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The initial screening for drugs of abuse invariably poses the risk for Compared to opioids, however, CNS and respiratory depres-
false positives due to cross-reactivity. The over-the-counter antitussive sion are generally not exhibited in therapeutic doses but can
medication dextromethorphan (DXM) can cause false-positive results be seen at much larger doses.4,5 Dextromethorphan, though,
for phencyclidine (PCP) upon urine drug screening (UDS). It is believed does not normally cause a patient to present with opiate syn-
that DXM can also cause a false positive for opiates, presumably due drome symptoms such as miosis, decreased bowel sounds, and
to structural similarities. This could have serious implications, as DXM respiratory depression.5,6
abuse is reported to be increasing. However, many of these claims are One of the toxicological mechanisms of DXM is that it
anecdotal, as no fully comprehensive studies exist. Furthermore, what
studies have been completed reveal that DXM does not cause a false
can inhibit serotonin reuptake at the 5-HTA receptors, lead-
positive for opiates, despite their similarity in structure. Laboratories ing to potential serotonin syndrome.7-10 The toxic dose is
have established cut-off limits for opiates for the initial screen, and like highly variablesymptoms are generally observed at doses
all presumptive positives, confirmation with more sensitive methods greater than 10 mg/kg.11
are strongly recommended to rule out false positives. Keywords: The abuse potential for DXM is a growing trend among
dextromethorphan, opiates, false positives, urine drug screen adolescents, due to its ability in large doses to induce a state
of intoxication similar to that of phencyclidine (PCP) abuse.8
D
The effects of DXM overdose can include confusion, agita-
extromethorphan (DXM) is an antitussive tion, impaired coordination, disorientation, distortions of
medication found in numerous over-the-counter motion or speech, and depersonalization, and can even induce
cold/cough medications, such as Delsym, an out of the body, dreamy state along with visual hallucina-
Robitussin Pediatric Cough Suppressant, and tions.12 Abuse is primarily seen in adolescents and young
Vicks 44 cough medications. The side effects adults due to the fact that this medication is easily obtained.13
of DXM use are generally mild, such as dia- Reports have even indicated that users are cutting heroin with
phoresis, fever, dizziness, nausea, vomiting, DXM to enhance the effects of the drug.14
and mydriasis. Structurally, DXM is strikingly similar to the opiates
Dextromethorphans pharmacokinetics indicates the drug (Figure 2) and is actually the methylated dextro-isomer of the
is rapidly absorbed from the GI tract with peak plasma con- opioid analgesic levorphanol. From a clinical laboratory per-
centrations being reached within 2.5 hours.1 The distribution spective, it is important to remember this when performing
of DXM is variable, but undergoes extensive first-pass hepatic an initial screen for drugs of abuse-urine (DAU), as structural
metabolism via the cytochrome P450 enzyme CYP2D6. The similarities can many times cause false positive results to
therapeutic efficacy is due to its main demethylated metabo- occur. To understand this, the basis behind the initial drug
lite, dextrorphan (DXO) (Figure 1).2 Dextromethorphan can screens must be understood. Most of the initial screens use a
also be metabolized by CYP3A4 and CYP3A5 into 3-meth- specific type of immunoassay, the enzyme multiplied immu-
oxymorphinan and 3-hydroxymorphinan, respectively. It must noassay technique (EMIT), (Dade Behring, San Francisco,
be emphasized, however, that a large portion of the popula- CA) because of its low level of cost and rapid turnaround
tion can have defects in their CYP2D6 metabolic activity, time.15 Other opiate assays exist, such as the fluorescence
giving rise to poor metabolizers, leading to a prolonged polarization immunoassay (FPIA) (Abbott Diagnostics, Abbott
duration of action due to decreased metabolism.3 Park, IL), radioimmunoassay (RIA), (Diagnostic Products,
The mechanism of action of DXM is exerted on the Los Angeles, CA), kinetic interaction of microparticles in
central nervous system (CNS). Dextromethorphan diminishes solution (KIMS), (Roche Diagnostics, Indianapolis, IN), and
the sensitivity of cough receptors and blocks the transmission cloned enzyme donor immunoassay (CEDIA), (Microgenics,
of cough impulses by depressing the medullas cough centers Fremont, CA).16 Typically, the EMIT DAU opioid assay can
via stimulation of the -receptors.4 Specifically, DXM and detect morphine, morphine-glucoronide, codeine, meperi-
DXO curtail the N-methyl-D-aspartate (NMDA) receptors dine, and synthetic opioids.17
that normally bind glutamate and adhere to the -receptors There are reports of DXM causing false positives during
leading to their stimulation acting as -receptor agonists. 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
Corresponding Author urine toxicology screen.19 It has been suggested that DXM
Michael F. Neerman, PhD can also cause false positives following the initial screen for
mneerman@iupui.edu 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-
Abbreviations leagues showed that adults who ingested doses of 20 mg and
DXM, dextromethorphan; PCP, phencyclidine; UDS, urine drug 40 mg did not test positive for opioids.17 A limitation of
screening; DXO, dextrorphan; CNS, central nervous system; NMDA, this study, however, was that the highest dose of DXM was
N-methyl-D-aspartate; DAU, drugs of abuse-urine; EMIT, enzyme 40 mg, and perhaps higher doses could possibly affect the
multiplied immunoassay technique; FPIA, fluorescence polarization outcome of the initial screen. The authors concluded that
immunoassay; RIA, radioimmunoassay; KIMS, kinetic interaction although structurally similar, DXM at therapeutic doses will
of microparticles in solution; CEDIA, cloned enzyme donor immu- not yield a false positive for the urine opioid screen. Another
noassay; SAMHSA, Substance Abuse and Mental Health Services
Administration; GC-MS, gas chromatography-mass spectrometry;
study by Storrow and colleagues investigated whether nalox-
LC-MS, liquid chromatography-mass spectrometry; HPLC, high- one could cause a false positive for the urine opiate screen.20
performance liquid chromatography Naloxone, a structural analogue of the opioids (specifically
oxymorphone), is typically used to counter the effects of an
458
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9. Browne B, Linter S. Monoamine oxidase inhibitors and narcotic analgesics: 16. Shaw LM, Kwong TC, eds. The Clinical Toxicology Laboratory. Washington,
A critical review of the implications for treatment. Br J Psychiatry. DC: AACC Press; 2001;8485.
1987;151:210212. 17. Storrow AB, Magoon MR, Norton J. The dextromethorphan defense:
10. Nierenberg DR, Semprebon M. The central nervous system serotonin Dextromethorphan and the opioid screen. Acad Emerg Med. 1995;2:791794.
syndrome. Clin Pharm and Ther. 1993;53:8488. 18. Rogowski R, Krenzelok, E. Averting the medical, social, and legal implications
11. Olson KR, ed. Poisoning and Drug Overdose. 4th ed. New York, NY: McGraw- of a false positive phencyclidine determination (Abstract No.167-NACCT
Hill; 2004:183184. Annual Meeting). Clin Toxicol. 1997;35:551.
12. Schwartz RH. Adolescent abuse of dextromethorphan. Clin Pediatr. 19. Desai S, Aldea D, Daneels E, et al. Chronic addiction to dextromethorphan
2005;44:565568. cough syrup: A case report. J Amer Board Fam Med. 2006;19:320323.
13. McFee RB, Mofenson HC, Caraccio TR. Dextromethorphan: Another 20. Storrow AB, Wians FH, Mikkelsen SL, et al. Does naloxone cause a positive
ecstasy? Arch Fam Med. 1999;8:99100. urine opiate screen? Ann Emerg Med. 1994;24:11511153.
14. Centers for Disease Control and Prevention. Scopolamine poisoning among 21. Goldfrank LR, Flomenbaum NE, Lewin NA, et al, eds. Goldfranks:
heroin users: New York City, Newark, Philadelphia, and Baltimore, 1995 Toxicological Emergencies. 8th ed. New York, NY: McGraw-Hill; 2006:104.
and 1996. MMWR Morb Mortal Wkly Rep. 1996;45:457460.
15. Neerman MF. Drugs of abuse: Analyses and ingested agents that can induce
interference or cross-reactivity. Lab Med. 2006;37:14.
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