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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)
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.
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.
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.?)
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
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.
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.
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).
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.
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
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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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
The Use of Opiates For Pain Management and the Problem of Drug Abuse
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 Use of Opiates For Pain Management and the Problem of Drug Abuse
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
The Use of Opiates For Pain Management and the Problem of Drug Abuse
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
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
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
The Use of Opiates For Pain Management and the Problem of Drug Abuse
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
The Use of Opiates For Pain Management and the Problem of Drug Abuse
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
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
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
The Use of Opiates For Pain Management and the Problem of Drug Abuse
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
The Use of Opiates For Pain Management and the Problem of Drug Abuse
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.
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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
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.
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
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:
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.
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.
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
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.
Drug
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
j Hydromorphone k l m n
Feedback Hydromorphone is a metabolite of morphine and hydrocodone. All of these drugs are available with a prescription.
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
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.
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.
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.