Counterfeit Alprazolam Poses a 'Major Public Health Threat'

Liam Davenport

August 08, 2016

Counterfeit versions of the benzodiazepine alprazolam (Xanax, Pharmacia and Upjohn) that contain the highly potent opioid fentanyl are being sold online, placing individuals at risk for serious adverse effects and even death, US experts warn.

Ann M. Arens, MD, California Poison Control System–San Francisco Division, California, and colleagues report eight cases in which individuals who ingested the tablets, some of which also contained the benzodiazepine etizolam, experienced central nervous system (CNS) depression and cardiovascular effects.

Fentanyl is approved by the US Food and Drug Administration for the treatment of severe pain and is commonly used by cancer patients. However, even very small amounts of the drug can cause rapid and profound respiratory depression, with a maximum effect attained within just 2 minutes.

"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," write the authors of a research letter published online August 8 in JAMA Internal Medicine.

Pill Molds Available Online

The researchers report cases involving eight individuals who were identified by the California Poison Control System–San Francisco Division between October and December 2015 as suffering from adverse effects associated with the ingestion of counterfeit alprazolam.

The individuals ranged in age from 8 months to 45 years. The most common feature at presentation was CNS depression. Cardiovascular manifestations developed in four patients. The majority recovered within 24 hours.

One patient with biventricular heart failure recovered after 5 days, and one patient who presented after cardiac arrest recovered after 2 days.

The researchers describe two index cases involving a man in his late 20s and a woman in her late 30s who were taken to the emergency department after ingesting illegally purchased, counterfeit alprazolam. A third individual was found dead at the same location where these two patients were found.

Both patients experienced demand cardiac ischemia, rhabdomyolysis, and compression neuropathy after using alcohol and cocaine and taking a counterfeit alprazolam tablet. The individuals experienced unusually prolonged sedation and awoke with unilateral weakness and paresthesia, the investigators report.

Liquid chromatography high-resolution mass spectrometry demonstrated serum fentanyl concentrations of 1.6 ng/mL in one patient and 0.61 ng/mL in the other. The first patient was found to have a serum etizolam concentration of 0.60 ng/mL. Postmortem urge and blood samples of the deceased individual contained fentanyl.

In the other individuals, serum fentanyl concentrations ranged from 0.15 mg/mL to 1.4 mg/mL. Three patients had serum etizolam concentrations of 0.26 to 55 ng/mL. In one individual, the serum alprazolam concentration was 101 ng/mL.

The researchers note that etizolam, which is not approved for use in the United States, is a benzodiazepine analogue that has been implicated in deaths from overdose. It can be bought online, which may allow its easy incorporation into counterfeit alprazolam.

"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," they add.

Intentional Poisoning?

In an accompanying commentary, Traci C. Green, PhD, Department of Emergency Medicine, Boston University School of Medicine, Massachusetts, and Michael Gilbert, MPH, Epidemico Inc, Boston, say that the cases form part of a wider outbreak of illicit fentanyl, which represents "a major public health threat."

They add that the authors "should be commended" for warning the public and attempting to prevent further harm.

However, they question the hypothesis put forward by Dr Arens and colleagues as to why fentanyl would be incorporated into a counterfeit alprazolam tablet, namely, that it may "indicate the desire for a product with a faster, more potent high."

The editorialists instead suggest that that there are several "more plausible" hypotheses for why the highly potent pills could have been created, such as by malice to "intentionally poison consumers or attract the attention of law enforcement to redistributors."

In their opinion, a "leading hypothesis" is that the pills were created by accident, owing to the "challenge of maintaining high levels of quality control in clandestine laboratories." Another possibility, albeit unlikely, is that of obfuscation, inasmuch as the criminal penalties in California for trafficking Schedule IV substances such as alprazolam are less severe than those for trafficking fentanyl.

Finally, the tablets may have been manufactured in this way through economic considerations, because fentanyl "is less expensive and easier to manufacture than heroin, and smaller, potent amounts reduce suppliers' transportation costs." In addition, local competition and law enforcement interventions that affected drug supply may have driven innovation.

The authors of the commentary also note that although the research letter underlines the "importance of public health surveillance of emerging drugs," it also underscores the "inadequacy of our current approaches," in that detection requires exposure at levels that almost cause death.

Calling for a "far more aggressive and strategic expansion of evidence-based interventions in geographic areas heavily affected by heroin and fentanyl," the editorialists note that drug checking services, such as those in many European countries, could "spare lives, detect trends earlier, and influence product safety.

"The Office of National Drug Control and Policy has provided leadership in supporting closer public health and public safety collaborations to address recent surges in heroin use.

"Similar oversight, direction, and coordination are needed to expedite implementation of responses and to navigate local, state, and federal opportunities and tensions around these new approaches."

The authors of the research letter have disclosed no relevant financial relationships. Dr Green is supported by a grant from the Agency for Healthcare Research and Quality and a grant from the National Institute on Drug Abuse and has been employed during the past 3 years by Inflexxion Inc. Michael Gilbert has disclosed no relevant financial relationsh0ps.

JAMA Intern Med. Published online August 8, 2016. Abstract, Commentary

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