cleared so it is often detected only in those who have used heroin in the last few hours. Immunoassays for codeine, morphine, and 6acetyl-morphine are commonly used in acute care settings, emergency settings, and pain management settings.

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Other Drugs of Interest


Before we delve into the issues and concerns of pain management we should mention some other drugs encountered in patients being screened for DOA. Although pain management usually involves opiates, there are a few other drugs that may be used and could be detected by the toxicology laboratory. These include; suboxone (buprenorphrine), fentanyl, tramadol and THC. Buprenorphine is a semi-synthetic opioid that is commonly used to treat opiate addiction. It is often given as a 2-drug preparation containing buprenorphine plus naloxone. This is sold under the trade name Suboxone. Buprenorphine is a mixed agonist/antagonist at the opiate receptor. Because of this, buprenorphine blocks the activity of other opiates and induces withdrawal in opiate-dependent individuals who are currently physically dependent on another opiate. Buprenorphine or Suboxone is given to patients to help wean them from their opiate dependence. In this way it is used very much like methadone. Buprenorphine is not detected by routine opiate screens. Fentanyl is a synthetic opioid, which has become popular in recent years. It is commonly prescribed as a transdermal patch. In this formulation it can provide chronic pain relief. Because it is a patch, oral ingestion is not possible (or at least not palatable), and so abuse is less likely. The important point concerning fentanyl is that it will not be detected by opiate screens since its structure is significantly different from morphine analogs. It is also present in very low concentrations. Specific assays for fentanyl are needed to detect this drug. Immunoassays for fentanyl are available. Tramadol is a very weak activator of the opioid receptor. Its main mechanism of action seems to have more to do with serotonin release and the inhibition of norepinephrine reuptake in the brain. However, metabolites of tramadol are more potent agonists of opioid receptors. Tramadol has some abuse potential but is less euphoric than opiates like morphine. Its use in pain management is increasing. THC: Marijuana is used medically by many patients since many states now have laws that permit its use in certain circumstances. The action of THC is more of a relaxant than a true analgesic. Most clinicians who are treating pain will ask their patients to not use THC if they are being prescribed an opiate; the choice is usually to use one or the other but not both. The use of THC in pain management patients is not common. However finding THC in the urine of patients undergoing pain management is common. Methadone is a synthetic opioid with a long duration of action. It is used to help wean patients from opiate dependency.

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Pain Management: The Problem


Drug abuse, and specifically prescription drug

abuse, in the United States is a huge problem. Consider the following facts taken from the US Drug Enforcement Agency's website:
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7 million Americans are abusing prescription drugs (that s more than cocaine, heroin, hallucinogens, ecstasy, and inhalants, combined). Prescription drug abuse increased 80% in the past 6 years. Opioid painkillers now cause more drug overdose deaths than cocaine and heroin combined. Hydrocodone is the most commonly diverted and abused controlled pharmaceutical in the United States The Centers for Disease Control and Prevention (CDC) estimates 20,000 people die each year from prescription drug overdose (74% from opiates) Opiate overdoses lead to 475,000 emergency department (ED) visits per year

Quest Diagnostics published a report in 2012 concerning prescription drugs found in urine. The study looked at 76,000 drug tests and found that 63% of all samples tested were not consistent with the physician s documented prescriptions. In 40% of cases, no drug was detected where one was expected.

The Use of Opiates For Pain Management and the Problem of Drug Abuse

The Problem, continued


The Quest study verified what people involved in DOA testing already knew: patients are not always compliant and drug testing is needed to help detect diversion and abuse. Diversion refers to the absence of a drug in a patient's sample because their prescribed drug was diverted to someone else (sold or given away). Diversion of a prescribed drug is just as serious as detecting an unprescribed drug. The Quest study showed that patients who were tested 30 days after an initial finding had 10% fewer unexpected findings. For pain medication, a 17% reduction was found when patients were retested. This shows that testing brought about less abuse by patients. The threat of getting caught caused at least some patients to become compliant before the next urine test. Also of note is that the study showed that there was little difference in abuse/diversion rates between genders, across ages, and even across income levels. The problem is not limited to certain demographics but is widespread.

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Dependence versus Addiction


Is everyone who needs opiates to help manage their pain addicted? Are all addicted people dependent? The difference between addiction and dependency is important to note. Dependency refers simply to the biological adaptation to a drug. Drug dependence means that a person needs a drug to function normally. Abruptly stopping the drug would lead to withdrawal symptoms in such a person. Many drugs elicit dependence, not just opiates. Anyone who takes opiates for a moderate amount of time will become dependent. The drug becomes necessary for normal

functioning. Increasing doses may also be needed due to tolerance. Tolerance occurs due to the fact that opiate receptors will down-regulate (reduce their expression) or activity in response to chronic stimulation. As a result, it will take more drug to elicit the same effect over time. Although all addicts have dependence, not all those with dependency are addicts. Addiction is a more dubious term. Addiction is the compulsive use of a substance, despite its negative or dangerous effects. Addiction is said to occur when a person continues to use a drug or even escalates the use of the drug in spite of the fact that it is causing social, physical, and economic harm to them and others.

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Ungraded Practice Question


Diversion is: Please select the single best answer j Susbstituting one analgesic for another k l m n j selling or giving one's medications to someone else k l m n j using a drug without a prescription k l m n j when a drug not prescribed is detected in the urine. k l m n

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Ungraded Practice Question


Diversion is: Please select the single best answer j Susbstituting one analgesic for another k l m n j selling or giving one's medications to someone else k l m n j using a drug without a prescription k l m n j when a drug not prescribed is detected in the urine. k l m n

Feedback Diversion occurs when a patient sells or gives their prescription drug to someone else. This is usually done for financial reasons. Narcotics used for pain management are strong analgesics and have significant street value. It is common to find patients who screen negative for a drug they were prescribed because they 'diverted' or sold the drug for cash.

The Use of Opiates For Pain Management and the Problem of Drug Abuse

The Goal of Pain Management (PM)


There are several goals in the practice of PM. Two obvious goals are:

1. Reduce or limit dependency on medications for pain control 2. Avoid addiction to pain medications

A primary tenet of PM is that a patient should not expect to be pain-free. Clinicians will ask patients what their expectations are for their pain control and will counsel them and explain that living pain-free is not a realistic goal. Few, it any, of us live pain-free. Instead, the goal of PM is to maximize a patient's quality of life; to get the patient to a place where he/she can function despite pain. Opiates are not the only tools available to the PM clinician. Counseling, group therapy, physical therapy, exercise, encouraging positive behaviors, acupuncture, and even hypnosis can be tried. The PM clinician is concerned with getting the patient to a lower pain level using the lowest possible dose of a drug, or no drug at all. PM can usually only reduce subjective pain around 30%. Thus, it's important for patients to have realistic expectations. When using drugs to lower pain the obvious goals of producing as few side effects as possible and having a daily plan to manage acute pain and flare-ups are important as well. Patients are often prescribed one opiate and are told to increase the dose temporarily, only if pain flares up.

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Testing the Pain Management (PM) Patient


The frequency of urine testing in PM depends on the agreement made between the patient and clinician (the opiate therapy plan or contract), as well as the nature of the patient. Patients who have a history of drug abuse or alcohol abuse will require more frequent monitoring than those at lower risk for addictive behaviors. Many patients will present to clinicians complaining of pain and will not be content to leave the clinician's office without a prescription for a narcotic. Patients who "doctor shop," trying to get prescriptions for pain medication, are relatively common. Some characteristics of patients who exhibit drug-seeking behavior are listed in the accompanying table. Prescribing narcotics to patients who do not have a genuine clinical need for them can cause clinicians to lose their licenses to prescribe medications or practice medicine. The stakes are high for patients and clinicians when it comes to opiate use. Thus, asking patients to undergo testing to monitor appropriate prescription drug use should not be seen as punitive but rather expected, given the high abuse rates for prescription drugs and the potential risk to the professional reputation of the ordering clinician. Clinicians will often test the urine of patients prescribed opiates every six months. In cases of patients with abuse histories or patients who have had previous abnormal urine screens, clinicians may elect to have patients tested every time they refill their prescription.

Some health care organizations also allow clinicians to order a pill count. A pill count is an order that instructs the patient to go to the pharmacy and have the pharmacist count how many opiate pills are remaining in the prescription container. The pharmacist can easily tell if the pills are indeed the prescribed medication and whether or not there are too few remaining, given the elapsed time period. Pill counts are another way to manage patients with suspicious behaviors. Ordering urine DOA screens on PM patients is very useful to verify whether the patient is compliant with the PM plan. The clinician expects to see the presence of the prescribed drug and will check to make sure that other abused drugs are not present. One problem with urine screening in PM patients is that the collections are usually not supervised. Usually, patients are asked to submit samples they collect themselves. This unsupervised collection means that patients could be submitting samples that are not theirs, samples that have been chemically altered, or samples that have been diluted. Supervised collections are more common in addiction medicine clinics and less common in the PM setting. However, the line between PM and addiction medicine can quickly blur. Urine DOA screens are only useful if the clinician and the laboratory professionals know how to interpret the findings.

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Ungraded Practice Question


Which statement below is true? Please select the single best answer j The number of deaths resulting from opiate use is slowly decreasing due to laboratory testing efforts. k l m n j It is uncommon to find more than one opiate or opioid in a patient's urine. k l m n j About 2/3 of patients who have drug screens have an unexpected result. k l m n

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Ungraded Practice Question


Which statement below is true? Please select the single best answer j The number of deaths resulting from opiate use is slowly decreasing due to laboratory testing efforts. k l m n j It is uncommon to find more than one opiate or opioid in a patient's urine. k l m n j About 2/3 of patients who have drug screens have an unexpected result. k l m n

Feedback A recent study by Quest Diagnostics showed that 63% of patients had unexpected results. The number of deaths and adverse events associated with opiates has increased rapidly over the past five years and it is very common to find more than one opiate/opioid in patient samples.

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Ungraded Practice Question


Which of the following drugs is a synthetic opioid with a very long duration of action and is used to help wean patients from opiate dependency? Please select the single best answer j Codeine k l m n j Morphine k l m n j Hydromorphone k l m n j Methadone k l m n

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Ungraded Practice Question


Which of the following drugs is a synthetic opioid with a very long duration of action and is used to help wean patients from opiate dependency? Please select the single best answer j Codeine k l m n j Morphine k l m n j Hydromorphone k l m n j Methadone k l m n

Feedback Methadone is a synthetic opioid with a long duration of action. Morphine and codeine are true opiates whereas hydromorphone is considered a semi-synthetic in that it is a metabolite of morphine but is not found in the poppy plant.

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Ungraded Practice Question


Which of the following is true? Please select the single best answer j Living pain free is the goal for pain management patients k l m n

j Pain management should occur over all the remaining years of a patient's life k l m n j Hydrocodone is the most commonly prescribed narcotic in the US. k l m n

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Ungraded Practice Question


Which of the following is true? Please select the single best answer j Living pain free is the goal for pain management patients k l m n j Pain management should occur over all the remaining years of a patient's life k l m n j Hydrocodone is the most commonly prescribed narcotic in the US. k l m n

Feedback Living pain free is not a realistic expectation. Instead, patients are given the goal of trying to reduce their pain so they can function at a maximum level. Pain management should be a finite process. Chronic pain management is common but the goal is to wean patients off of analgesics eventually. Hydrocodone is currently the most prescribed narcotic analgesic in the US.

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Ungraded Practice Question


In the practice of pain management, the absence of a compound in the urine is often just as significant as the presence of a compound. Select true or false j True k l m n j False k l m n

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Ungraded Practice Question


In the practice of pain management, the absence of a compound in the urine is often just as significant as the presence of a compound. Select true or false

j True k l m n j False k l m n

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Ungraded Practice Question


True or false: The goal of pain management is to have the patient live pain-free. Select true or false j True k l m n j False k l m n

The Use of Opiates For Pain Management and the Problem of Drug Abuse

Ungraded Practice Question


True or false: The goal of pain management is to have the patient live pain-free. Select true or false j True k l m n j False k l m n

Feedback The goal of pain management is to maximize function and get patients to be as active as they normally would be. Being pain-free is not a realistic goal.

Interpretation of Drugs of Abuse Testing in Pain Management

Pain Management Drug Screen Interpretation Competencies


To interpret urine drug screen results confidently in the context of pain management, the clinical laboratory professional should possess these competencies:

l l l l l

Be able to recognize adulterated samples Know which opiate metabolites would be expected with a given drug Know the cross-reactivities of the laboratory's immunoassay methods, or where to access this information Be familiar with prescription pain drug trade names Be able to answer some of the common questions posed to toxicology laboratory personnel

Interpretation of Drugs of Abuse Testing in Pain Management

Adulterants and Urine Samples Collected for Prescription Drug Monitoring


As discussed earlier, adulterants are chemicals that can be added to a urine sample to obscure or confound drug screens. Since most urine collections in the pain management setting are self-collected and unsupervised, it is easy for a person to adulterate his/her specimen, if that person wishes to deceive the clinician. Adulteration of a urine sample for drugs-of-abuse screening, performed for employment or legal reasons, may be done to produce a false-negative result. However, adulteration of the urine sample in the pain management setting may be done to produce a false-positive result. That is, a patient may adulterate the urine sample by adding the drug that should be there when in fact, the patient did not ingest the drug. For example, a patient who is being treated with methadone for an addiction to heroin may put methadone pill dust into his/her urine sample to trick the clinician into thinking he/she is compliant with taking the medication. In reality, the patient skipped the methadone dose in order to get a greater "high" when using heroin or other opiates. For this reason, toxicology laboratories should only report methadone as positive when they detect the parent and the metabolite (the metabolite will only be present if the drug was injected and not present if pill dust is added).

Interpretation of Drugs of Abuse Testing in Pain Management

Opiate Metabolites
In PM, a confirmation should be performed if a screening result is positive. Since confirmatory methods use mass spectrometry, specific compounds can be identified and quantitated. However, we need to be able to make sense of the specific compounds that are found. The accompanying diagram on the right and table below contain essentially all that is needed to know about opiate metabolism for routine PM testing. Posting this information in the laboratory is very useful. Laboratory testing personnel may find that they quickly memorize the parent and metabolite relationships when reviewing opiate confirmation results. The information contained in the table below may be included with opiate confirmation results to help clinicians understand the results.

Detected Drug Codeine Hydrocodone

Possible Parent Drug Codeine Hydrocodone, codeine, dihydrocodeine

Detection Window 2-3 days 2-3 days

Hydromorphone Hydromorphone, hydrocodone, morphine 2-3 days Morphine Oxycodone Oxymorphone Morphine, codeine, heroin Oxycodone Oxymorphone, oxycodone 2-3 days 2-3 days 2-3 days

Interpretation of Drugs of Abuse Testing in Pain Management

The Problem with Oxycodone and Oxymorphone (Oxys) In Immunoassay Methods


A typical drugs-of-abuse (DOA) screen contains the following tests:
l l l l l l l l

Amphetamines THC Barbiturates Benzodiazepines Methadone Cocaine Opiates Oxycodone/Oxymorphone (oxys)

Notice that methadone, opiates, and oxycodone are all individually tested. This may seem strange since these are all opioids/opiates. But the fact is, there are modifications to the chemical structures of opiates that will make them undetectable to immunoassay methods that recognize the general prototype structure of morphine. As a result, it takes three immunoassays to detect the three common opiate drugs/classes of methadone, opiates, and oxcodone/oxymorphone (oxys). In general we can think of opiates and opioid screens in this way:

Drug Screen Opiates Oxys Methadone Fentanyl

Detects Morphine, codeine, hydrocodone, hydromorphone Oxycodone, oxymorphone Methadone Fentanyl

If a clinician fails to recognize that different immunoassays are needed to screen for different opioids, confusion will result. It is not uncommon for clinicians to misinterpret screens and accuse patients of not taking their medications when in fact the patient is positive for the medication but the wrong screen was used. Clinicians may assume that any drug, which moderately resembles an opiate in its action, will be detectable using an opiate drug screen. This is not true. For example, one of the most commonly prescribed drugs in the US, oxycodone, will not typically be detected on an opiate screen but instead requires a specific "OXY screen." It may be the case that a regular opiate immunoassay screen will pick up oxycodone, yet the OXY screen will usually not detect regular opiates. For example, a patient taking morphine should be positive for opiates, but will likely be negative for oxys. Yet a patient taking oxymorphone may be positive for oxys and positive on the opiates immunoassay screen as well. Note that oxycodone and oxymorphone can produce a positive opiate screen as well as a positive OXY screen. However, codeine, morphine, hydrocodone, and hydromorphone will typically not produce a positive OXY screen on most immunoassay instruments. For these reasons it's critical that you know the performance of your laboratory's assays. The toxicology technologist must be able to reference the laboratory vendor's cross-reactivities information to know what to expect.

Interpretation of Drugs of Abuse Testing in Pain Management

Cross-Reactivities
Every vendor will disclose a list of drugs that can cross-react with their immunoassay. This information is essential for proper interpretation of immunoassay results. In the immunoassay example on the right, morphine is defined as the standard (100%). Notice that some drugs, such as codeine, are detected better than morphine with this assay. Yet some drugs, like oxycodone, oxymorphone, and meperidine, cross-react less than15%. That is, these drugs will not be detected with sufficient sensitivity using this opiate screen. Laboratory personnel need to educate clinicians in how to use the laboratory's drug screen. Laboratories may note in the patient results which drugs of the same class are NOT detected using their particular immunoassay, or may supply an interpretation table so that clinicians are aware that one assay cannot detect all drugs of a given class.

Interpretation of Drugs of Abuse Testing in Pain Management

Common Pain Management (PM) Drugs and Trade Names


The most commonly prescribed drugs for PM are listed in the table below along with some of their trade names. There are more trade names; these are the more common ones in the US:

Prescription Drug Codeine Fentanyl Hydrocodone

Trade Names Tylenol number 2, 3, etc., Codoplus, Codopyrin, Corex, Codin Sublimaze,Durgesic, Duragesic, Fentora, Haldid, Onsolis,Instanyl, Abstral Dicodid, Duodin, Hycet, Hycodan Hydrococet, Lorcet, Lortab, Norco, Norgan,Panacet, Symtan, Synkonin, Vicodin Dilaudid, Exalgo, Hydromorph Contin, Palladone Demerol Symoron, Dolophine, Amidone, Methadose, Physeptone, Heptadon Contin, Avinza, Kadian, Oramorph, Roxanol, Kapanol Oxycontin, Oxecta, Roxicodone, Supeudol Opana, Numorphan, Numorphone

Hydromorphone Meperidine Methadone Morphine Oxycodone Oxymorphone

Interpretation of Drugs of Abuse Testing in Pain Management

Ungraded Practice Question


Morphine is a metabolite of codeine. Select true or false j True k l m n j False k l m n

Interpretation of Drugs of Abuse Testing in Pain Management

Ungraded Practice Question


Morphine is a metabolite of codeine. Select true or false j True k l m n j False k l m n

Feedback Codeine is metabolized in the body to morphine. Identifying the metabolites of specific opiates is essential when interpreting urine drug confirmations in the context of pain management.

Interpretation of Drugs of Abuse Testing in Pain Management

Half-Lives and Windows


One of the more common questions the toxicology laboratory professional is asked by a patient is, "How long will it take before I can pass a drug test." The clinician may ask, "How long should I expect the patient's result to be positive?" The kinetics of drug metabolism and the presence of parent drugs and metabolites in the urine can be hard to predict since urine is not a homeostatically-controlled fluid. Urine concentration, unlike serum concentration, will vary significantly depending on how much one drinks. Also, people metabolize drugs at different rates depending on age, the presence of other drugs, as well as dietary and genetic factors. It takes around five half-lives for a drug to become undetectable. A half-life is the amount of time it takes for a drug concentration in the body to decrease by 50%. Despite the variability in metabolism, a general rule of thumb can be made for each of the drug classes. The information below can serve as a guideline:

Drug

Half-life (hours) Approximate Window of Detection in Urine (days)

Amphetamine Barbiturate (long-acting) Barbiturate (short-acting) Benzodiazepines (long-acting) Benzodiazepines (short-acting)

7-30 80-120 35-88 21-37 6-27

2-3 5-10 3-7 7-10 2-3 3-5 1 2 2 1-2 3-7 2-3 2-3 2 2-15

Benzoylecogonine (cocaine metabolite) 12-15 Cocaine Codeine Hydrocodone MDMA Methadone Methamphetamine Morphine Oxycodone THC 0.75-1.50 2-4 3.5-9 4-6 15-55 6-15 1.5-6.5 4-6 24-72

Interpretation of Drugs of Abuse Testing in Pain Management

Ungraded Practice Question


Which of the following drugs is a metabolite of another opiate but is also itself available as a prescription drug? Please select the single best answer j Codeine k l m n j Oxycodone k l m n j Hydromorphone k l m n

Interpretation of Drugs of Abuse Testing in Pain Management

Ungraded Practice Question


Which of the following drugs is a metabolite of another opiate but is also itself available as a prescription drug? Please select the single best answer j Codeine k l m n j Oxycodone k l m n

j Hydromorphone k l m n

Feedback Hydromorphone is a metabolite of morphine and hydrocodone. All of these drugs are available with a prescription.

Interpretation of Drugs of Abuse Testing in Pain Management

Frequently Asked Questions (FAQs) To the Toxicology Laboratory


Although these questions are not all related to pain drugs, they are often asked by pain management (PM) clinicians so they are worth addressing. Will Nyquil cause a positive DOA screen? Nyquil contains acetaminophen, dextromethorphan, doxylamine succinate and ethanol. With high consumption, the alcohol content could cause a positive alcohol screen but it should not cause immunoassays for DOA to be falsely positive at normal doses (Note: always refer to your assay's cross-reactivity specs). My patient is taking Adderall for ADHD/ADD. Why are they positive for amphetamine? The drug Adderall contains both isomers of amphetamine. It is therefore not surprising that when amphetamine is prescribed, the urine will test positive for amphetamine. My patient is taking methyphenidate (Ritalin) for ADHD/ADD why is the test not positive for amphetamines? Methylphenidate is not structurally similar to amphetamine. Although both drugs are used in ADHD/ADD, it should not be assumed that both will cause positive amphetamine results. Methylphenidate will not be detected with routine drug screens. Do poppy seeds really cause positive opiate screens? Yes this is possible, as discussed earlier in the course. Does dose correlate with urine concentration? No. Since urine concentration varies dramatically depending on how much a person drinks we cannot treat a quantitative urine drug result like we would a serum result. Although we have minimum cutoffs for drug detection in urine, there are no therapeutic ranges or 'target' ranges. Urine concentration does not parallel serum concentration in a predictable or reliable way. Does the drug zolpidem (Ambien) cause a positive benzodiazepine screen? No. Zolpidem is not a benzodiazepine; it belongs to a different class of drugs. Although zolpidem is a sleeping aid (a hypnotic) it will not cause a false benzo or barbiturate screen. My patient says he/she tested positive for THC due to second-hand smoke. Is this possible? No. The amount of time and exposure it would take to have the urine positive would essentially deem such exposure first-hand and not second-hand exposure. Will tramadol, fentanyl, buprenorphine or carisoprodol be detected by the opiate/Oxy screen? No. None of these drugs will typically cause a positive result. Specific testing for these agents is needed if the clinician wants to monitor their use.

Interpretation of Drugs of Abuse Testing in Pain Management

Ungraded Practice Question


Scenario 1 A patient with a urine creatinine of 25 mg/dL who has reportedly been taking codeine has codeine present in her urine but no morphine present. Which statement is true? Please select the single best answer j The urine is adulterated, so the confirmation is not reliable k l m n j The parent drug is detected, which is expected. The metabolite morphine need not be detected to call the patient compliant. k l m n

j A positive result for morphine would not be expected if codeine was taken. k l m n j Without the presence of both codeine and morphine, it can be concluded that the patient is noncompliant. k l m n

Interpretation of Drugs of Abuse Testing in Pain Management

Ungraded Practice Question


Scenario 1 A patient with a urine creatinine of 25 mg/dL who has reportedly been taking codeine has codeine present in her urine but no morphine present. Which statement is true? Please select the single best answer j The urine is adulterated, so the confirmation is not reliable k l m n j The parent drug is detected, which is expected. The metabolite morphine need not be detected to call the patient compliant. k l m n j A positive result for morphine would not be expected if codeine was taken. k l m n j Without the presence of both codeine and morphine, it can be concluded that the patient is noncompliant. k l m n

Feedback If the patient takes codeine we would expect codeine and perhaps morphine. However the finding of metabolite is not essential in this case. The drug may have been recently consumed and so significant amounts of morphine may not yet be present. The urine is dilute but >20 mg/dL. However, with a dilute urine the sensitivity of the assay for morphine may be decreased. Finding both parent and metabolite is useful but not essential to determining compliance.

Interpretation of Drugs of Abuse Testing in Pain Management Scenario 2 A clinician calls and says the laboratory made an error on the opiate screen he had ordered for one of his patients to detect methadone, which was being prescribed for this patient. The clinician states that the patient always takes his/her methadone at the correct time each day, yet the urine opiate screen is negative. The clinician also wonders why the urine creatinine is flagging abnormal (it is 15 mg/dL). Why is the opiate screen negative if the patient is taking methadone regularly as prescribed? What does the abnormal creatinine result probably indicate?

Consider why the opiate screen is negative if the patient is taking methadone regularly. Then click on this text to compare your response to the correct response. Consider what the abnormally low creatinine result probably indicates. Then click on this text to compare your response to the correct answer.

Interpretation of Drugs of Abuse Testing in Pain Management Scenario 2 A clinician calls and says the laboratory made an error on the opiate screen he had ordered for one of his patients to detect methadone, which was being prescribed for this patient. The clinician states that the patient always takes his/her methadone at the correct time each day, yet the urine opiate screen is negative. The clinician also wonders why the urine creatinine is flagging abnormal (it is 15 mg/dL). Why is the opiate screen negative if the patient is taking methadone regularly as prescribed? What does the abnormal creatinine result probably indicate?

Consider why the opiate screen is negative if the patient is taking methadone regularly. Then click on this text to compare your response to the correct response. Consider what the abnormally low creatinine result probably indicates. Then click on this text to compare your response to the correct answer.

Feedback

Interpretation of Drugs of Abuse Testing in Pain Management

Ungraded Practice Question


Scenario 3 A clinician has a patient taking Vicodin 750-7.5 mg daily (The numbers refer to 750 mg acetaminophen and 7.5 mg hydrocodone per tablet). The lab reported finding hydromorphone in the confirmation, but does not report a positive result for hydrocodone. The clinician is now asking the toxicology laboratory technologist if this result is consistent with the patient's prescription. Which of the following is a correct response? Please select the single best answer j Yes the result is consistent with the k l m n prescribed medication. Hydromorphone is a metabolite of hydrocodone and perhaps only metabolite is present in the urine. j No it is not consistent with the prescribed k l m n medication. Hydrocodone should be positive because it is present in the prescribed medication.

Interpretation of Drugs of Abuse Testing in Pain Management

Ungraded Practice Question


Scenario 3 A clinician has a patient taking Vicodin 750-7.5 mg daily (The numbers refer to 750 mg acetaminophen and 7.5 mg hydrocodone per tablet). The lab reported finding hydromorphone in the confirmation, but does not report a positive result for hydrocodone. The clinician is now asking the toxicology laboratory technologist if this result is consistent with the patient's prescription. Which of the following is a correct response? Please select the single best answer j Yes the result is consistent with the k l m n prescribed medication. Hydromorphone is a metabolite of hydrocodone and perhaps only metabolite is present in the urine. j No it is not consistent with the prescribed k l m n medication. Hydrocodone should be positive because it is present in the prescribed medication.

Feedback The findings are consistent with the prescription. Since the patient is taking hydrocodone the finding of hydromorphone makes sense because hydromorphone is a metabolite of hydrocodone. The fact that there was no hydrocodone found is a bit unusual but not impossible. If the patient missed a dose, it's possible that only metabolite and no parent drug is present in the urine.

The fact that there was no hydrocodone parent drug found may be concerning to the clinician if the patient says that he/she took a tablet recently. However, it is not good laboratory practice to look at ratios of parent to metabolite to try and guess the time of the last dose. As stated previously in the course, urine concentrations don't reflect serum concentrations and can't be used to firmly establish drug kinetics.

Interpretation of Drugs of Abuse Testing in Pain Management

Summary
In summary, pain management has become a significant driver and utilizer for lab toxicology testing. Screening and confirming opiates, and other drugs, in the urine of patients being prescribed analgesics has become very common. The abuse of prescription medications (opiates) is a serious and growing problem. The laboratory can play a vital role in assessing the compliance of patients and in assisting clinicians in their management of PM patients. Because many physicians who practice PM are not trained in toxicology or even PM (and are often only primary care physicians learning PM as they go), they often need help interpreting laboratory results. The laboratorian can provide a key service to clinicians in PM and addiction medicine if they are able to:
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Explain their screening assay's performance and cross reactivities Help make sense of results given the prescription of the patient Identify adulterated samples Answer routine questions about what services and which drugs the lab can detect and not detect.

The laboratorian can take an active role in PM. Once the value of the knowledgeable toxicology technologist is known to a clinician group that technologist will quickly become a reference and resource for many clinicians. Such recognition helps to elevate one's scope of practice, self esteem and the practice of laboratory medicine.

Interpretation of Drugs of Abuse Testing in Pain Management

Ungraded Practice Question


A patient with hydrocodone, hydromorphone, codeine, and morphine in his/her urine would likely be taking which of the following drug combinations? Please select the single best answer j Codeine and morphine k l m n j Oxycodone and hydrocodone k l m n j Morphine and oxymorphone k l m n j Hydrocodone and hydromorphone k l m n

Interpretation of Drugs of Abuse Testing in Pain Management

Ungraded Practice Question


A patient with hydrocodone, hydromorphone, codeine, and morphine in his/her urine would likely be taking which of the following drug combinations? Please select the single best answer j Codeine and morphine k l m n j Oxycodone and hydrocodone k l m n j Morphine and oxymorphone k l m n j Hydrocodone and hydromorphone k l m n

Feedback Codeine will give rise to morphine and (to a lesser extent) hydrocodone. Morphine will result in the hydromorphone metabolite. Thus, given the choices, only codeine and morphine will give this finding.

References

References
Brunton L, Lazo J, Parker K. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 11th ed. McGraw-Hill, 2005. Burtis CA, Ashwood ER, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 4th ed. Philadelphia: WB Saunders, 2005. Kaplan LA, Pesce A, Kazmierczak S. Clinical Chemistry: Theory, Analysis, Correlation. 4th ed. New York: Mosby, 2002. Perrine D. The Chemistry of Mind-Altering Drugs: History, Pharmacology, and Cultural Context. American Chemical Society Publication, 1996. Quest Diagnostics, Study Report on Urine Testing for Prescription Drugs. January 2011. Reisfield et al., Clin Chem, 2009: 55 1765-1768.