Episode 018 — Veterinary tranquilizers and sea voyages

Posted in: Physiology Posted on

Episode 18 covers opioids and opiates: nomenclature, potency, mechanisms, rare but high yield adverse effects, as well as reversal agents. We also explore the world’s most common toxin-related seafood poisoning and the “Lake Wobegon effect” for EBM.

General background

  • Fentanyl → remember the difference between OPIATE and OPIOID (opioids are the broader group)
    • Drug screen tie-in → fentanyl is not detected on routine drug screens
      • enzyme immunoassay [routine/firstline] vs gas chromatograph [$$$ + often offsite]
      • Interestingly, fentanyl appears to cause a positive result on many immunochemistry LSD screens [1]
    • Mechanism of death in opioid overdose? Respiratory depression.
    • Fentanyl & Naloxone pearls (see articles way below on flash pulmonary edema and chest wall rigidity)
    • Carfentanil is 10,000 times more potent than morphine & 100 times more potent than fentanyl

Naloxone and harms?

On very rare occasions it seems that naloxone might be harmful, but otherwise has generally been considered safe (given the indications for which it is used) since the 1990s. Here is a case report of naloxone causing two sudden deaths (link to PDF) … as we mentioned during the clinical pearls discussion on naloxone and pulmonary edema, it’s been suggested that naloxone might just be unmasking existing edema that resulted from a reaction to the opioid. Naloxone increases respiratory rate (when the opioid is antagonized) and causes a catecholamine surge, which could both exacerbate the edema or at least make it more apparent.

Is there an overdose so large that naloxone can’t reverse it?

“Massive OxyContin Ingestion Refractory to Naloxone Therapy.” Ann Emerg Med. 2002.

After a brief, witnessed, generalized convulsion, paramedics arrived to find a 45-year-old woman lying on the ground with a nearly full bottle containing OxyContin. She was cyanotic with RR of 6, pinpoint pupils, and had frequent PVCs. Two mg of naloxone were administered IV, with full reversal of LOC, hypoventilation, and miosis. She told the paramedics that she had ingested a handful of OxyContin in a suicide attempt…

On arrival to the emergency department, the patient was alert and oriented and denied ingesting other medications. Vital signs were BP 90/60, HR 90, RR 18, T 97.8, and pulse oximetry 88% ORA. Her physical examination was remarkable for the presence of symmetric crackles at both lung bases, the absence of needle track marks, and a normal neurologic examination. Initial radiography revealed a normal heart size with the presence of pulmonary edema. The ECG results were normal.

Unfortunately, the bottle of OxyContin was left near her bedside, and approximately 20 minutes after arrival, she ingested the remaining contents. The bottle originally contained 100 pills, each containing 40 mg of OxyContin (total of 4,000 mg).

Over the course of slightly less than 11 hours in the ED, she received a total of 188 mg of intravenous naloxone. Given both bolus and GTT naloxone; intubated when 24mg/hr GTT proved insufficient.

“Controversies and carfentanil: We have much to learn about the present state of opioid poisoning.” Am J Emerg Med. 2017. https://www.ajemjournal.com/article/S0735-6757(17)30694-0/fulltext 

“Carfentanil is extremely potent; commercially produced carfentanil (Wildnil®) is used by veterinarians in doses ranging from 1 to 13 mg to immobilize large animals such as African elephants…”

“The sole, and best defined, symptomatic human occupational exposure 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. Within 2 min the patient became nauseated, sedate (Glasgow Coma Scale 12), and hypotensive. 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 occurred 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) into the theater incapacitating nearly all inside. Despite the facts that carfentanil was weaponized to maximize absorption and naloxone was unavailable for hours, only 15% of the hostages died.”

“Fatal fentanyl: one pill can kill.” Academic Emergency Medicine. 2017. https://onlinelibrary.wiley.com/doi/full/10.1111/acem.13034 

“We have identified an outbreak of exaggerated opioid toxicity caused by fentanyl adulterated tablets purchased on the street as hydrocodone/acetaminophen.”

Fentanyl ~30% bioavailable.

Reported post-mortem serum concentrations in other studies vary from 5-120 ng/mL (mean of 36 ng/mL)

Most pills recovered varied from 5000 – 6900 µg/each of fentanyl → these could achieve ~500 ng/mL

  • 1 patient ultimately died (12 minutes after arriving at ED; 3mg narc bolus)
    • Patient’s UDS → (+) for:
      • Amphetamine, Fentanyl, Hydrocodone, Norfentanyl, Promethazine
    • Urine fentanyl concentration: 6,800 ng/mL
  • 5 patients needed CPR
  • 1 patient required extracorporeal life support
  • 3 patients required intubation
  • 2 received bag-valve-mask ventilation.
  • 1 patient had recurrence of toxicity after 8 hours after naloxone discontinuation.
  • 17 of 18 patients required boluses of naloxone, and four required naloxone infusions of 26–39 hrs
    • Patient “#6” → fentanyl concentration → serum 162 ng/mL → urine 34,000 ng/mL

“The Pharmacokinetics and Pharmacodynamics of Carfentanil After Recreational Exposure: A Case Report.” Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 2018. https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/phar.2117

  • First published ‘real world’ study of the halflife of carfentanyl → they find it to be ~6 hours

A 34-year-old, 87-kg male was admitted to hospital after being found down and bradypnic by emergency medical services (EMS) shortly after 3 AM. His friend recounted to EMS that they had just insufflated a white powder and then the patient became blue and stopped breathing.

The patient was intubated and required mechanically-assisted ventilation for 31 hours until he was able to breathe safely on his own. Pharmacokinetic modeling of 3 timed blood samples identified the elimination half-life as 5.7 hours for carfentanil and 11.8 hours for the norcarfentanil metabolite. Awakening and breathing spontaneously corresponded to an interpolated blood carfentanil concentration of 0.52 ng/mL.

“Naloxone dosage for opioid reversal: current evidence and clinical implications.” Ther Adv Drug Safety. 2017. https://journals.sagepub.com/doi/full/10.1177/2042098617744161

  • Really nice review paper with lots of technical details → 200 citations!

“Due to its high lipophilicity, fentanyl rapidly equilibrates between the plasma and the cerebrospinal fluid, leading to a fast onset of both analgesia and respiratory depression, while this same property results in extensive redistribution to less highly perfused tissues such that fentanyl is typically considered a very short-acting opioid when given IV; however, its duration of action is prolonged by large doses that progressively saturate these tissues, and delayed respiratory depression may even be seen.”

“The duration of reversal of opioid-induced respiratory depression is brief and dependent upon the dose and potency of the opioid given, as well as the amount of naloxone administered. In healthy volunteers, a 0.4 mg IV dose of naloxone reversed the sedation induced by morphine 0.3–0.6 mg/kg within 2 min of administration, but the subjects began to feel the effects of the morphine again after 15–30 min and returned to the pre-naloxone level of sedation within 45 min. Surgical patients receiving high-dose morphine required additional doses of IV naloxone anywhere from 30 min to 90 min after initial reversal.”

“Naloxone in opioid poisoning: walking the tightrope.” Emerg Med J. 2005. https://emj.bmj.com/content/emermed/22/9/612.full.pdf

“Ordering Five Million Deaths Online.” New York Times. 2018. https://www.nytimes.com/2018/04/04/opinion/carfentanil-fentanyl-opioid-crisis.html

…in my ‘brown paper packages wrapped up with strings’ comments I was kidding around, but also hinting at a massive problem that has no present solution: fentanyl smuggling. When carfentanyl is 10,000x as potent as morphine, the equivalent of 10 kilos of heroin is a single gram of carfentanyl. It’s certainly a lot harder to catch envelopes and small packages used for smuggling than it would be to catch shipping containers filled with drugs. The above article is from a psychiatrist at Cornell and discusses the ease of ordering carfentanyl online.

Vocab

A 43 year old man presents to your emergency department. He returned yesterday from Barracuda fishing in Cancun. On the final day of his trip he caught a 21 pound Barracuda, which he and his friends cooked thoroughly and then consumed that evening. He reports experiencing diarrhea a few hours later. Today he complains of paresthesias, allodynia, asthenia, and temperature dysesthesia. His illness is most likely caused by:

  1. Dinoflagellate spp.
  2. Vibrio spp.
  3. Scombroid spp.
  4. Yersinia spp.
  5. Aeromonas spp.

What is the most frequently reported seafood-toxin illness in the world? Ciguatera poisoning.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367029/ (good review article)

https://jnnp.bmj.com/content/70/1/4 — Neurology of ciguatera

Pearn, J. (1994). AROUND THE RIM: THE ROLE OF SURGEONS IN DISCOVERY AND RESEARCH IN THE PACIFIC RIM. PART I. SURGEONS IN THE PACIFIC: EXPEDITIONERS AND EXPEDITION LEADERS. ANZ Journal of Surgery, 64(1), 38–44. doi:10.1111/j.1445-2197.1994.tb02131.x

“Resolution sailed on to the central Pacific where Anderson described a peculiar form of fish poisoning which occurred among the ship’s crew; a poisoning that we now know as an endemic problem in Australia and the entire Pacific, the enigmatic condition of ciguatera.’~ His description of that condition, with its unpleasant skin tingling, reversal of tactile heat sensation and nausea, remains one of the classic descriptions of the disease.“

Anderson, W. (1776). An Account of Some Poisonous Fish in The South Seas. In a Letter to Sir John Pringle, Bart. P. R. S. from Mr. William Anderson, Late Surgeon’s Mate on Board His Majesty’s Ship the Resolution, Now Surgeon of That Ship. Philosophical Transactions of the Royal Society of London, 66(0), 544–574. doi:10.1098/rstl.1776.0038 → https://royalsocietypublishing.org/doi/pdf/10.1098/rstl.1776.0038 ← PDF

Scombroid poisoning → https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314039/

Clinical Pearls

Fentanyl and chest wall rigidity → https://www.ncbi.nlm.nih.gov/pubmed/22561320 (infant low dose case reports)

  • Reverse with naloxone (Rosen says often doesn’t work) or use neuromuscular blocker

Naloxone, opioids, and flash pulmonary edema

EBM

Lake Wobegon effect → Vickers, et al. Annals of Internal Medicine. 2015. https://annals.org/aim/article-abstract/2246123/lake-wobegon-effect-why-most-patients-below-average-risk

 

— Episode credits —

Hosted by Addie, Kim, and Alex. Audio production and editing by Addie. Show notes written by Addie. Theme music (Too Cool, and Laserpack) by Kevin MacLeod of incompetech.com, licensed under Creative Commons: By Attribution 3.0 License.