Abstract

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.

Dextromethorphan (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 diaphoresis, fever, dizziness, nausea, vomiting, and mydriasis.

Dextromethorphan’s pharmacokinetics indicates the drug is rapidly absorbed from the GI tract with peak plasma concentrations 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 metabolite, dextrorphan (DXO) (Figure 1).2 Dextromethorphan can also be metabolized by CYP3A4 and CYP3A5 into 3-methoxymorphinan and 3-hydroxymorphinan, respectively. It must be emphasized, however, that a large portion of the population 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 medulla’s cough centers via stimulation of the σ-receptors.4 Specifically, DXM and DXO curtail the N-methyl-D-aspartate (NMDA) receptors that normally bind glutamate and adhere to the σ-receptors leading to their stimulation acting as σ-receptor agonists. Compared to opioids, however, CNS and respiratory depression 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 syndrome 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, leading to potential serotonin syndrome.7–10 The toxic dose is highly variable—symptoms 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, agitation, impaired coordination, disorientation, distortions of motion or speech, and depersonalization, and can even induce an out of the body, dreamy state along with visual hallucinations.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 perspective, 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 immunoassay 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, meperidine, 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 colleagues 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 naloxone 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 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 presence 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 metabolites is 2000 ng/mL, or 10 ng/mL for 6-acetylmorphine, for the EMIT initial screen. The cut-off level for confirmatory 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 substances 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. 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 another 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 interferences 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 patient’s history, mental status, and current medications) to determine if there is something that could possibly interfere or cause cross-reactivity with this patient’s 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 spectrometry (GC-MS), liquid chromatography-mass spectrometry (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.

Figure 1

The metabolism of dextromethorphan (DXM) into its predominant metabolite dextrorphan (DXO) via the cytochrome P450 isoform CYP2D6.

Figure 1

The metabolism of dextromethorphan (DXM) into its predominant metabolite dextrorphan (DXO) via the cytochrome P450 isoform CYP2D6.

Figure 2

The structural similarities between dextromethorphan and 2 common opiates: morphine and codeine.

Figure 2

The structural similarities between dextromethorphan and 2 common opiates: morphine and codeine.

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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 immunoassay

  • 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