Toxicology Laboratorys Role in Pain Management

8/12/2019 Toxicology Laboratorys Role in Pain Management

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The Toxicology Laboratory's Role in Pain Management

Aut ho r: Kev in F. Fo ley , PhD , DABCC , MT, SC

Review e r: Rob e rt E. Mo o re, MLS(ASCP)C M

, SCC M

, TC (NRCC )


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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 prac tice questions within the c ourse, which are not graded or

recorded.


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Course Info

This course carries the following continuing education credits:

l P.A.C .E. Contac t Hours: 2.00 hour(s)

Course Number: 578-018-13

l Florida Board of C linica l Laboratory Science C E - General (Clinical Chemistry/UA/ Toxicology): 2.00 hour(s)


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Laboratory Testing Methods For Drugs of Abuse

Course Introduction

Toxicology is the study of adverse effects of chemicals on living organisms. General toxicology is typica lly assoc iated 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 spec ifically in the context of pain management. DOA testing

in non-medica l settings, including employment testing and legal testing is not within the scope of this course.


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 ascreen and moves toward confirmation of spec ific d rugs, only if the

screen is positive.

Drug screening:

l Is fast

l Is qua litative, not quantitative

l Is generally performed on urine

l Can be done as a point-of-ca re (POC) test

l 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:

l Cocaine

l THC (Marijuana)

l Barbiturates

l Benzodiazepines

l Amphetamine and methamphetamine

l Opiates

l Oxycodone/oxymorphone

l Methadone

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


Drugs of Abuse (DOA) Screening Tests, continued

A DOA screen can be done quickly using an immunoassay method. Immunoassays use antibodies direc ted against spec ific


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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 detec t drugs used for pain management. An immunoassay c an tell you that a n opiate is present

but it cannot tell you which op iate 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 pa in drugs are present (ie, is it morphine, hydrocodone, etc.?)


Cutoff Concentrations for DOA Screening Tests

Drug screens use cutoff conc entrations 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 c utoff po ints

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.

C linicians 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 c utoff conc entration established by the manufac turer o

laboratory for that drug. For example, if a sample screens negative for oxycodone, there may be oxycodone present in the sample,

but the c oncentration 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:


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 c ase of pain

Drug Typical Cutoff Concentration

Amphetamine 500 ng/ mL

Barbiturates 200 ng/mL

THC 50 ng/mL

Cocaine/BE 300 ng/mL

Oxycodone/ Oxymorphone 100 ng/ mL

Opiates 300 ng/ mL

Methadone 300 ng/mL

Benzodiazepines 200 ng/mL


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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 chemica l

compounds. Mass spectrometry techniques can produce quantitative results, although not a ll laboratories report quantitative

results. In most cases, the clinician is only looking for the identity of the drug and not the quantity.


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 extrac ted from urine

samples using a series of organic

solvents. The elutions are theninjected 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 chromatography-

mass 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 thesample 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 a nd c ount 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 eac h piece of candy to pass by our eye one at a time, in single file, we could easily analyze and count eac h

piece. This is the purpose of the initial chromatography step; it allows a myriad of c ompounds to be injec ted 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

trajec tory through the vacuum can be controlled using magnetic and radio frequency adjustments that will allow only ions of a

certain mass to hit the detec tor. The amount of ions that hit the detector is directly proportiona l 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 c an tell us which drugs are present and a t what concentrations. Labs can develop

and valida te methods that can detec t a given drug or metabolite with a specificity of >99.99%. The reason for this high degree of


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specificity is that a compound must have very specific qualities to be detected. If we a re looking for morphine, for example, we

know that our GC-MS instrument will only identify morphine if:

1. The c ompound has the exact retention time as morphine on our chromatography co lumn.

2. The compound fragments into the specific ions with the exact mass/charge found for morphine.

3. The ratios of those spec ific 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.


False-Positive Opiate Results

Although confirmation methods should never produc e false-positive results,

the initial drug screens for opiates can sometimes be falsely positive. False-

positive 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

trac e (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 immunoa ssays. Since

many drugs of the opiate class can c ross-react in drug screens, confirmation

that an opiate is present and identification of the opiate that is present isimportant, espec ially for pa in management.


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 reflec ts the exac t metabolic state of the pa tient. 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 trac es 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 c leared fairly rapidly, within hours.

Urine, on the other hand, tends to conc entrate drugs. This is due to the simple fact that urine is a small amount of volume


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compared to the total fluid in the body. As drugs are c leared by the kidneys, the urine bec omes 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 effec t of urine, we don't even c all a patient's urine positive for codeine until the

conc entration reac hes 150 ng/ mL. This is greater than 10-times more conc entrated than serum!

Other advantages to urine as samples for DOA testing are:

l The samples are read ily preserved by freezing.

l Drugs are stable in urine (Generally no c ells present to further metabolize the drugs).

l 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

add ition of some agent (salts, ac ids, oxidizers or

even water) to one's urine sample to produc e a

falsely negative result. Adulteration is done to

trick the c linician 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 reduc e

proteins, or change the ionic environment such

that the detection antibodies don't effectively

bind the drugs that are present or the chemicals

inac tivate the antibody-linked detection systems.

Some adulterants that are used include:

l Klear (KNO2)

l Whizzies (potassium nitrate)

l Urine Aid (glutaraldehyde)

l Synthetic urine

l Water dilution

Individuals have a lso 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 prec ipitates, 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 ava ilab le, such as the exampleshown on the right, that test for the presenc e 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 spec ific 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 c reatinine value


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Ungraded Practice Question

Adulteration of a urine sample collected for drugs of abuse testing refers to:

Plea se selec t the single b est answer



Adulteration of a urine sample collected for drugs of abuse testing refers to:

nmlkjSubmitting another person's sample in place of your own.

nmlkj Adding something to the sample to cause interference and elicit a negative result.

nmlkj Concentrating one's sample to increase the chance of detecting a drug.

nmlkj Combining or using older samples over time to change the perceived time that someone took a drug.


Feedback

Adulteration of a sample for drugs of abuse testing refers to the add ition of some agent (salts, ac ids, oxidizers or even wa ter) 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 prac tice of pa in

mana gement is more involved than simply prescribing analgesics.

We will discuss the goals of pain management in coming sections.

The concept of a "pa in management contrac t," or an "opiate

therapy plan" is important to mention. When a patient's pain is

going to be managed with opiates or other prescription

ana lgesics the patient and clinician must agree to the terms of this

treatment.

nmlkj Submitting another person's sample in place of your own.

nmlkj Adding something to the sample to cause interference and elicit a negative result.

nmlkj Concentrating one's sample to increase the chance of detecting a drug.

nmlkj Combining or using older samples over time to change the perceived time that someone took a drug.


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Opiates are narcotics. A narcotic can refer to any drug derived

from op ium or opium-like c ompounds. 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 contrac t has these provisions:

l Patient will not seek medica tions from other providers

l Patient will only use med ications that a re provided to

him/her

l Patient will not sell or give his/her medications to others

These contrac ts are important to establish trust and expectations

between the c linician and the patient. These c ontrac ts will often

also specify the requirements for routine urine drug testing.


Opiates

Opiates define a large c lass of drugs with structural similarity to morphine (a

major analgesic found in opium extrac t from the poppy flower). The term opioid

is often used interchangeably with the term opiate. However, the term op ia te

more properly refers to the na tural narcotic c ompounds (alkaloids) found in the

resin of the opium poppy (Pap ave r som niferum). Use of the term "opioid" shouldbe reserved for semi-synthetic substances that are derived from the opium poppy

or made completely in the lab. Opiates/opioids include the following drugs:

l Morphine: Contin, Oramorph, Roxanol

l Oxycodone: Oxycontin, Percoset

l Hydrocodone: Codan, Hycodan, Hydromet

l Hydromorphone: Dilaudid

l Loperamide: Imodium

l Methadone: Dolophin

Opiates activate opiate receptors found in the central nervous system (CNS). The

endogenous ligands for these receptors are endorphins and endorphin-likepeptides. 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 c hanges 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 pa in is also a ltered with opiate use. Opiates

are often referred to as euphoric medications since they can elevate mood. They also c an induce physical and emotional

dependence and addiction.


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Opiates, continued

Opiates/opioids are used predominantly for pain. However

opiates such as codeine c an be used as antitussives (to reduce

coughing). A well-known effect of opiates is that they decrease

GI motility. Opiate-induced constipation is a c ommon side effec t

of opiates. This side effec t is exploited in the drug loperimide(sold as Imodium). Loperimide is used to treat diarrhea. However

loperimide does not c ross into the brain so it does not have

abuse potential.

Opiates are Schedule 2 drugs, meaning they require a

prescription and have abuse potential. C linical uses for opiates

include:

l diarrhea

l migraine

l moderate pa in

l myalgia

l severe pain

l 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 a lso 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 ac tive compound (see figure).

Opiates can cause:

l miosis (pinpoint pupils) and thus blurred vision

l confusion

l constipation

l drowsiness

l euphoria

l

hypotensionl nausea/vomiting

l physiological dependence / tolerance

l respiratory depression

l syncope


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


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initially lose one ac etyl group. The resulting

compound is 6-acetyl-morphine (abbreviated 6-

AM). The finding of 6-AM is conc lusive 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 6-

acetyl-morphine are commonly used in acute

care settings, emergency settings, and pain

management settings.


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. A lthough pain management usually involves opiates, there are a few other drugs that may

be used and could be detec ted 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 a s 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 ac tivity of other opiates and induces

withdrawa l in opiate-dependent individuals who a re 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 c hronic pa in relief. Because it is a patch, oral ingestion is not possible (or at least not pa latable), 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 conc entrations. Specific assays for fentanyl are needed to

detec t 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 medica lly by many patients since many states now have laws that permit its use in certain circumstanc es.

The ac tion of THC is more of a relaxant than a true analgesic. Most clinicians who are treating pa in will ask their pa tients 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 pa in management is common.

Methadoneis a synthetic opioid with a long duration of action. It is used to help wean patients from opiate dependency.


Pain Management: The Problem

Drug abuse, and specifically prescription drug


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abuse, in the United States is a huge problem.

Consider the following fac ts taken from the US

Drug Enforcement Agency's website:

l 7 million Americans are abusing

prescription drugs (thats more than

cocaine, heroin, hallucinogens, ecstasy,

and inhalants, combined).

l Prescription drug abuse increased 80% in

the past 6 years.

l Opioid pa inkillers now c ause more drugoverdose deaths than cocaine and heroin

combined.

l Hydrocodone is the most commonly

diverted and abused controlled

pharmaceutical in the United States

l The Centers for Disease Control and

Prevention (CDC) estimates 20,000 people

die eac h year from prescription drug

overdose (74% from opiates)

l Opiate overdoses lead to 475,000

emergency department (ED) visits per year

Quest Diagnostics published a report in 2012 conc erning 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 physicians documented prescriptions. In 40% of cases, no drugwas detected where one was expec ted.


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% reduc tion 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 c ompliant before the next urine test.

Also of note is that the study showed that there was little difference in abuse/ diversion rates between genders, ac ross ages, and

even across income levels. The problem is not limited to certain demographics but is widespread.


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. Dependenc y refers simply to the biologica l

adaptation to a drug. Drug dependenc e means that a person needs a drug to function normally. Abruptly stopping the drug

would lead to withdrawa l 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


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functioning. Increasing doses may also be needed due to tolerance. Tolerance occurs due to the fac t that opiate receptors will

down-regulate (reduce their expression) or activity in response to c hronic 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 dependenc y are addicts. Add iction is a more dubious term. Addiction is

the compulsive use of a substance, despite its negative or dangerous effects. Addiction is said to oc cur when a person c ontinues 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.



Diversion is:




Diversion is:

nmlkj Susbstituting one analgesic for another

nmlkj selling or giving one's medications to someone else

nmlkj using a drug without a prescription

nmlkj when a drug not prescribed is detected in the urine.


Feedback

Diversion occurs when a pa tient sells or gives their prescription drug to someone else. This is usually done for financial reasons.

Narcotics used for pain management are strong ana lgesics 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.

nmlkj Susbstituting one analgesic for another

nmlkj selling or giving one's medications to someone else

nmlkj using a drug without a prescription

nmlkj when a drug not prescribed is detected in the urine.


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The Goal of Pain Management (PM)

There are several goa ls in the prac tice of PM.

Two obvious goals are:

1. Reduce or limit dependency on medica tions for pain control

2. Avoid add iction to pain medica tions

A primary tenet of PM is that a patient should not expect to be pain-free. C linicians 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 goa l of PM is to maximize a patient's quality of life; to get the patient to a plac e where he/ she can function despite

pain.

Opiates are not the only tools available to the PM clinician. Counseling, group therapy, physical therapy, exercise, enc ouraging

positive behaviors, ac upuncture, and even hypnosis can be tried. The PM clinician is concerned with getting the patient to a lower

pa in level using the lowest possible dose of a drug, or no drug a t all.

PM can usually only reduce subjective pain around 30%. Thus, it's important for pa tients to have realistic expectations. When using

drugs to lower pain the obvious goals of produc ing 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 pa in flares up.


Testing the Pain Management (PM) Patient

The frequency of urine testing in PM depends on

the agreement made between the patient andclinician (the opiate therapy plan or contrac t), as

well as the na ture of the pa tient. 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 c linician's office without a prescription

for a narcotic. Patients who "doctor shop," trying

to get prescriptions for pain medication, are

relatively common. Some c haracteristics 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 medica tions 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 elec t to have pa tients tested every time they refill their

prescription.


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Some health care organizations also a llow c linicians to order a pill count. A pill count is an order that instructs the pa tient to go to

the pharmac y and have the pharmac ist count how many opiate pills are remaining in the prescription c ontainer. 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 c linician

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 c hemically altered, or samples that have been diluted. Supervised collec tions 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 c linician and the laboratory professionals know how to interpret the findings.



Which statement be low is true?




Which statement be low is true?

nmlkj The number of deaths resulting from opiate use is slowly decreasing due to laboratory testing efforts.

nmlkj It is uncommon to find more than one opiate or opioid in a patient's urine.

nmlkj About 2/3 of patients who have drug screens have an unexpected result.


Feedback

A recent study by Quest Diagnostics showed that 63% of patients had unexpected results.

The number of deaths and adverse events assoc iated 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.

nmlkj The number of deaths resulting from opiate use is slowly decreasing due to laboratory testing efforts.

nmlkj It is uncommon to find more than one opiate or opioid in a patient's urine.

nmlkj About 2/3 of patients who have drug screens have an unexpected result.


18/32



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?




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?

nmlkj Codeine

nmlkj Morphine

nmlkj Hydromorphone

nmlkj Methadone


Feedback

Methadone is a synthetic opioid with a long duration of ac tion. Morphine and c odeine are true op iates whereas hydromorphone is

considered a semi-synthetic in that it is a metabolite o f morphine but is not found in the poppy plant.



Which of the following is true?

nmlkj Codeine

nmlkj Morphine

nmlkj Hydromorphone

nmlkj Methadone


nmlkj Living pa in free is the goal for pain management pa tients


19/32



Which of the following is true?

nmlkj Pain management should occur over all the remaining years of a patient's life

nmlkj Hydrocodone is the most commonly prescribed narcotic in the US.


Feedback

Living pa in free is not a realistic expectation. Instead, patients are given the goal of trying to reduce their pa in 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.



In the prac tice of pain management, the absence of a compound in the urine is often just as significant as the presence of a

compound.

nmlkj Living pa in free is the goal for pain management pa tients

nmlkj Pain management should occur over all the remaining years of a patient's life

nmlkj Hydrocodone is the most commonly prescribed narcotic in the US.

Selec t true or fa lse



In the prac tice of pain management, the absence of a compound in the urine is often just as significant as the presence of a

compound.

nmlkj True

nmlkj False



20/32



True or false: The goal of pain management is to have the patient live pa in-free.

nmlkj True

nmlkj False




True or false: The goal of pain management is to have the patient live pa in-free.

nmlkj True

nmlkj False


Feedback

The goal of pain management is to maximize function and get patients to be as ac tive as they normally would be. Being pa in-free

is not a rea listic goal.

Interpretation of Drugs of Abuse Testing in Pain Managemen

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 competenc ies:

l Be able to recognize adulterated samples

l Know which opiate metabo lites would be expec ted with a given drug

l Know the cross-reactivities of the laboratory's immunoassay methods, or where to a ccess this information

l Be familiar with prescription pain drug trade names

l Be able to answer some of the common questions posed to toxicology laboratory personnel

nmlkj True

nmlkjFalse


21/32


Adulterants and Urine Samples Collected for Prescription Drug Monitoring

As discussed earlier, adulterants are c hemicals that can be a dded to a urine sample to obscure or confound drug screens.

Since most urine collections in the pain management setting are self-collec ted and unsupervised, it is easy for a person to

adulterate his/her specimen, if that person wishes to dec eive 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 pa in management setting may be done to produce a false-positive result. That is, a pa tient may

adulterate the urine sample by adding the drug that should be there when in fac t, 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 p ill dust into his/her urine

sample to trick the c linician into thinking he/she is compliant with taking the medication. In reality, the pa tient 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 detec t the parent and the metabolite (the metabolite will only be present if the drug

was injected and not present if pill dust is added).


Opiate Metabolites

In PM, a c onfirmation

should be performed if a

screening result is positive.

Since confirmatory methods

use mass spectrometry,

spec ific 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 thelaboratory 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 Possible Parent Drug Detection Window

Codeine Codeine 2-3 days

Hydrocodone Hydrocodone, codeine, dihydrocodeine 2-3 days


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

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

l Amphetamines

l THC

l Barbiturates

l

Benzodiazepinesl Methadone

l Cocaine

l Opiates

l 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 fac t is, there a re modifications to the chemical structures of opiates that will make them undetec table 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 c an

think of opiates and opioid screens in this way:

If a c linician 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 ac cuse patients of not taking their medica tions when in fac t 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 ac tion, will be detec table using an op iate 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 op iate 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 performanc e of your laboratory's assays. The toxicology tec hnologist must be ab le to

reference the laboratory vendor's cross-reactivities information to know what to expect.

Hydromorphone Hydromorphone, hydrocodone, morphine 2-3 days

Morphine Morphine, codeine, heroin 2-3 days

Oxycodone Oxycodone 2-3 days

Oxymorphone Oxymorphone, oxycodone 2-3 days

Drug Screen Detects

Opiates Morphine, codeine, hydrocodone, hydromorphone

Oxys Oxycodone, oxymorphone

Methadone Methadone

Fentanyl Fentanyl


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Cross-Reactivities

Every vendor will disclose a list of drugs that c an

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, c ross-react less

than15%. That is, these drugs will not be detected

with sufficient sensitivity using this opiate screen.

Laboratory personnel need to educate c linicians

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 detec t all drugs of

a given class.


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 Trade Names

Codeine Tylenol number 2, 3, etc., Codoplus, Codopyrin, Corex, Codin

Fentanyl Sublimaze,Durgesic, Duragesic, Fentora, Haldid, Onsolis,Instanyl, Abstral

Hydrocodone Dicodid, Duodin, Hycet, Hycodan Hydrococet, Lorcet, Lortab, Norco, Norgan,Panacet, Symtan, Synkonin,

Vicodin

Hydromorphone Dilaudid, Exalgo, Hydromorph Contin, Palladone

Meperidine Demerol

Methadone Symoron, Dolophine, Amidone, Methadose, Physeptone, Heptadon

Morphine Contin, Avinza, Kadian, Oramorph, Roxanol, Kapanol

Oxycodone Oxycontin, Oxecta, Roxicodone, Supeudol

Oxymorphone Opana , Numorphan, Numorphone


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Morphine is a metabolite of codeine.




Morphine is a metabolite of codeine.

nmlkj True

nmlkj False


Feedback

Codeine is metabolized in the body to morphine. Identifying the metabolites of specific opiates is essential when interpreting urine

drug confirmations in the c ontext of pain management.


Half-Lives and Windows

One of the more c ommon questions the toxicology laboratory professional is asked by a patient is, "How long will it take

before I can pass a drug test." The c linician may ask, "How long should I expec t 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 d rug 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 c an be made for eac h of the drug c lasses. The information below

can serve a s a guideline:

nmlkj True

nmlkj False

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


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Which of the following drugs is a metabolite o f another opiate but is also itself available as a prescription drug?

Ampheta mine 7-30 2-3

Barbiturate (long-ac ting) 80-120 5-10

Barbiturate (short-acting) 35-88 3-7

Benzodiazepines (long-ac ting) 21-37 7-10

Benzodiazepines (short-acting) 6-27 2-3

Benzoylecogonine (cocaine metabolite) 12-15 3-5

Coc aine 0.75-1.50 1

Codeine 2-4 2

Hydrocodone 3.5-9 2

MDMA 4-6 1-2

Methadone 15-55 3-7

Methamphetamine 6-15 2-3

Morphine 1.5-6.5 2-3

Oxycodone 4-6 2

THC 24-72 2-15




Which of the following drugs is a metabolite o f another opiate but is also itself available as a prescription drug?

nmlkj Codeine

nmlkj Oxycodone

nmlkj Hydromorphone


nmlkj Codeine

nmlkj Oxycodone


26/32

Feedback

Hydromorphone is a metabolite of morphine and hydrocodone. A ll of these drugs are available with a prescription.


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 ac etaminophen, dextromethorphan, doxylamine succ inate and

ethanol. With high consumption, the alcohol content could ca use a positive alcohol screen but it should not cause

immunoassays for DOA to be falsely positive at normal doses (Note: a lways 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 i

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

typica lly cause a positive result. Specific testing for these agents is needed if the c linician wants to monitor their use.



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?

nmlkj Hydromorphone


nmlkj The urine is adulterated, so the confirmation is not reliable

nmlkj The parent drug is detected, which is expected. The metabolite morphine need not be detected to ca ll the patient compliant
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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?

nmlkj A positive result for morphine would not be expected if codeine was taken.

nmlkj Without the presence of both codeine and morphine, it can be concluded that the patient is noncompliant.


Feedback

If the patient takes codeine we would expec t 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 dec reased. Finding both parent

and metabolite is useful but not essential to determining compliance.


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 c linician 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 indica te?

nmlkj The urine is adulterated, so the confirmation is not reliable

nmlkj The parent drug is detected, which is expected. The metabolite morphine need not be detected to ca ll the patient compliant

nmlkj A positive result for morphine would not be expected if codeine was taken.

nmlkj Without the presence of both codeine and morphine, it can be concluded that the patient is noncompliant.

Consider why the opiate screen is negative if the patient is taking methadone regularly. Then c lick on this text to

compare your response to the correct response.

Consider what the abnormally low creatinine result probably indicates. Then c lick on this text to compare your

response to the correct answer.
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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 c linician 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 indica te?

Feedback



Scenario 3

A c linician has a pa tient

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

tec hnologist if this result is

consistent with the patient's

prescription.

Which of the following is a

correct response?

Consider why the opiate screen is negative if the patient is taking methadone regularly. Then c lick on this text to

compare your response to the correct response.

Consider what the abnormally low creatinine result probably indicates. Then c lick on this text to compare your

response to the correct answer.


nmlkj Yes the result is consistent with the

prescribed medication. Hydromorphone is a

metabolite of hydrocodone and perhaps

only metabolite is present in the urine.

nmlkj No it is not consistent with the prescribed

medication. Hydrocodone should be

positive bec ause it is present in the

prescribed medication.
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Scenario 3

A c linician has a pa tient

taking Vicodin 750-7.5 mgdaily (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

tec hnologist if this result is

consistent with the patient's

prescription.

Which of the following is a

correct response?


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.

nmlkj Yes the result is consistent with the

prescribed medication. Hydromorphone is a

metabolite of hydrocodone and perhaps

only metabolite is present in the urine.

nmlkj No it is not consistent with the prescribed

medication. Hydrocodone should be

positive bec ause it is present in the

prescribed medication.


30/32

The fact that there was no hydrocodone parent

drug found may be c oncerning to the c linician 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 conc entrations don't reflec t serum concentrations and c an't be used to firmly establish drug kinetics.


Summary

In summary, pain management has become a significant d river and utilizer for lab toxicology testing. Screening and

confirming opiates, and other drugs, in the urine of pa tients 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 clinic ians in their management o f PM patients. Because many physicians who prac tice

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 c linicians in PM and addiction medicine

if they are able to:

l Explain their screening a ssay's performanc e and cross reactivitiesl Help make sense of results given the prescription of the pa tient

l Identify adulterated samples

l Answer routine questions about what services and which drugs the lab c an detec t and not detect.

The laboratorian can take an active role in PM. Onc e the value of the knowledgeable toxicology technologist is known to a

clinician group that technologist will quickly bec ome a reference and resource for many clinicians. Such recognition helps to

elevate one's scope of prac tice, self esteem and the practice of laboratory medicine.



A patient with hydrocodone, hydromorphone,

codeine, and morphine in his/her urine would

likely be taking which of the following drug

combinations?


nmlkj Codeine and morphine

nmlkj Oxycodone and hydrocodone

nmlkj Morphine and oxymorphone

nmlkj Hydrocodone and hydromorphone


31/32



A patient with hydrocodone, hydromorphone,

codeine, and morphine in his/her urine would

likely be taking which of the following drug

combinations?


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.

Reference

References

Brunton L, Lazo J , Parker K.Go od m a n & G i lm an 's The Pharma c olog ica l Bas is of Therap eut ics. 11th ed. McGraw-Hill, 2005.

Burtis CA, Ashwood ER, eds. Tietz Textb oo k of C l in ica l Chem istry and Mo lecu lar Dia gn ost ics, 4th ed. Philadelphia: WB Saunders,

2005.

Kaplan LA, Pesce A, Kazmierczak S. Clinic a l Ch em istry: The ory, A na lysis, C orrelation. 4th ed. New York: Mosby, 2002.

Perrine D. The Che m istry of Mind-Al ter ing Drugs: History , Pha rma c olog y, and Cul tura l Co ntext .American Chemical Soc iety

Publication, 1996.

Quest Diagnostics, Study Report on Urine Testing for Prescription Drugs. January 2011.

Reisfield et al.,C l in C hem, 2009: 55 1765-1768.

nmlkj Codeine and morphine

nmlkj Oxycodone and hydrocodone

nmlkj Morphine and oxymorphone

nmlkj Hydrocodone and hydromorphone


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Documents

Toxicology Laboratorys Role in Pain Management