Article

Controversies and carfentanil: We have much to learn about the present state of opioid poisoning

Unlabelled imageAmerican Journal of Emergency Medicine 35 (2017) 1743-1745

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American Journal of Emergency Medicine

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Controversy

Controversies and carfentanil: We have much to learn about the present state of opioid poisoning

Jon B. Cole, MDa,?, Lewis S. Nelson, MDb

a Minnesota Poison Control System, Department of Emergency Medicine, Hennepin County Medical Center, University of Minnesota Medical School, Minneapolis, MN, United States

b Department of Emergency Medicine, Division of Medical Toxicology, Rutgers New Jersey Medical School, New Jersey Poison Information & Education System, Newark, NJ, United States

A R T I C L E I N F O

Article history:

Received 29 June 2017

Received in revised form 10 August 2017

Accepted 19 August 2017

Keywords:

Carfentanil Naloxone opioid overdose Ems

law enforcement

  1. Introduction

Over the last 30 years North America has witnessed a tremendous rise in prescription Opioid abuse, addiction, overdose, and death [1]. It is now clear that this was in large part an iatrogenic epidemic with a multifaceted etiology with contributions made from nearly every spe- cialty in medicine [2-6]. In response, the medical establishment moved to reduce opioid prescribing, create abuse deterrent formula- tions, implement Prescription Drug Monitoring Programs, and expand access to medication-assisted therapy, all with limited success. Simulta- neously, the falling price and increasing purity of heroin and the re- duced availability and high cost of Prescription opioids caused some with prescription Opioid use disorder to transition to heroin [7].

The rise in heroin use in the late 2000?s occurred at a time when other synthetic psychoactive agents, such as Synthetic cannabinoids and cathinones (amphetamine-like compounds), were gaining national prominence [8]. These drugs were synthesized overseas in abundance and imported cheaply and covertly. Following a similar pattern, fenta- nyl, a synthetic opioid with 50 times the potency of heroin that had pre- viously been abused most commonly as a result of repurposed pharmaceuticals, began appearing in the U.S. heroin supply. Deaths

? Sources of support: none.Prior presentations: none.

* Corresponding author at: 701 Park Ave, Mail Code: RL.240, Minneapolis, MN 55415, United States.

E-mail addresses: [email protected], @jonbcole2 (J.B. Cole).

from non-pharmaceutical fentanyl skyrocketed in 2013 and have con- tinued to rise [9]. Subsequently in 2015, fentanyl analogues, such as acetylfentanyl [10], butyrfentanyl [11], and furanylfentanyl [12] began to replace fentanyl and similarly capitalize on loopholes in our drug laws. As with cathinones and cannabinoids, subtle changes in the mo- lecular structure allowed these analogues to circumvent federal con- trolled substance rules, and to be “not illegal” for a brief period of time.

  1. Carfentanil background

Among the fentanyl analogues of greatest concern is carfentanil. Carfentanil is approximately 10,000 times more potent than morphine and 100 times more potent than fentanyl [13]. In July of 2016 an inves- tigation in Cincinnati, Ohio, into a sudden increase in the number of suspected heroin overdoses identified the adulteration of the local her- oin supply with carfentanil, marking its first appearance in the North American heroin supply. Carfentanil has subsequently been detected in Minneapolis, Chicago, New York, Vancouver, and numerous other cit- ies. While other brief fentanyl analogue micro-epidemics have occurred in the past [14], carfentanil’s widespread appearance in the U.S. raises many important law enforcement, patient-level, and public health is- sues, including risks to emergency personnel [15]. Though carfentanil represents the most current threat in the opioid epidemic, introduction of any new ultra-potent opioid to the U.S. heroin supply will raise sim- ilar questions in the future.

Pharmacology of Carfentanil

Carfentanil is extremely potent; commercially produced carfentanil (Wildnil(R)) is used by veterinarians in doses ranging from 1 to 13 mg to immobilize large animals such as African elephants [16]. Regardless of potency, death from any opioid ostensibly occurs for mostly one rea- son: dose-related apnea. Though it may initially appear to be more le- thal than familiar opioids, carfentanil, assuming it is dosed properly, may actually produce less apnea. The therapeutic index (TI) of a drug, which represents the median lethal dose (LD50) divided by the median lowest effective dose (ED50), is higher for carfentanil (10,000) than for morphine (70) or fentanyl (300) [13]. Carfentanil’s contribution to the continuing rise in opioid deaths in the U.S. is better explained by uncon- trolled dosing resulting in massive overdose, than by the potency of the drug itself. It is intriguing to consider that as illicit opioid distributors learn to integrate potency data into their wares, the risk of overdose

http://dx.doi.org/10.1016/j.ajem.2017.08.045

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1744 J.B. Cole, L.S. Nelson / American Journal of Emergency Medicine 35 (2017) 17431745

may return to previous, though still high, levels. Regardless, a case fatal- ity rate for carfentanil is nearly impossible to determine because the exact prevalence and concentration at any given time is uncertain and sufficient analytical testing capabilities are not widely available.

Human Carfentanil exposures

The sole, and best defined, symptomatic human occupational expo- sure involves a veterinarian who was splashed in the eyes and mouth while pulling from a tree a misfired dart containing 1.5 mg of carfentanil originally intended to sedate an elk [17]. Within 2 min the patient be- came nauseated, sedate (Glasgow Coma Scale 12), and hypotensive [18]. After receiving 100 mg of intramuscular naltrexone (also originally intended for the elk), the patient returned to baseline and was safely discharged after 24 h of observation.

Perhaps the most noteworthy human carfentanil exposures oc- curred in October 2002 after nearly 800 people were taken hostage in a Moscow theater. In response, the Russian military released a “gas” (later confirmed to be carfentanil) [19] into the theater incapacitating nearly all inside [13]. Despite the facts that carfentanil was weaponized to maximize absorption and naloxone was unavailable for hours, only 15% of the hostages died [13].

Carfentanil and naloxone dosing

Because of carfentanil’s potency it has been suggested that unusually Large doses of naloxone may be required to reverse carfentanil intoxica- tion [20]; animal data suggest otherwise. Elk immobilized with carfentanil dosed at 10 mcg/kg rapidly improved within 5 min when naloxone was administered in a 2:1 naloxone: carfentanil ratio [21], suggesting familiar naloxone doses may still be adequate in all but the largest exposures. Supporting this, patients poisoned with hydrocodone tablets, surreptitiously containing up to 6.9 mg of fentanyl were report- ed to have “required” higher doses of naloxone [22], however the medi- an naloxone bolus dose prior to beginning an infusion was 2 mg with the largest dose being 8 mg [22]. These data are consistent with the known potency of naloxone; 13 mcg/kg of IV naloxone occupy 50% of available human Opioid receptors [23]. Though the FDA has recently de- bated the proper initial bolus dose of naloxone for prescriptions and Public health programs [24], data suggest currently available doses of naloxone should be effective to achieve the desired outcome of restor- ing some, even minimal, respiratory effort. While lay media and sec- ond-hand reports of carfentanil overdoses have suggested large doses of naloxone are required to reverse carfentanil poisoning [20], the med- ical literature currently has only two published overdoses of carfentanil followed by pharmacologic reversal; the veterinarian described above, and a recreational overdose where the dose of naloxone was not report- ed [25]. Regardless, neither complete reversal of the opioid’s effects nor precipitation of Opioid withdrawal are necessary or desired outcomes; restoration of ventilation should be the goal. Doses of naloxone may be escalated as needed to a total dose of 10; if such a dose is reached with no response, a definitive airway should be established [26,27]. Ul- timately, proper support of Ventilation and oxygenation, such as with a bag-valve mask, should take precedence over naloxone at any dose.

  1. Duration of observation after naloxone reversal

Though older literature written prior to the frequent adulteration of heroin with ultra-potent opioids suggests it may be safe to discharge pa- tients from the ED after 1 h of observation following naloxone reversal [28], this guideline may no longer apply [29]. Though multiple studies exist documenting an extremely low mortality risk for patients rapidly discharged from the emergency department after naloxone reversal [30,31], these studies contain multiple flaws. Many of these studies are retrospective [30-32], and used mortality identified by medical ex- aminer records as a primary outcome [30,31]. Such studies may not

only miss deaths that occurred outside the local Medical Examiner‘s ju- risdiction, they do not account for patients that suffer non-lethal but still serious consequences from other adverse events such as opioid-induced pulmonary edema or recurrent intoxication resulting in hypoxia and subsequent Anoxic brain injury. One study developed a clinical decision rule based on prospective data collected after one hour of emergency department observation that allowed for safe discharge of ambulatory, properly oriented heroin overdose patients with normal vital signs at one hour [33], however this rule was never validated [34]. Perhaps the greatest flaws in these studies, however, are that they studied only pa- tients with heroin overdose, and were conducted during a time when heroin adulteration with Synthetic opioids was infrequent or even non- existent. Heroin is now frequently adulterated with synthetic opioids such as fentanyl analogues [35], making drug kinetics unpredictable and thus older literature on heroin obsolete. For instance, prolonged naloxone infusions of over 24 h were required in 4 of the 18 patients poisoned with the concentrated fentanyl pills discussed in Section 2.3, including one patient who suffered a respiratory arrest after being off naloxone for 8 h. These data suggest that it is the duration of observation after naloxone reversal that may need evaluation as much or more than the “wake up” initial bolus dose. Extended emergency department ob- servation (e.g. 4 h) after naloxone reversal is recommended if larger than standard doses are administered (e.g., greater than 0.4 mg) until the natural history of ultra-potent opioid poisoning is better understood to ensure a large bolus dose of naloxone does not mask recurrent opioid toxicity until after the patient is discharged from the emergency depart- ment [26].

This longer period of observation may lead to both ethical and legal issues as patients frequently desire to leave the Emergency Department shortly or immediately after naloxone reversal. The patient’s desire for autonomy must be balanced against the goal of beneficence for the patient’s future (e.g. knowing naloxone has a limited duration of effect in the event a longer-acting opioid is suspected); assessing the patient’s decisional capacity is critical in balancing these occasionally competing principles. Complicating matters further, the ability of physicians to place mental health holds on patients varies substantially from state to state [36]. Though most states allow physicians to involuntarily hold a patient for 48-72 h, in some states, such as Wisconsin, law en- forcement or a psychiatrist, rather than emergency physicians, must place involuntary holds [37]. Becoming knowledgeable of local laws re- garding emergency holds along with coordination with institutional risk management and legal counsel is recommended to ensure patient safety in a legal manner while maximally respecting autonomy. In the event a patient is deemed to have decisional capacity and is not holdable, clear instructions to return to the Emergency Department should be given if symptoms of recurrent intoxication or pulmonary edema occur, and the patient should ideally be discharged in the com- pany of a sober, competent adult. Offering an outpatient naloxone pre- scription is also recommended.

  1. Safety of law enforcement and emergency medical services

Concern exists regarding the safety of law enforcement and emer- gency medical providers if inadvertent exposures to ultra-potent opi- oids occur from field environments or secondary contamination from patients. Lay-media reports even describe law enforcement receiving naloxone for symptoms following trivial skin and mucous membrane exposures [38]. Recent DEA guidance instructs agents that mucosal or dermal absorption of fentanyl could be rapidly fatal [15]. Though this DEA roll call video contains testimonials from two officers suffering symptoms after a powdered Fentanyl exposure, the symptoms de- scribed are inconsistent with opioid poisoning and no confirmatory an- alytical testing was available. The evidence, both real-world and foundational, suggests the concept of environmental or occupational opioid poisoning should be treated with healthy skepticism (see Table 1). Existing pharmacokinetic and clinical data do not suggest

J.B. Cole, L.S. Nelson / American Journal of Emergency Medicine 35 (2017) 17431745 1745

Table 1

Prehospital & law enforcement concerns regarding ultra-potent opioids.

Concern Rationale for skepticism

Inhalational route of exposure Powdered drugs are solids with no

vapor pressure; dispersion of drug is required to make particles briefly airborne. Aerosolization, as in Russia, requires a deliberate event.

Dermal absorption Dermal absorption requires solubilized drug and permeation enhancers to reach concerning Blood concentrations,

and rates of absorption are slow.

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Opioid poisoning from scenes with powdered opioids

Canines poisoned and revived with naloxone may be a harbinger of human poisoning.

Descriptions of “poisoning” from drug powder in the air or from brushing powder off clothes

Users and dealers do not suffer significant poisoning from ambient exposure despite daily encounters. Unlike humans, dogs place noses extremely close to objects they smell; dogs also lick their noses after smelling. Symptoms described from testimonials in law enforcement videos are not consistent with opioid poisoning and no cases are publicly available with empiric data such as vital signs or drug concentrations. Response to naloxone may be non-pharmacological and due to noxious effects of insufflation or injection. Law enforcement may have experienced psychogenic effects.

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any risk from ambient dermal exposure, and it is unquestionable that both Drug users and sellers contact the product on a regular basis with- out apparent harm [39]. Nevertheless, until more detail about environ- mental risks are available, including case data such as vital signs and blood drug concentrations, modest Personal protective equipment such as gloves and masks seem wholly rational.

  1. Summary

The emergence of carfentanil in the U.S. heroin supply signals a new era in opioid abuse. Until more data emerge, titrated pharmacologic nal- oxone doses with a focus on restoration of normal respiration with bag- valve mask ventilation should be the mainstay of therapy, while longer ED observation periods may be needed. Similarly, until more data are collected regarding occupational and environmental exposure to fenta- nyl analogues, a cautious approach with sensible use of standard PPE should be utilized. For the foreseeable future emergency physicians, EMS personnel, epidemiologists, law enforcement, and even drug dealers, should no longer think about heroin, fentanyl, carfentanil, or any specific opioid overdose; rather they will need to consider all issues under the generic rubric of “opioid overdose,” forcing us to each learn new tactics even as we approach a decades old problem.

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