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Figure.  Counterfeit Alprazolam (Xanax) Tablet Compared With Brand-name Xanax Tablet
Counterfeit Alprazolam (Xanax) Tablet Compared With Brand-name Xanax Tablet

A, Counterfeit alprazolam tablet containing 3.4 mg of fentanyl and 10.6 µg of etizolam. B, Brand-name 2-mg Xanax tablet (Pfizer). Image reprinted with permission from https://www.drugs.com.

Table.  Survivors Exposed to Counterfeit Alprazolam Products in the San Francisco Bay Area
Survivors Exposed to Counterfeit Alprazolam Products in the San Francisco Bay Area
1.
Thoren  KL, Colby  JM, Shugarts  SB, Wu  AH, Lynch  KL.  Comparison of information-dependent acquisition on a tandem quadrupole TOF vs a triple quadrupole linear ion trap mass spectrometer for broad-spectrum drug screening.  Clin Chem. 2016;62(1):170-178.PubMedGoogle ScholarCrossref
2.
Peng  PW, Sandler  AN.  A review of the use of fentanyl analgesia in the management of acute pain in adults.  Anesthesiology. 1999;90(2):576-599.PubMedGoogle ScholarCrossref
3.
O’Connell  CW, Sadler  CA, Tolia  VM, Ly  BT, Saitman  AM, Fitzgerald  RL.  Overdose of etizolam: the abuse and rise of a benzodiazepine analog.  Ann Emerg Med. 2015;65(4):465-466.PubMedGoogle ScholarCrossref
4.
Chow  SL, Houseman  D, Phung  T, French  WJ.  Transient acute decompensated heart failure following propofol and fentanyl administration in a healthy 19-year-old patient.  Congest Heart Fail. 2010;16(2):80-81.PubMedGoogle ScholarCrossref
Research Letter
October 2016

Adverse Effects From Counterfeit Alprazolam Tablets

Author Affiliations
  • 1Department of Emergency Medicine, University of California–San Francisco
  • 2California Poison Control System–San Francisco Division
  • 3Department of Laboratory Medicine, University of California–San Francisco
JAMA Intern Med. 2016;176(10):1554-1555. doi:10.1001/jamainternmed.2016.4306

From October 15 to December 31, 2015, the California Poison Control System–San Francisco division identified 8 patients who experienced adverse effects associated with the ingestion of counterfeit alprazolam tablets found to contain fentanyl and, in some cases, etizolam. The identification of these patients resulted in a coordinated response that included state and local public health departments, a toxicology laboratory, and media outlets, and resulted in an investigation by local law enforcement agencies.

Report of Cases

A man in his late 20s and a woman in her late 30s (patients 1 and 2, respectively) (Table) were transported to the emergency department after ingesting illegally purchased tablets that were purportedly alprazolam. A third individual was found deceased at the same location as the first 2 patients. Both patients experienced unusually prolonged sedation and awoke with unilateral weakness and paresthesias. The neurologic manifestations in patient 1 were distal to his left elbow, while those in patient 2 were in her right lower extremity. Laboratory test results for patient 1 were significant for leukocytosis (white blood cell count, 30 000/µL [to convert to  × 109/L, multiply by 0.001]), acute renal insufficiency (creatinine level, 1.68 mg/dL [to convert to micromoles per liter, multiply by 88.4]), and undetectable serum ethanol. Results of the complete blood cell count and chemistry panel for patient 2 were normal, and her serum ethanol concentration was 68 mg/dL (to convert to millimoles per liter, multiply by 0.2171). Patients 1 and 2 had rhabdomyolysis (creatine kinase level, 1012 and 354 U/L, respectively [to convert to microkatals per liter, multiply by 0.0167]) and elevation of aspartate aminotransferase (528 and 120 UL, respectively [to convert to microkatals per liter, multiply by 0.0167]) and alanine aminotransferase levels (683 and 64 U/L, respectively [to convert to microkatals per liter, multiply by 0.0167]), with normal hepatic function. Compression neuropathy was diagnosed in both patients after results of magnetic resonance imaging studies were unremarkable. Patients 1 and 2 were also diagnosed with demand cardiac ischemia with peak troponin levels of 4.62 and 1.43 ng/mL, respectively (to convert to micrograms per liter, multiply by 1.0). The patients’ symptoms improved within 24 hours. During the following 2 months, 6 additional patients presented to the emergency department after exposure to counterfeit alprazolam tablets.

This study was exempt from approval by the University of California–San Francisco institutional review board. As no patient identifiers were included, informed consent was waived by the University of California–San Francisco institutional review board.

Results

The Table summarizes the demographic data, clinical characteristics, and laboratory test results of the patients exposed to counterfeit alprazolam. Their ages ranged from 8 months to 45 years, and central nervous system depression was the most common feature at presentation. Four patients developed cardiovascular manifestations and most recovered within 24 hours. Patient 3, who developed biventricular heart failure, recovered after 5 days, while patient 8, who presented after cardiac arrest, recovered after 2 days.

Using a liquid chromatography high-resolution mass spectrometry (5600 QTOF MS; AB Sciex) method previously described,1 fentanyl, norfentanyl, and etizolam were identified in the index cases. Serum fentanyl concentrations were 1.6 ng/mL in patient 1 and 0.61 ng/mL in patient 2. Analgesic serum concentrations of fentanyl range from 0.6 to 3.0 ng/mL.2 Patient 1 also had a serum etizolam concentration of 0.60 ng/mL (peak serum concentration after therapeutic dosing, 9.3 ng/mL).3 The fatal case at the scene of the first incident was investigated by the San Francisco Office of the Chief Medical Examiner (N. P. Lemos, PhD, H. S. Narula, MD, X. van Wijk, PhD, K. Lynch, PhD, A. H. B. Wu, PhD, K. Vo, MD, A. Arens, MD; and C. Smollin, MD, unpublished data, March 2016). Postmortem urine and blood samples contained fentanyl. Analysis of a tablet (Figure) in the possession of patient 3 revealed 3.4 mg of fentanyl and 10.6 µg of etizolam.

Discussion

Fentanyl is a synthetic opioid with rapid onset of action and the potential to produce significant depression of the central nervous system and respiratory system.2 Toxic cardiovascular effects have been previously described with the intravenous administration of fentanyl.4 Its incorporation into a counterfeit product may indicate the desire for a product with a faster, more potent high. Etizolam is a benzodiazepine analogue implicated in overdose deaths and is not approved for use in the United States.3 Etizolam can be purchased online, which may allow for easy incorporation into a counterfeit product.3 It is unclear how these alprazolam tablets were manufactured; however, pill press molds with the characteristics seen on the recovered tablets are available for purchase online.5

This case series represents a burgeoning public health threat. Clinicians should be aware of the potential for further outbreaks and serious toxic effects associated with counterfeit prescription medications.

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Article Information

Corresponding Author: Ann M. Arens, MD, California Poison Control Center, 2789 25th St, San Francisco, CA 94110 (annie.m.arens@gmail.com).

Published Online: August 8, 2016. doi:10.1001/jamainternmed.2016.4306

Author Contributions: Dr Arens had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Arens, Wu, Smollin.

Acquisition, analysis, or interpretation of data: VanWijk, Vo, Lynch, Wu, Smollin.

Drafting of the manuscript: Arens, van Wijk, Vo.

Critical revision of the manuscript for important intellectual content: Arens, van Wijk, Vo, Lynch, Wu, Smollin.

Administrative, technical, or material support: Arens, Lynch, Wu, Smollin.

Study supervision: Arens, Lynch, Wu, Smollin.

Conflict of Interest Disclosures: None reported.

Additional Contributions: Roy Gerona, PhD, and the laboratory staff at the University of California–San Francisco, as well as the clinical laboratory staff at Zuckerberg San Francisco General Hospital and Trauma Center, performed the rapid clinical laboratory analysis of these cases. They were not compensated for their contributions.

References
1.
Thoren  KL, Colby  JM, Shugarts  SB, Wu  AH, Lynch  KL.  Comparison of information-dependent acquisition on a tandem quadrupole TOF vs a triple quadrupole linear ion trap mass spectrometer for broad-spectrum drug screening.  Clin Chem. 2016;62(1):170-178.PubMedGoogle ScholarCrossref
2.
Peng  PW, Sandler  AN.  A review of the use of fentanyl analgesia in the management of acute pain in adults.  Anesthesiology. 1999;90(2):576-599.PubMedGoogle ScholarCrossref
3.
O’Connell  CW, Sadler  CA, Tolia  VM, Ly  BT, Saitman  AM, Fitzgerald  RL.  Overdose of etizolam: the abuse and rise of a benzodiazepine analog.  Ann Emerg Med. 2015;65(4):465-466.PubMedGoogle ScholarCrossref
4.
Chow  SL, Houseman  D, Phung  T, French  WJ.  Transient acute decompensated heart failure following propofol and fentanyl administration in a healthy 19-year-old patient.  Congest Heart Fail. 2010;16(2):80-81.PubMedGoogle ScholarCrossref
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