Featured Article

Submitted 1.26.10 | Revision Received 3.3.10 | Accepted 3.8.10

Is Dextromethorphan a Concern for Causing

a False Positive During Urine Drug Screening?
Michael F. Neerman, PhD, FACB,
Chinemerem L. Uzoegwu, BSN, RN
(North Texas Poison Center, Parkland Health
& Hospital System, Dallas, TX)
DOI: 10.1309/LMC384VVWIPJFXCZ

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The initial screening for drugs of abuse invariably poses the risk for
false positives due to cross-reactivity. The over-the-counter antitussive
medication dextromethorphan (DXM) can cause false-positive results
for phencyclidine (PCP) upon urine drug screening (UDS). It is believed
that DXM can also cause a false positive for opiates, presumably due
to structural similarities. This could have serious implications, as DXM
abuse is reported to be increasing. However, many of these claims are
anecdotal, as no fully comprehensive studies exist. Furthermore, what
studies have been completed reveal that DXM does not cause a false
positive for opiates, despite their similarity in structure. Laboratories
have established cut-off limits for opiates for the initial screen, and like
all presumptive positives, confirmation with more sensitive methods
are strongly recommended to rule out false positives. Keywords:
dextromethorphan, opiates, false positives, urine drug screen
D
extromethorphan (DXM) is an antitussive
medication found in numerous over-the-counter
cold/cough medications, such as Delsym,
Robitussin Pediatric Cough Suppressant, and
Vicks 44 cough medications. The side effects
of DXM use are generally mild, such as dia-
phoresis, fever, dizziness, nausea, vomiting,
and mydriasis.
Dextromethorphans pharmacokinetics indicates the drug
is rapidly absorbed from the GI tract with peak plasma con-
centrations being reached within 2.5 hours.1 The distribution
of DXM is variable, but undergoes extensive first-pass hepatic
metabolism via the cytochrome P450 enzyme CYP2D6. The
therapeutic efficacy is due to its main demethylated metabo-
lite, dextrorphan (DXO) (Figure 1).2 Dextromethorphan can
also be metabolized by CYP3A4 and CYP3A5 into 3-meth-
oxymorphinan and 3-hydroxymorphinan, respectively. It must
be emphasized, however, that a large portion of the popula-
tion can have defects in their CYP2D6 metabolic activity,
giving rise to poor metabolizers, leading to a prolonged
duration of action due to decreased metabolism.3
The mechanism of action of DXM is exerted on the
central nervous system (CNS). Dextromethorphan diminishes
the sensitivity of cough receptors and blocks the transmission
of cough impulses by depressing the medullas cough centers
via stimulation of the -receptors.4 Specifically, DXM and
DXO curtail the N-methyl-D-aspartate (NMDA) receptors
that normally bind glutamate and adhere to the -receptors
leading to their stimulation acting as -receptor agonists.
Corresponding Author
Michael F. Neerman, PhD
mneerman@iupui.edu
Abbreviations
DXM, dextromethorphan; PCP, phencyclidine; UDS, urine drug
screening; DXO, dextrorphan; CNS, central nervous system; NMDA,
N-methyl-D-aspartate; DAU, drugs of abuse-urine; EMIT, enzyme
multiplied immunoassay technique; FPIA, fluorescence polarization
immunoassay; RIA, radioimmunoassay; KIMS, kinetic interaction
of microparticles in solution; CEDIA, cloned enzyme donor immu-
noassay; SAMHSA, Substance Abuse and Mental Health Services
Administration; GC-MS, gas chromatography-mass spectrometry;
LC-MS, liquid chromatography-mass spectrometry; HPLC, high-
performance liquid chromatography
458
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Compared to opioids, however, CNS and respiratory depres-
sion are generally not exhibited in therapeutic doses but can
be seen at much larger doses.4,5 Dextromethorphan, though,
does not normally cause a patient to present with opiate syn-
drome symptoms such as miosis, decreased bowel sounds, and
respiratory depression.5,6
One of the toxicological mechanisms of DXM is that it
can inhibit serotonin reuptake at the 5-HTA receptors, lead-
ing to potential serotonin syndrome.7-10 The toxic dose is
highly variablesymptoms are generally observed at doses
greater than 10 mg/kg.11
The abuse potential for DXM is a growing trend among
adolescents, due to its ability in large doses to induce a state
of intoxication similar to that of phencyclidine (PCP) abuse.8
The effects of DXM overdose can include confusion, agita-
tion, impaired coordination, disorientation, distortions of
motion or speech, and depersonalization, and can even induce
an out of the body, dreamy state along with visual hallucina-
tions.12 Abuse is primarily seen in adolescents and young
adults due to the fact that this medication is easily obtained.13
Reports have even indicated that users are cutting heroin with
DXM to enhance the effects of the drug.14
Structurally, DXM is strikingly similar to the opiates
(Figure 2) and is actually the methylated dextro-isomer of the
opioid analgesic levorphanol. From a clinical laboratory per-
spective, it is important to remember this when performing
an initial screen for drugs of abuse-urine (DAU), as structural
similarities can many times cause false positive results to
occur. To understand this, the basis behind the initial drug
screens must be understood. Most of the initial screens use a
specific type of immunoassay, the enzyme multiplied immu-
noassay technique (EMIT), (Dade Behring, San Francisco,
CA) because of its low level of cost and rapid turnaround
time.15 Other opiate assays exist, such as the fluorescence
polarization immunoassay (FPIA) (Abbott Diagnostics, Abbott
Park, IL), radioimmunoassay (RIA), (Diagnostic Products,
Los Angeles, CA), kinetic interaction of microparticles in
solution (KIMS), (Roche Diagnostics, Indianapolis, IN), and
cloned enzyme donor immunoassay (CEDIA), (Microgenics,
Fremont, CA).16 Typically, the EMIT DAU opioid assay can
detect morphine, morphine-glucoronide, codeine, meperi-
dine, and synthetic opioids.17
There are reports of DXM causing false positives during
the initial screen with most reporting false positives for
PCP.4,18-19 Desai and colleagues found that a 66-year-old
woman who had chronically ingested large amounts of DXM
in order to induce euphoria, tested positive for PCP from her
urine toxicology screen.19 It has been suggested that DXM
can also cause false positives following the initial screen for
opiates due to structural similarities, though according to
the literature, no conclusive evidence has supported these
claims.17,20 On the contrary, a study by Storrow and col-
leagues showed that adults who ingested doses of 20 mg and
40 mg did not test positive for opioids.17 A limitation of
this study, however, was that the highest dose of DXM was
40 mg, and perhaps higher doses could possibly affect the
outcome of the initial screen. The authors concluded that
although structurally similar, DXM at therapeutic doses will
not yield a false positive for the urine opioid screen. Another
study by Storrow and colleagues investigated whether nalox-
one could cause a false positive for the urine opiate screen.20
Naloxone, a structural analogue of the opioids (specifically
oxymorphone), is typically used to counter the effects of an
 Featured Article

opioid overdose. In this particular study, 14 healthy subjects

were administered 2 mg or 4 mg IV naloxone, and urine drug
screening (UDS) was performed before administration and
at 60 minutes, 6 hours, and 48 hours after administration.
None of the time points gave a positive opiate result using
the EMIT assay, despite structural similarities and the pres-
ence of naloxone in the urine.
Laboratories following the Mandatory Guidelines for
Federal Workplace Drug Testing Programs published by the
Substance Abuse and Mental Health Services Administration
(SAMHSA) have set in place cut-off values for urine drug
testing.21 For the opiates, the cut-off level for urinary metabo- Figure 1_The metabolism of dextromethorphan (DXM) into its
lites is 2000 ng/mL, or 10 ng/mL for 6-acetylmorphine, for predominant metabolite dextrorphan (DXO) via the cytochrome P450
the EMIT initial screen. The cut-off level for confirmatory isoform CYP2D6.
testing via GC-MS is again 2000 ng/mL for morphine and
codeine and 10 ng/mL for 6-acetylmorphine.
To date, other studies have reported that certain sub-
stances can cause false-positive urine drug results:15 poppy
seeds for opiates, ma huang and ephedrine for amphetamines,
coco leaf tea for cocaine, and large doses of DXM for PCP.

From a clinical laboratory perspective, it is

important to remember that DXM is strikingly
similar to the opiates when performing an
initial screen for drugs of abuse.

However, no comprehensive study has proven that DXM

use can cause false positives on initially screening for opiates.
This paucity of data warrants such studies to assess if yet an-
other substance can lead to false positives for the UDS. It is
paramount to factor into the equation those agents that can
interfere or cross-react with the initial UDS, especially in the
workplace setting where peoples jobs are contingent on urine
drug testing. Although clinically relevant overdoses mandate
immediate management, generally the UDS turnaround time
is not rapid enough to dictate treatment. However, it is still
important for the clinical staff to be aware of possible interfer-
ences if performing patient follow-up. Most if not all assay
kit inserts have a list of suspected agents and medications that
can induce interference or cross-reactivity, and it is always
important to consult with the clinical laboratory if results are
suspicious. Moreover, it is also contingent on the clinical staff
to fully assess the patient (ie, the patients history, mental
status, and current medications) to determine if there is some-
thing that could possibly interfere or cause cross-reactivity
with this patients initial drug screen. Whether or not these
criteria can be determined, all initial screens testing positive
should always be confirmed with more sophisticated, precise,
and accurate methods, such as gas chromatography-mass spec-
trometry (GC-MS), liquid chromatography-mass spectrom-
etry (LC-MS), or high-performance liquid chromatography
(HPLC). These methods can definitively rule out any false
positives and confirm the presence and amount of the illicit
substance. LM
Figure 2_The structural similarities between dextromethorphan
and 2 common opiates: morphine and codeine.
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