Cyanide Wishes and Thallium Dreams!
Howard – The story of the year? The Tox and The Hound! Toxicology’s foray into the world of FOAM has had an auspicious start. I am obviously biased, but I think that we have a phenomenal team and have put forth some outstanding content. From toxicology·fundamentals, to the classics (including many·things·alcohol·related), new·dangers and very·bad·poisons, something for the Fellows, and even a little controversy·now·and·again, we’ve had a wild ride. We even have pediatricians! 😉
But if I had to pick one toxic thing that happened this year, that I can’t get out of my mind, it would be this NSFW event. Go Canada!
Dan – My choice for most interesting toxicology story of the year is the brodifacoum outbreak in synthetic cannabinoid users.1 As of last count, there have been six deaths and over 300 persons affected. It has so far involved ten states and a variety of differently-named products. So how is it that highly concentrated rat poison ended up in packets of synthetic marijuana sold around the country? Like any good mystery, there are more questions than answers. What is known: In March, large numbers of synthetic cannabinoid users started presenting to hospitals in the Chicago area with bleeding problems.2 Toxicologists, being the smart folks that we are, quickly figured out that the culprit was the long-acting anticoagulant brodifacoum. Furthermore, we figured out (we are so clever) that the route of exposure was smoking synthetic marijuana. What started in Chicago quickly spread to Indiana, Maryland, Wisconsin, Pennsylvania, Florida and several other states. While the most common presentation was hematuria, cases of intracranial, intraabdominal, and other life-threatening hemorrhages were also reported.1 The most common lab finding was an elevated INR. How elevated? Like too-high-to-measure elevated.
So, what is going on? Well, that is the most interesting and frightening part. We don’t know.
How did the brodifacoum get into such innocent-sounding products as Scooby Snax and OMG? One thought is the stupid hypothesis. Say you have a large warehouse full of synthetic marijuana and you want to keep the rats from eating your stash – it could happen.ell, you could spray rat poison around the place, and if you are not very careful you end up with rat poison in your product. While I think this is highly unlikely, I have seen Pineapple Express. Another thought is maybe someone added rat poison because they thought it would make the buzz better. Now as dumb as that sounds, there is at least a case of someone doing this with crack cocaine.3 Maybe drug dealers read the NEJM? I think the most likely, and scariest scenario, is the evil theory. This theory posits that someone, or some organization, added brodifacoum with the expressed intent of causing harm. That this could be either domestic or international terrorism, is not as far-fetched as it might seem.4 There are cases of terrorist groups coating bomb fragments with anticoagulants to make them more lethal. The criminal investigation so far has led to only one arrest and that was of a shop owner selling synthetic cannabinoids illegally. How will this story end? I don’t know, but until we know more, we would all be wise to ask about drug use in anyone presenting with hematuria, nose bleeds, or other bleeding problems.
Andrew – My nominee for tox story of the year is just a continuation of the tox story of the decade. Fentanyl and its analogs are soaring past heroin to become the most prevalent opioid we see. In 2017, the CDC reported that the number of overdose deaths from “synthetic opioids other than methadone” rose 45%. The DEA collects data from forensic labs, and found positive fentanyl tests are skyrocketing, while at the same time, positive heroin tests are declining.
Why is fentanyl worse than the other opioids? Fentanyl is harder to “cut” because, unlike most opioids which are dosed in milligrams, fentanyl is dosed in micrograms. Small errors in calculation result in deadly overdoses. Reversing large errors in dosing may require high doses of naloxone, although “naloxone-resistant” fentanyl has been a myth, so far. Fentanyl is synthetic, which poses its own set of problems. The seemingly infinite number of fentanyl analogs confounds testing and interdiction. Because the drug is completely made in a lab, there are no fields of opium-poppies that need to be defended from law enforcement. Instead of leaving war-torn areas with smugglers, fentanyl is shipped from “respectable” places in UPS boxes. The distribution model for fentanyl may be challenging established urban drug networks, resulting in violent clashes for supremacy. The “Opioid Epidemic” is becoming the “Fentanyl Epidemic.”
Jeanna – Money, money, money, MUN-NAY!! My top story of 2018 isn’t the plummeting stock market. Let’s be honest; money is a central motivating force to make the world go ‘round. The healthcare system is not immune to this. We all know that prescription drug costs are on the rise. Did you know that drug costs have increased by $300 billion from 1980 to 2016 and are at $330 billion per year? And antidotes are not immune to this rise either. A recent review compared the average wholesale price (AWP) of 33 commonly used antidotes from 2010 to 2015, and their findings were astonishing. 15 of the 33 antidotes had an increase greater than 50% of AWP in 5 years. One antidote, calcium disodium edetate, had an increase of 5000%!5
Let’s get to my top story of 2018. Unless you live under a rock, you know that patients with opioid use disorder are succumbing to their illness at unprecedented rates. Cue fentanyl above. Naloxone is probably the most widely used antidote in the US, and saves lives in mere seconds. Just a few days ago (December 19, 2018), an FDA panel suggested that naloxone be co-prescribed with opioid analgesics. The demand for this antidote is on the rise. As is its price tag. It costs less than $1 to manufacture naloxone – yet in the past 2 years, the wholesale price rose from $20 to $140! A brand name auto-injector can be purchased for a mere $4000. In early 2019, there will be a cheaper generic auto-injector, costing 95% less. Which, if I did my math correctly, means it will be $200. How much is too much to charge for this antidote? Is $20 too much? What about $200? It’s impossible to place a price tag on a life and the solution to this problem is indeed not a simple one. What I know for sure is that the rising cost of naloxone, other antidotes, and drugs in general is not sustainable. We need to do better.
Diane – 2018 rang in with the latest viral video craze, the Tide Pod Challenge. The proliferation of YouTube videos depicting teens preparing and eating these brand-name laundry detergent packets, each video more extreme (and disgusting) than the next, captured big-time attention. Which, of course, was the whole point.
These packets are a bit of a sore subject among us pediatric toxicology types, because they were released onto the U.S. market in 2012 despite reports of adverse effects in children overseas6 with no child-resistant packaging in place. Then, as if surprised by the occurrence of the very same cases here in the US from the very same products, the manufacturers added some degree of child-resistant packaging: an opaque container tub with a latch that is a little hard to open. Still, despite these efforts of unclear efficacy, laundry detergent pod exposures in young children continue to occur. The reason is obvious: they look DELICIOUS. Brightly colored, swirly gels covered in a thin membrane which look like they could just burst with flavor inside your mouth.And burst they do, except not with flavor but propylene glycol, ethoxylated alcohols, and highly concentrated detergents.
So, young kids eat them. And so do adults with dementia. Generally they do alright, except for the rare, but worrisome cases when they develop respiratory depression, coma, acidosis, and require intensive care.7 Tragically, rare fatalities are reported.8,9 Naturally, then, we had reason to fret when older, more presumably sentient adolescents decided to deliberately fry, sauté, bake, and eat these morsels of domestic cleanliness. What will happen? Don’t they know this is a colossally bad idea?
Unfortunately, internet challenges thrive on bad ideas. For those who have taken the far more benign, non-toxicologic “Ice Bucket Challenge”, you know the power of being dared to do something which is pretty stupid, and seriously uncomfortable, in a public forum (the internet). It’s almost worth it…until you’re freezing and near-syncopal, yet daring your closest friends and family to follow suit.
Now imagine the challenge involves doing things far more dangerous, in adolescents without fully formed brains or judgement (as in, most adolescents), with the intoxicating power of peer pressure. You get all kinds of shenanigans: the Cinnamon Challenge (swallow a ton of dried cinnamon without drinking anything), the Condom Challenge (snort a latex condom and try to cough it up), and Neknomination – a dare to drink large quantities of hard liquor, quickly, and then do something requiring skill and coordination like drive a motorcycle on a winding road. “Stupid” is an inadequate descriptor.
It’s not too surprising, then, that these weird little laundry detergent treats made it to the show. And what happened? Fortunately, very little. A few ended up in the ED. Poison Control Centers definitely got calls, but the effects were minor. Thankfully, this time, the fame-hungry fools in their quest for infinite likes and followers were spared. This time.
Meghan – One of the top tox stories of 2018 has to be the poisoning of former Russian military officer and UK double agent Sergei Skripal and his daughter Yulia with a Novichok (“newcomer”) nerve agent in Salisbury, England. Novichok agents are potent binary organophosphate weapons (similar to VX and sarin) developed by Russia in the late 20th century. Like other agents of its class, Novichok agents bind to acetylcholinesterase and prevent breakdown of acetylcholine, resulting in a cholinergic toxidrome (think SLUDGE symptoms), ultimately resulting in a respiratory death due to pulmonary secretions or respiratory paralysis.10 Although father and daughter remained critically ill for several weeks, both survived the attack. Another individual believed to have come across the discarded vial from the attack was not so lucky. This prominent assassination attempt got me thinking. What other poisonings have happened this year? Who, other than double agents, are often targets of poisoning attempts? I have a new (hopefully irrational) fear of being poisoned. Given this, I want to be aware of symptoms of popular or up-and-coming poisons in case my enemies take ideas from current events. A quick search from last year revealed several notable poisonings.
Thallium, a now-banned rodenticide, made a good showing in 2018. A woman in Southern California was diagnosed with thallium toxicity after a prolonged illness that included hair loss and weakness. The diagnosis of thallium poisoning was eventually made with the help of local toxicologists and her husband is now under investigation for attempted murder.. More recently, a student at Lehigh Valley also experienced significant toxicity secondary to thallium which included GI symptoms. The main suspect in the case (his roommate) is a former chemistry student at the university, and is believed to have been poisoning his roommates drinks over time. Thallium, a colorless, odorless, and tasteless metal, was historically used not only as a rodenticide, but also medicinally. Classic symptoms of thallium toxicity include alopecia and a painful ascending neuropathy that both occur within the first 1-2 weeks after poisoning. Abdominal pain with vomiting and diarrhea or constipation, kidney injury, and psychiatric symptoms can also be present. Thallium is radiopaque, so it may be seen on abdominal x-ray, and 24-hour urine testing is typically obtained to make the diagnosis. Charcoal (yes, thallium is the only metal for which activated charcoal is recommended) and Prussian Blue are the mainstays of treatment.11
In South Carolina, a nurse admitted to fatally poisoning her husband with eye drops, after putting them in his water for several days. (As an aside, she had previously shot him with a crossbow in a reported “accident”. . .) Tetrahydrozoline, the active ingredient in allergy eye drops such as Visine, is an imidazoline and central alpha-2 agonist. In overdose, it causes initial hypertension (peripheral alpha agonism), followed by hypotension, bradycardia, and respiratory and CNS depression. The diagnosis of imidazoline toxicity is made clinically, and management is primarily supportive. Keep in mind oxymetazoline (Afrin™ nasal spray) and naphazoline (Naphcon™ eye drops) and clonidine all cause similar symptoms.
Two BMW employees in Canada (even the friendly Canadians poison each other!) attempted to poison their coworker with engine coolant (antifreeze) last year. Luckily, the targeted victim noticed the unusual flavor of his water and did not consume enough to do serious harm. Antifreeze contains ethylene glycol, a toxic alcohol not uncommonly used in self-harm poisonings. Ethylene glycol, the non-toxic parent compound, undergoes transformation into toxic metabolites including oxalic acid and glycolic acid. These metabolites classically cause an anion gap metabolic acidosis and kidney injury. Surrogate laboratory markers including the dreaded osmol gap are often (misguidedly) used to make the diagnosis, and the primary treatments are fomepizole and hemodialysis. Although often consumed in attempts at self-harm, ethylene glycol has certainly been used as an effective malicious poison in other cases.12
What have we learned from this review of prominent 2018 poisonings? Always suspect romantic partners and coworkers in poisoning events, especially if they work in healthcare or laboratory settings. Unless, of course, you are a Russian spy, a job I cannot recommend as a toxicologist. Pay close attention to your food sources but know that not all poisons have a distinct flavor. And for me, I’ve got my eye out for symptoms of thallium poisoning. It’s the perfect agent: colorless, tasteless, and easily accessible. Its symptoms can be insidious and non-specific but carry significant morbidity and mortality. Luckily, its classic presentation of hair loss, peripheral neuropathy, and GI symptoms are now on your radar for the new year.
Chris – I continue to be amazed. Not only did we see the first release of a Novichok agent (which was only recently listed by the Organisation for the Prevention of Chemical Weapons (OPCW) because it was not officially stated to truly exist – mere rumor from scientists from the former Soviet Union), but also that this release occurred in another sovereign country. The use of such potent chemical weapons for assassination in public arenas should raise a marked call to action from other countries. Theresa May, as the British prime minister, stated there were just two plausible explanations for the release of such an agent on British soil: “Either this was a direct act by the Russian state against our country, or the Russian government lost control of this potentially catastrophically damaging nerve agent and allowed it to get into the hands of others.”
There was also an equally concerning event that occurred that was buried in the news cycles: there was a Russian cyber-attack on the headquarters of the OPCW which is charged to investigate the release of chemical weapons throughout the world. At the time of the cyber-attack, the OPCW was investigating the attempted assassination of Sergei Skripal and his daughter Yulia in the UK, as well as a chemical weapons attack in Douma, Syria. This cyber-attack, which occurred using a car parked outside of the OPCW building, was disrupted by Dutch military intelligence just weeks after the Salisbury Novichok agent attack.For those who have not visited The Netherlands, the OPCW is housed next to the International Criminal Court in The Hague. This is an important association, as the OPCW investigation into these recent world events could be instrumental for future international trials. If those accused of releasing such potent chemical agents are able to tamper with the international investigative body, future trials may never be able to take place. This has tremendous ramifications for preventing future attacks and may embolden the perpetrators to continue their poisoning without constraint. As clinical toxicologists, it is not only the release of such agents, but also the potential inability to prosecute the perpetrators that we should find terrifying.
Sarah – One of the strangest toxicology stories, which turns out to be a really sad one, is the reports surrounding the death of Jack Chapman. The story has it all: young muscled men, rumors of a sex cult, and a tragic death in the pursuit of the ideal. Unfortunately, Jack Chapman is not alone in his death. There is a steady trickle of news stories about people who die from injection-related complications. The stories are often mired with reports of illegal practitioners, setting up home-grown shops selling cheap perfection. People line up thinking they’re getting a deal without understanding the risks involved. Look to a future post to learn more about what can go wrong with injection-related aesthetics.
Dave – My pick for story of the year doesn’t involve Russian nerve agents or fentanyl or an Adderall-snorting narcissistic man-baby with nuclear launch codes. No, my pick isn’t front-page stuff, but it’s fascinating and I think it could have huge implications for clinicians and patients. It’s a simple case report.13
Here’s the summary: A 30-year-old woman (“Alice”) starts using oxycodone recreationally. A few years later, she stops and goes through opioid withdrawal. No surprise. But the weird thing is that her withdrawal is accompanied by severe pain in her right knee. Now, she’d injured that knee a few times between the ages of 13 and 15, but it hadn’t bothered her at all for more than a decade. Knee pain just wasn’t an issue when she started using oxy. After a while, the knee pain goes away. But 7 months later, she starts using oxy again, and with every subsequent attempt to stop, she develops intense (10/10) pain in her right knee.
In hindsight, she perceived her pain to be the result of a chronic knee problem, although she wondered if the oxy might have had something to do with it. The increase in pain with opioid cessation was a major barrier to stopping opioid use. Here are some quotes from her narrative:
The term applied to what happened to Alice is Withdrawal-Associated Injury Site Pain (WISP), and the same researchers who described her case published a similar albeit less detailed case series in 2016.14
To me, this report is fascinating for two reasons. First, it reminds us how little we know about the neural pathways underlying the genesis of pain, and about the sometimes-super-weirdness of adverse drug events more generally. But second — and this is where I think the implications at the population level could be huge — is a simple observation: if opioids can rekindle severe pain from a remote injury, might they do the same with a more recent (or even active) injury? Of course the answer is yes. And with that in mind, it’s fair to ask: when someone on chronic opioid therapy says their pain is lessened by opioids, how much of that pain is actually drug-related?