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A Case of Unusual Drug Screening Results.

Case Description

A 27-year-old man was found unconscious in his car by police. He was taken to an outside hospital where results of his serum alcohol and initial urine drug screen were reportedly negative. On arrival to our hospital, the patient was awake, partially oriented, and able to follow simple commands. He reported feeling sedated and "loopy," was unable to remember any events before hospitalization, and was an overall poor historian. He denied illicit drug use, suicidal ideation, homicidal ideation, or any physical complaints. He did express delusions including that he "was an alien with green blood." Past medical history was significant for schizophrenia with continued auditory hallucinations secondary to noncompliance with risperidone therapy. A review of the medical record revealed a prescription for tramadol.

Vital signs were normal save for borderline tachycardia and the physical exam was noncontributory. The patient's complete metabolic panel was significant for mild hypokalemia (potassium 3.1 mmol/L, reference interval 3.5-5.2 mmol/L), hypophosphatemia (phosphorous 0.7 mg/dL, reference interval 2.3-4.3 mg/dL), slightly increased aspartate aminotransferase (60 U/L, reference interval 10-37 U/L), and indirect bilirubinemia (3.7 mg/ dL, reference interval 0.3-1.2 mg/dL). The initial troponin I concentration was 0.16 ng/mL (reference <0.06 ng/mL) that peaked at 0.21 ng/mL ([greater than or equal to] 0.20 ng/mL suggestive of myocardial damage) approximately 5 hours later. His creatine kinase (CK) (3) was 1017 U/L (reference interval 40-230 U/L). Serial electrocardiograms were performed and showed evidence of left axis deviation but were otherwise unremarkable.

The patient was admitted for observation and treated with intravenous fluids. A transthoracic echocardiogram was performed and did not show any evidence of wall motion abnormality. On the second day of hospitalization, he was deemed medically stable with a plan to resume risperidone therapy as an outpatient. His CK had trended downward to 403 U/L by the time of discharge.

A urine drug screen was performed upon admission using the Abbott Architect c4000 analyzer (Abbott Diagnostics). The test menu consisted of amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, opiates, and phencyclidine (PCP) screens (Abbott Diagnostics). The only positive result was for PCP (cutoff of 50 ng/mL). Confirmation testing was performed using an Agilent 7890A/5975C GC-MS (Agilent Technologies) in full scan mode. No PCP was detected; however, the presence of 3-methoxyphencyclidine (3-MeO-PCP) (Fig. 1) was confirmed. No other drugs, including tramadol, were detected.

DISCUSSION

PCP was introduced in the 1950s as an anesthetic and subsequently withdrawn from the market in the 1960s owing to hallucinogenic side effects. During the following decades, recreational use of PCP skyrocketed, but this drug has since fallen out of favor and is among the less commonly encountered drugs of abuse. PCP abuse has historically had the highest prevalence in the southwest US; however, its use is increasing in numerous metropolitan areas throughout the country. While PCP is currently a schedule II compound in the US, newer designer versions such as 3-MeO-PCP and 4-MeO PCP now exist for research and illicit purposes. Neither is currently scheduled by the Drug Enforcement Agency.

Typically, immunoassays for drugs of abuse are the first line of testing for their ease of use, amenability to automation, and rapid turnaround time. Invariably these assays display some cross-reactivity with drugs from the same class as well as with unrelated medications. While confirmatory testing using mass spectrometry (GC-MS or LC-MS/MS) may be available, medical decisionmaking occurs before these results have returned. Another issue arises if confirmatory testing is simply not performed. As with any medical test, proper interpretation should take into account known sensitivity and specificity issues to determine whether the results fit the clinical picture. In the context of PCP, some laboratories have chosen to remove PCP screening from their standard panels because false positives may outnumber confirmed positives (1). Even in facilities that perform PCP screening, when confirmatory results are regularly negative, the ordering physicians may instinctively dismiss positive screening results. Given the proliferation of novel psychoactive substances (NPSs), any decision to not test for PCP, not perform confirmatory testing, or not trust a positive result must be done with careful consideration. Herein we have presented a case of 3-MeOPCP intoxication involving delirium with increased troponin I and CK that easily could have been attributed erroneously to the patient's prescription for tramadol, if not for the confirmatory testing.

Any given immunoassay is prone to cross-reactivity with unrelated compounds. Issues regarding the specificity of PCP immunoassays have been well documented in the literature. Known potential interferences are tramadol and venlafaxine (1) since both drugs share structural similarities with PCP (Fig. 2).

Another potential pitfall in this patient's presentation involves his use of tramadol. Potential side effects include seizures and serotonin syndrome (2). Both can occur with tramadol monotherapy but are more likely with concomitant antidepressant usage, particularly of selective serotonin reuptake inhibitors.

Reexamination of this patient's clinical presentation reveals that it is entirely possible that serotonin excess could have played a role. Although he did not confirm taking tramadol, it was listed in his medical record and overdose should have been considered. He also displayed mental status changes (confusion and memory loss), slight tachycardia, and mildly increased serum CK that although nonspecific, could occur in serotonin syndrome. Another confounding factor was the fact that the time of his most recent dose was not known, as symptoms of serotonin syndrome often begin to abate within 24 h of discontinuing tramadol.

PCP is a well-known N-methyl-D-aspartate receptor antagonist; however, evidence suggests it also exerts agonist-like effects at serotonin 5-H[T.sub.2] receptors (3). Although serotonin syndrome has not been linked to PCP, there are accounts of rhabdomyolysis with and without acute renal failure in cases of PCP intoxication (4).

Despite its recent emergence, there are only a few reports documenting clinical findings in 3-MeO-PCP abuse. Dissociation, hallucination, and delirium are effects of 3-MeO-PCP, with one report detailing the attempted murder of a user's father while abusing 3-MeO-PCP, methylenedioxypyrovalerone, and butane gas (5). Another study (6) noted that tachycardia and hypertension were common with 3-MeO-PCP. Internet user forums provide many first-person accounts of the effects of different NPSs but most lack methodical histories, physical exam findings, and ancillary testing.

The patient in our case was known to have untreated schizophrenia, and his auditory hallucinations and delusional beliefs could be attributed to his underlying condition. However, the significant confusion and amnesia were likely more a result of acute 3-MeO-PCP intoxication. Tachycardia was present, albeit minimally, and hypertension was not or possibly no longer present. This may reflect the waning of symptoms because it was unclear how much time had elapsed since his last dose. The increased serum CK, while not convincing for massive muscle necrosis, was not entirely unexpected given that PCP abuse is a known risk factor for developing seizures and rhabdomyolysis (4). Perhaps more interesting was the slight increase in troponin that did not peak until 6 h after the second hospitalization. While troponin concentrations may be increased in chronic kidney disease patients without cardiac pathology, our patient had no evidence of renal insufficiency. Increases in cardiac troponin I above the 99th percentile in patients with chronic kidney disease in the absence of acute coronary syndrome have been shown to occur although at a slightly lower frequency compared to troponin T (7). A literature search did not yield any studies linking PCP with myocardial ischemia in humans but a small case series (8) reported peak troponins ranging from 0.08 to 8.07 ng/mL occurring in 5 patients with gacyclidine, a PCP derivative, in their system. Animal models have demonstrated that PCP can alter myocardial calcium ATPase activity (9) and cause lethal ventricular arrhythmias (10). Whether 3-MeO-PCP resulted in direct myocardial toxicity or secondarily via tachycardia and hypertension leading to demand ischemia is unclear. However, it is probable that the rise in troponin was indicative of myocardial injury.

In summary, we have described. the clinical presentation of a young adult male with 3-MeO-PCP intoxication, an NPS that has been the subject of only a limited number of studies (5, 6). This case reinforces how confirmatory testing for drugs of abuse can provide clarity in clinical situations when the toxidrome is uncertain and the issue of false positivity is conspicuous. Mass spectrometry corroborated the initial drug screen and established there was no evidence of tramadol or metabolites, or other serotonergic drugs. It was fortunate that 3-MeO-PCP shares enough structural homology with PCP to trigger a positive screen. The risk that lies ahead is whether future iterations of this drug, or any other NPS, will cross-react with immunoassays. By not ensuring that a mass spectrometry method is available, our dependence on immunoassays could soon prove woefully inadequate and even detrimental to patient care.

QUESTIONS TO CONSIDER

1. Very few drugs of abuse have a specific antidote (e.g., naloxone, N-acetyl-cysteine); however, why is it still clinically relevant to undertake emergent testing for the many that do not?

2. Excluding administrative and technical error, how might one explain a negative GC-MS confirmatory result performed at an outside laboratory on a screen-positive sample that is nonetheless highly likely to be a true positive?

3. Given the proliferation of NPSs where immunoassay kits are unavailable could high throughput mass spectrometry platforms fill the void?

POINTS TO REMEMBER

* Thorough documentation of prescription as well as over-the-counter medications is critical for accurate interpretation of drugs of abuse screening results.

* Most NPSs have not been well characterized in clinical settings and their effects may be quite varied from those of their "parent" drug.

* Features of serotonin syndrome that can overlap with PCP intoxication include altered mental status, tachycardia, hypertension, rhabdomyolysis, and acute renal failure.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

References

(1.) Saitman A, Park HD, Fitzgerald RL. False-positive interferences of common urine drug screen immunoassays: a review. J Analyt Toxicol 2014;38:387-96.

(2.) Sansone RA,Sansone LA.Tramadol: seizures, serotonin syndrome, and coadministered antidepressants. Psychiatry (Edgmont) 2009;6:17-21.

(3.) Kapur S, Seeman P. NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2) receptors-implications for models of schizophrenia. Mol Psychiatry 2002;7:83744.

(4.) Akmal M, Valdin JR, McCarron MM, Massry SG. Rhab domyolysis with and without acute renal failure in patients with phencyclidine intoxication. Am J Nephrol 1981;1:91-6.

(5.) Stevenson R, Tuddenham L. Novel psychoactive substance intoxication resulting inattempted murder. J Forensic Leg Med 2014;25:60 -1.

(6.) Backberg M, Beck O, Helander A. Phencyclidine analog use in Sweden-intoxication cases involving 3-MeO-PCP and 4-MeO-PCP from the STRIDA project. Clin Toxicol (Phila) 2015;53:856-64.

(7.) Abbas NA, John RI, Webb MC, Kempson ME, Potter AN, Price CP, et al. Cardiac troponins and renal function in nondialysis patients with chronic kidney disease. Clin Chem 2005;51:2059-66.

(8.) Chenoweth JA, Gerona RR, Ford JB, Sutter ME, Rose JS, Albertson TE, et al. Altered mental status and end organ damage associated with the use of gacyclidine: a case series. J Med Toxicol 2015;11:115-20.

(9.) Pande M, Cameron JA, Vig PJ, Desaiah D. Phencyclidine block of Ca2+ ATPase in rat heart sarcoplasmic reticulum. Toxicology 1998;129:95-102.

(10.) Davis WM, Hackett RB, Obrosky KW, Waters IW. Factors in the lethality of i.v. phencyclidine in conscious dogs. Gen Pharmacol 1991;22:723-8.

Brian N. Chang [1] and Michael P. Smith [1,2] *

[1] Beaumont Health System, Royal Oak, MI; [2] Oakland University William Beaumont School of Medicine, Rochester Hills, MI.

* Address correspondence to this author at: Beaumont Hospital-Royal Oak, 3601 W13 Mile Rd., Royal Oak, MI 48073. Fax248-551-0557; e-mail Michaelp.smith@beaumont.org.

Received August 3, 2016; accepted September 29, 2016.

DOI: 10.1373/clinchem.2016.264507

[3] Nonstandard abbreviations: CK, creatine kinase; PCP, phencyclidine; 3-MeO- PCP, 3-methoxyphencyclidine; NPS, novel psychoactive substance.

Caption: Fig. 1. (Top), Mass spectrum of the patient sample from a peak eluting at 16.21 min. (Bottom), Reference mass spectrum of 3-MeO-PCP.

Caption: Fig. 2. (Top, left), PCP. (Top, right), 3-MeO-PCP. (Bottom, left), Tramadol. (Bottom, right), Venlafaxine.
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Title Annotation:Clinical Case Study
Author:Chang, Brian N.; Smith, Michael P.
Publication:Clinical Chemistry
Article Type:Clinical report
Date:May 1, 2017
Words:2023
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