outs of DOA screens
William Check, PhD
Screening for drugs of abuse is basically clinical chemistry.
Sometimes such testing even takes place in a clinical chemistry laboratory.
Yet many features make testing for drugs of abuse unique, such as
the primacy of specificity.
"Specificity is the most important analytical criterion in this
type of testing," says Wayne R. Markus, MD, staff pathologist at
Physicians Laboratory Services in Omaha, Neb. "If someone is taking
hydromorphone [Dilaudid] or hydrocodone, you wouldn’t want to accuse
them of abusing morphine or heroin."
When it became evident that people who ate poppy seed pastries
could have enough morphine in their urine to test positive on an
opiate screen, some regulatory agencies and vendors raised their
cutoff levels from 300 to 2,000 ng/mL to avoid that possibility.
Whether a laboratory uses an opiate assay with a higher cutoff
depends on context. Barbarajean Magnani, PhD, MD, acting chief of
the Department of Laboratory Medicine and director of clinical chemistry
at Boston Medical Center, prefers an opiate assay with the lower
cutoff. "We don’t do workplace drug testing, where you are primarily
interested in detecting heroin abusers," she explains. Dr. Magnani
may be screening a sample from a person brought to the emergency
department with an overdose or from a person treated in a pain or
rehabilitation clinic. "I am interested in any opiate that the patient
may have taken that may produce symptoms or that they may have been
prescribed," she says.
Dr. Magnani’s typical phone call demonstrates the difference between
her practice and standard clinical chemistry. "I may get a call
from a rehabilitation physician treating a patient who had back
surgery who is getting slow-release oxycodone," she says. Such patients
typically get prescriptions month-to-month and are screened at the
end of each month for compliance. "If the test comes back negative
and the patient insists that they are taking the drug, the treating
physician faces a dilemma," Dr. Magnani continues. "The physician
wonders whether the patient is maybe selling the drug or whether
the drug is being diverted by a family member, especially if the
patient says the prescription is not adequate and asks for a higher
dose. At this point, they call me."
Dr. Magnani explains to the treating physician that opiate screening
tests may not detect the amount of oxycodone typically prescribed
for pain. And she has to convince the physician not to accuse the
patient of nonadherence or of selling the drug, "which can be devastating
to the patient." Dr. Magnani sends the sample out for a confirmatory
test. "Many times the test comes back positive," she says, "which
validates the patient and makes the physician feel better."
Tai Kwong, PhD, professor of pathology and laboratory medicine
and director of the regional toxicology laboratory at the University
of Rochester Medical Center, specializes in screening urine samples
from people in drug-treatment programs. He too spends time clearing
up misunderstandings about test results. Dr. Kwong’s typical phone
call follows a positive drug test. "The patient claims he has been
clean for so many weeks or months and the positive test must be
residual excretion," Dr. Kwong says. The patient could be telling
the truth—after a person has stopped using a drug, there is
a window during which it is still detectable. This period varies
by drug, dose, and the extent of the user’s experience.
"First I try to get as much information as possible from the clinician,"
Dr. Kwong says. "And I have to help the physician or nurse question
the patient more closely to determine their credibility. Sometimes
I can rule out the patient’s claim, and sometimes I can only say
A different set of issues confronts Jeffrey Jentzen, MD, chief
medical examiner for Milwaukee County, Wis. "This is a very challenging
field," Dr. Jentzen says, "because of test interpretation problems
as well as the difficulty of obtaining histories for dead people."
Dr. Jentzen’s difficulty in determining whether a death was due
to drug abuse is aggravated by the fact that the age for people
using illicit drugs is increasing.
"Just yesterday we had a person 72 years old who died from cocaine
toxicity," he says. "Stroke, heart attack, aortic dissection, seizures—you
can’t assume any longer that those events are not drug related.
They all can be caused by cocaine."
Laboratories doing workplace screening for drugs of abuse face
complications not often seen in a standard clinical chemistry laboratory.
Patients having urine glucose measurements don’t alter their specimens,
but some workers being tested for drugs of abuse do. "Substituted
specimens are the hot issue in workplace testing today," says Michael
Peat, PhD. Now vice president of operations at Atherotech, he spent
many years managing workplace screening for LabOne in Kansas City.
Patients may dilute their urine specimens with water before giving
them to a collector. Dr. Peat says four to five years ago the government
issued a definition of a substituted specimen based on creatinine
and specific gravity. "Now the majority of regulated laboratories
test for substitution and adulteration, and it is being increasingly
done outside of regulated laboratories," he says.
Almost all laboratories screening for drugs of
abuse share one important feature with standard clinical
chemistry laboratories: the need to define a limited test panel.
"Years ago if a person came in with an overdose we would do a comprehensive
screen," Dr. Magnani says. "Those are fairly expensive. Most laboratories
today don’t have the equipment to do that. And with the technologist
shortage, we don’t have the luxury anymore of having technologists
who specialize in toxicology and having a separate toxicology laboratory."
Now almost all non-reference laboratories that test for drugs of
abuse do immunoassay screening and offer a limited menu of tests.
One common panel, Dr. Markus says, is the "NIDA five," mandated
for all regulated workplace screening: amphetamines (d-amphetamine
and methamphetamine), opiates (morphine and codeine), phencyclidine
(PCP), cocaine metabolite (benzoylecgonine), and marijuana metabolite
(11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid, THCA). Barbiturates
and benzodiazepines (BDZ) can be added to make a seven-drug panel,
while some employers opt for a nine-drug panel with propoxyphene
(Darvon) and methadone. Amphetamine assays can be expanded to include
MDMA (ecstasy), and specific confirmation assays for the opioids
hydromorphone (Dilaudid) and hydrocodone (Vicodan) can be added.
(Standard opiate screening tests do not reliably detect other opioids,
including oxycodone, methadone, and propoxyphene.)
Outside regulated workplace screening, variations are common.
Dr. Kwong substitutes BDZ for PCP. Dr. Magnani includes barbiturates
and BDZ in her initial five-drug screen and offers PCP and THCA
on an expanded panel. "We don’t see much PCP here in Boston," she
says. "I only run that if they ask for it." Benzodiazepines have
a low abuse potential but are so heavily prescribed that some abuse
still occurs. The BDZ result could help diagnose a patient who comes
to the emergency room mildly neurologically impaired, Dr. Magnani
notes. "The physician might be wondering, Should I get a head CT
or could this be benzodiazepine-induced drowsiness and confusion?"
Screens rarely include methaqualone (Quaalude), which is mostly
a holdover from the past. "Methaqualone has not been seen since
the 1980s, when it was made a schedule one drug," Dr. Peat says.
"But some employer-employee agreements for drug testing negotiated
years ago are still in force."
In the hospital setting, clinicians may order tests for two so-called
date rape drugs: Rohypnol (flunitrazepam) and GHB (gamma hydroxybutyrate),
a derivative of the neurotransmitter GABA. "You only need a very
low dose of Rohypnol to knock someone out," Dr. Markus says, "and
it can be fairly hard to detect on some standard benzodiazepine
assays. I am concerned we won’t be able to pick it up."
Dr. Magnani, too, worries about the adequacy of available tests.
"I would like to urge vendors to start making screening products
that are appropriate for what we see today," she says. Teenagers
can overdose on dextromethorphan, which current screening assays
do not pick up. Another example is MDMA. "Some amphetamine assays
will detect it," Dr. Magnani says, "but others don’t. One company
has come out with a specific assay for MDMA. I would like to see
more of that."
Dr. Jentzen cites the opioid oxycodone as an instance of vendors
responding to new drugs of abuse. "Oxycodone is not easily detected
by routine opiate screening methods," he says. "You need a directed
assay. Manufacturers responded very quickly in providing directed
assays for oxycodone."
Accurate oxycodone detection has become a major issue. Soon after
slow-release oxycodone (Oxycontin) became available, drug users
found they could get a big, fairly cheap high by crushing and snorting
the pills. So emergency room physicians and drug-treatment programs
order screening for oxycodone. And, as Dr. Magnani notes, its use
is monitored in pain patients who have a prescription, a practice
stimulated in part by JCAHO’s pain control mandate.
Historically, opiate screening assays were designed to detect
heroin, and unfortunately they don’t always pick up oxycodone. "This
is not well understood by health centers that are affiliated with
a hospital rehabilitation program," Dr. Magnani says. When she gets
a negative result for oxycodone, she sends it out for confirmatory
testing by gas chromatography/mass spectrometry, or GCMS. "I hate
to see a patient dropped out of a rehab program for the wrong reason,"
Dr. Kwong has a similar perspective. "It is amazing how many physicians
don’t realize that an opiate assay does not pick up oxycodone very
well," he says. "This is a real concern." When a physician sends
a urine specimen from a pain patient being treated with Oxycontin
to be tested for the presence of the drug, the physician should
tell the laboratory to look specifically for oxycodone, Dr. Kwong
says. "Then we can go directly to an HPLC [high pressure liquid
chromatography] or GCMS assay."
Similarly, methadone tests are often ordered to check compliance
in heroin abusers on methadone maintenance, but many professionals
don’t know that opiate assays don’t detect methadone and that a
special test must be ordered. Dr. Magnani gets calls from physicians
whose patients have tested positive on an opiate test and who assume
that means the patient is taking the methadone. "I tell them, No,
your heroin abuser is most likely using heroin again.
"The story I really like," she continues, "was the physician who
called me about a urine specimen he had sent to a reference laboratory
from a heroin abuser in treatment." The physician had sent the sample
to find out whether the patient was taking codeine that had been
prescribed for postoperative pain. The physician told Dr. Magnani
that the test result had come back consistent with codeine. When
she asked for details, he told her the test found morphine, codeine,
and 6-monoacetyl morphine (6-MAM). Codeine is metabolized to morphine,
so those compounds were to be expected. And the clinician assumed
that 6-MAM was another metabolite of codeine.
"But 6-MAM is only a metabolite of heroin," Dr. Magnani says.
"So I told him that the test result really meant his patient was
back on heroin. The reference laboratory just reported what they
found, not what it implied or what the metabolic pathways are. That’s
why someone has to be available to answer clinicians’ questions."
Dr. Kwong works with methadone maintenance programs for treating
heroin addicts. They are interested primarily in whether clients
have relapsed into illicit drug use. So, to save money, they may
not test for methadone routinely, since most of the patients are
taking their methadone dose and should test positive. "Methadone
programs don’t order methadone testing routinely," he says. "The
only time they want us to check for methadone is when they suspect
a patient is not taking it."
Although some clients request urine alcohol in a screen for drugs
of abuse, in Dr. Markus’ view this is not prudent. "Alcohol is a
legal drug," he points out. People can drink a few hours before
going to work and still have alcohol in their urine during work.
"So if you do find a small concentration of alcohol, what would
you do?" he asks. "Most employers don’t require that you never drink,
while they can require that you never illegally use drugs." Breath
alcohol testing, used by some bigger companies, is a much better
technology than urine testing, Dr. Markus says: "A breath test or
blood alcohol concentration reflects your state of intoxication
at that moment."
As a programmatic requirement, Dr. Kwong says, some methadone
programs test all patients for alcohol when they come to get their
methadone dose. They may choose to use a breath alcohol test for
an instantaneous result. "A urine alcohol test sent to the laboratory
takes too long for the results to come back," he says.
Some drug-treatment programs present special needs. "For some
programs, the range of drugs that we may have to help them monitor
can be quite extensive. Most are not detectable by commercially
available immunoassays," Dr. Kwong says. For example, such programs
may treat adolescents abusing dextromethorphan. "We have to set
up something special for that," he says.
Another especially challenging type of program treats drug-abusing
health professionals. Their treatment may be under the supervision
of a regulatory agency with specific laboratory monitoring requirements.
"Physicians, nurses, and pharmacists have access to drugs that are
not typical street drugs," Dr. Kwong notes. "In addition to the
standard drugs, like morphine and codeine, those programs would
have specific drugs they want to look for. These would include opiates
like hydrocodone, hydromorphone, oxycodone, and nalbuphine, and
opioids like fentanyl, meperidine, methadone, and propoxyphene."
Everyone in these programs has a fairly specific history of abuse,
and the test volume for any given drug is low. "It is hard for a
clinical toxicology laboratory to maintain quality and proficiency
for so many drugs under these conditions," Dr. Kwong says. For this
reason, a few specialty laboratories do all of this testing. "I
tell the treatment programs, ’Don’t even send those specimens to
me,’" Dr. Kwong says.
He also declines to test for LSD routinely. "There is still a
low level of LSD activity out there," he says, "but we are fooling
ourselves if we think that we can detect it accurately in a typical
clinical laboratory setting. Immunoassays for LSD are notoriously
nonspecific and confirmation is very difficult." If a patient’s
history or clinical symptoms are strongly suggestive of LSD, Dr.
Kwong sends the specimen to a reference laboratory. The long turnaround
time means that the result does not contribute to the immediate
management plan for the patient.
Dr. Kwong is being asked to do more drugs-of-abuse testing for
organ transplantation purposes. "There is a long waiting list for
donor organs," he says, "and transplant programs want to evaluate
whether potential recipients are substance abusers." Results can
affect patients’ candidacy and their ranking on the list.
As a medical examiner, Dr. Jentzen faces unique issues.
"Drugs are becoming an increasingly important part of death investigations,"
Dr. Jentzen says. "Almost half of all cases we do have something
to do with drug toxicity or drug-to-drug interaction." Illicit drugs
contribute to many of these cases, but a large portion of the medical
examiner’s clientele abuses therapeutic drugs, such as pain medications
or antidepressants. "And a high percentage take an intentional overdose,"
Drugs of abuse tend to come in waves, he finds. In the mid- to
late ’80s, propoxyphene was popular. Before that it was barbiturates.
Further back, BDZs were abused. Now heroin has become more readily
available and oxycodone is causing many accidental deaths. "It’s
always changing, depending on what drug is in fashion and readily
available," Dr. Jentzen says.
Determining which drug was involved in any particular death is
challenging. In some cases the patient may have been resuscitated
in the emergency room and interviewed before dying. In other cases
drug paraphernalia or empty containers or pill vials found at the
scene of death indicate what the deceased took. In many cases, however,
there is no patient interview and no physical evidence. "So we don’t
know what they may have taken," Dr. Jentzen says. Even when there
are hints, full testing is still mandatory. That dictates broad-spectrum
"Our work is different from occupational drug testing, which looks
at a limited number of drugs," Dr. Jentzen says. "We would not be
content to do specific directed assays. We do a broad screen, then
directed confirmation." Dr. Jentzen uses Toxi-Lab, a commercial
thin-layer liquid chromatography method, to screen urine, and he
uses GC or GCMS, or both, to screen blood samples.
Sometimes simply obtaining an adequate sample for postmortem testing
is troublesome. "Physicians working in a hospital have the luxury
of taking blood from a person alive and talking to you," Dr. Jentzen
says. "You get samples in good condition and can even take repeat
samples." In postmortem drug testing, the person may have been dead
for a prolonged time and recovering sufficient volume for testing
may be difficult. On the other hand, blood isn’t the only sample
available; there are liver and brain tissue, gastric contents, and
vitreous fluid, which has the advantage of not deteriorating as
much as other body fluids.
Postmortem drug redistribution complicates the interpretation
of test results. "Postmortem drug redistribution has been appreciated
only for the last 10 years or so," Dr. Jentzen says. "Before, if
we saw a very high concentration of a drug in the blood, we would
have said that person took an overdose. Now we know that drug can
come out of tissue [after death] and artifactually elevate the amount
in blood." A pathologist who looked at a postmortem blood drug level
and concluded it was high enough to cause death would be wrong in
40 percent of cases. To minimize this possibility, peripheral samples—arteries
and veins of the legs and upper extremities—are taken. "We
also need to know which drugs are more prone to postmortem drug
redistribution," Dr. Jentzen says, such as antidepressants and digoxin.
In those cases, tissue levels are measured.
New long-acting drugs complicate interpretation as well. With
Oxycontin, for example, a large number of pills in the stomach doesn’t
necessarily translate into a high blood drug level, because the
pills break down slowly over time.
"A new concept that we are involved in here is pharmacogenetics,"
Dr. Jentzen says. "We now know that genetics plays a large role
in drug metabolism." In general, cytochrome P450 liver enzymes strongly
influence drug levels. "Now in our laboratory we routinely do genetic
testing when a drug level doesn’t fit with the history or scene-of-death
information," Dr. Jentzen says. In a recent case, a woman’s very
high antidepressant drug level did not fit her clinical history.
Dr. Jentzen determined that she lacked one of the enzymes needed
to metabolize that drug. "So instead of calling it a suicide, we
called it an accidental overdose."
Maintaining a chain of custody is an extra burden on any laboratory
doing postmortem drug testing or any other kind of forensic drug
testing. "Without complete documentation, we might as well throw
out the sample," Dr. Jentzen says. "It will not hold up in court."
Forensic issues can arise in workplace testing and in
as well. Dr. Magnani cites the case of a female known drug abuser
who delivers a baby. The baby’s urine or meconium may be sent for
a drug screen. "If we are just concerned about treating the baby
and the baby’s urine tests positive for cocaine, there is no problem,"
she says. "But if there is any question that mom and baby might
have social services involved and there might be a filing to remove
baby from mother, you had better be sure you have established a
chain of custody. Otherwise all you will be able to say in court
is that you got a positive result on a tube with the baby’s name
Workplace testing for drugs of abuse differs in substantive ways
from testing in other settings, Dr. Peat says. Workplace drug testing
may be regulated or nonregulated. Regulated testing covers federal
government agencies and companies required under government regulation
to test certain employees for drugs of abuse. "The principal federal
agency that requires drug testing in the workplace is the Department
of Transportation," Dr. Peat says.
Testing for drugs of abuse in the nonregulated arena occurs chiefly
by union agreement and, more frequently, by company policy. It generally
includes preemployment, random, and post-accident testing. "Much
less random testing is done in the nonregulated arena," he says.
Positivity rates in workplace drug testing are very low, says
Dr. Peat, and have been declining over the past decade, as data
on Quest Diagnostics’ Web site demonstrate. In 2001, tests performed
by Quest in the general U.S. workforce had the following positivity
rates: amphetamines, 0.29 percent; barbiturates, 0.34 percent; BDZ,
0.6 percent; cocaine, 0.69 percent; marijuana, 3.17 percent; opiates,
0.29 percent; PCP, 0.02 percent; propoxyphene, 0.52 percent.
"Another major difference between workplace and non-workplace
drug testing is the role played by the medical review officer,"
Dr. Peat says. A medical review officer, or MRO, is an occupational
health physician who can be an independent contractor or an employee
of a corporation but not an employee of a laboratory. "A number
of large companies have their own occupational health physicians,"
Dr. Peat says.
An MRO’s most important function is determining whether a positive
drug test can be explained by authorized use of a legitimate drug.
Use of Tylenol No. 3 containing codeine, for example, results in
urine positive for codeine and morphine. If an MRO verifies that
use, he or she will report the result to the employer as negative.
In principle, the employer never knows the specimen was positive.
Validity testing—detecting specimens that have been adulterated
or substituted—poses a major challenge in workplace drug testing.
Urine can be adulterated with tampering agents bought over the Web
and ingested. "Companies that sell these products claim they clean
you up," Dr. Peat says. "But their product inserts also suggest
that you drink copious amounts of water, which sounds like flushing
drugs out of your system."
Drug users can also buy products to add to urine after it’s collected.
"These products come in small tubes that you can hide in your socks,"
Dr. Peat says. "In today’s world, their main purpose is to destroy
THCA." Since these adulterants are basically oxidizing agents—nitrites,
bleach, pyridinium chlorochromate—reference laboratories have
devised processes to detect them. "Quest Diagnostics in particular
has been enthusiastic about detecting oxidants," Dr. Peat says.
According to Quest’s Web site, the fraction of urine samples containing
oxidants declined from 0.23 percent in 1999 to 0.05 percent in 2001.
People have also used bleach or household soap as adulterants
for decades. "Depending on the amount and on the laboratory, those
products can often be detected," says Dr. Peat.
Substituting urine specimens has come to the fore in the last
few years. As Dr. Peat notes, one method is to dilute urine with
water, which can be detected by measuring creatinine and specific
gravity. The MRO, in what Dr. Peat calls a "gatekeeper capacity,"
must review these results to ensure there is no medical explanation.
"Say the laboratory concludes that creatinine and specific gravity
are too low and not consistent with human urine and the specimen
was substituted," Dr. Peat says. "The MRO can contact the donor
and give them a chance to explain the result. The reviewer may suggest
that person consult a urologist, who sends a report to the MRO.
Then the MRO makes a final determination."
A more sophisticated form of substitution is to purchase clean
urine online and carry it under an arm in a bag to keep it near
body temperature. "Females sometimes carry negative urine in their
vagina in condoms and pierce them when they need to give a specimen,"
Dr. Peat says. This practice is hard to detect without DNA testing.
"Some people believe you should do directly observed urine collection,"
Dr. Peat says. "Directly observed collection is mandatory in the
military but only rarely performed elsewhere."
At the frontier of drug testing, says Dr. Peat, are attempts
to use specimens other than urine, especially oral fluid
and hair. "Hair has been used for a number of years and oral fluid
for the last three years or so," he says. Hair and oral fluid can
be tested in immunoassays but not those used for urine. Both are
accepted alternative tests to urine but are not currently approved
specimens in the regulated arena.
Neither oral fluids nor hair detects anything that urine doesn’t,
but each has putative advantages. "People who do hair testing claim
it can detect drugs for longer times than urine," Dr. Peat says.
"There is some truth in that, but a lot of debate." Hair is unsuitable
for post-accident drug testing, for example. If a person took a
drug shortly before an accident or took just a single dose, a detectable
concentration would not have built up in hair.
Oral fluid, on the other hand, has a window for detection similar
to that of urine. Its clinical sensitivity and pickup rate also
resemble that of urine. Oral fluid’s main advantage is that it is
more suitable than urine for directly observed collection. Dr. Peat
says LabOne has done the majority of work on oral fluid to date.
In technology, Dr. Peat says, "probably the biggest change in
the last five years outside the government arena has been increased
use of point-of-collection testing devices for urine and oral fluids."
A large number of handheld products are available with variable
pickup rates. "Do thorough market research before buying," Dr. Peat
advises. Point-of-collection devices are used primarily in preemployment
screening. "You can generally get a person into the workplace sooner
with them," Dr. Peat says.
These diverse sites of drugs-of-abuse testing share one mandate—the
need for good communication between the treating physician and the
laboratory to avoid misunderstandings about the test results. "We
pathologists have to be very clear about the capabilities and limitations
of the tests we use," Dr. Magnani says, "so that we can advise clinicians
when to send for confirmatory testing." Education is one form of
communication. "The pathologist’s role is to educate staff," Dr.
Magnani says. "Not just laboratory staff but medical staff as well.
For example, I have printed up charts available at the hospital
that detail what we can and cannot test for."
Dr. Kwong agrees. "We have to educate clinicians, nurses, and
drug counselors about what they should and should not expect from
a drug test," he says. "My general principle is that as long as
the laboratory understands the limitations of its assays, and communicates
them to clinicians, then the clinicians know when to ask the laboratory
for a special test."
Dr. Kwong’s bottom line: "If clinicians don’t talk to you, you
talk to them."
William Check is a medical writer in Wilmette, Ill.