Download A Case of Unusual Drug Screening Results

Clinical Case Study
Clinical Chemistry 63:5
958–962 (2017)
A Case of Unusual Drug Screening Results
Brian N. Chang1 and Michael P. Smith1,2*
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 (ⱖ0.20
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
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 W 13 Mile
Rd., Royal Oak, MI 48073. Fax 248-551-0557; e-mail [email protected].
Received August 3, 2016; accepted September 29, 2016.
DOI: 10.1373/clinchem.2016.264507
© 2016 American Association for Clinical Chemistry
3
Nonstandard abbreviations: CK, creatine kinase; PCP, phencyclidine; 3-MeO-PCP, 3-methoxyphencyclidine; NPS, novel psychoactive substance.
958
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?
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.
Clinical Case Study
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.
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
Clinical Chemistry 63:5 (2017) 959
Clinical Case Study
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.
Fig. 2. (Top, left), PCP. (Top, right), 3-MeO-PCP. (Bottom,
left), Tramadol. (Bottom, right), Venlafaxine.
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-HT2 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
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Clinical Chemistry 63:5 (2017)
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 trama-
Clinical Case Study
dol 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.
Author Contributions: All authors confirmed they have contributed to
the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising
the article for intellectual content; and (c) final approval of the published
article.
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;7:837–
44.
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 in attempted murder. J Forensic Leg Med 2014;25:60 –1.
6. Bäckberg 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.
Commentary
Barbarajean Magnani*
Designer drugs can be found worldwide and include
novel psychoactive substances, opioid compounds, benzodiazepines, and cannabinoids. Many of these new
drugs have little or no cross-reactivity with existing immunoassays and may even be difficult to identify with
more sensitive and specific technologies. This clinical
case study illustrates the challenges to clinical hospital
laboratories, and ultimately reference laboratories, in detecting emerging novel synthetic drugs.
Chang and Smith report a case of a patient who
presented with an altered mental status and evidence of
cardiac ischemia. Possible explanations of his symptoms
included the patient’s underlying mental illness, current
prescription medications, or unknown drug toxicity.
Identification and quantification of drugs are critical in
cases for which an antidote is available, for example,
N-acetylcysteine for acetaminophen toxicity, or in cases
for which opioid overdose is suspected and treatment
with naloxone is warranted. However, in most cases of
drug toxicity the patients are managed symptomatically.
Still, information on the causative agent is helpful in
identifying emerging drugs so that early medical intervention, and even social intervention, can be obtained.
Cases with a history consistent with an opioid overdose
that respond to an opioid antagonist but with no traditional opioids detected in the toxicological analysis
should be subjected to further investigation for a novel
compound. In addition, if immunoassay screening results are repeatedly positive for a specific analyte or a class
of drugs and cannot be confirmed by a more specific
analytical method, this should prompt the laboratory to
explore nontraditional drugs. These scenarios could herald the emergence of a designer drug in a particular geographic area.
With presumably hundreds of new compounds
flooding the illicit drug market, the clinical laboratory is
faced with considerable challenges in its efforts to provide
care for patients. Be vigilant of the designer drugs; they
are on our doorstep.
Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, MA.
* Address correspondence to the author at: Tufts Medical Center, 800 Washington St., Box 115,
Boston, MA 02111. Fax 617-636-7128; e-mail [email protected].
Received October 24, 2016; accepted October 27, 2016.
DOI: 10.1373/clinchem.2016.268078
© 2016 American Association for Clinical Chemistry
Author Contributions: All authors confirmed they have contributed to
the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising
the article for intellectual content; and (c) final approval of the published
article.
Clinical Chemistry 63:5 (2017) 961