Invitation to a Bloodletting with Apologies to Vladimir Nabokov

Aaarr matey…Avast ye! Fifty doubloons and a bucket o’ blood! Blimey!”

 

“I am here through an error—not in this prison, specifically—but in this whole terrible, striped world; a world which seems not a bad example of amateur craftsmanship, but is in reality calamity, horror, madness, error—and look, the curio slays the tourist, the gigantic carved bear brings its wooden mallet down upon me.” 

“I suppose the pain of parting will be red and loud.” 
― Vladimir Nabokov, Invitation to a Beheading

In 2001, one of my cousins, Colin, drove from his home in the Smoky Mountains of North Carolina to the Atlantic coast. Hale, hardy, he was 62, could have passed for 42, and was a frequent hardscrabble backpacker and inveterate outdoorsman.  During the drive, a nagging neck and shoulder ache started up, and he reached into his rucksack for a bottle of his standby, naproxen. He took one twice daily. At the coast, he met up with a charter fishing boat at dawn. He loved to fish.

The boat went perhaps 50 miles offshore, and at the apex of its excursion, Colin was overcome with a wave of nausea. He sought shade, clenched, breathed slow and deep. There was no warding off what the queasiness heralded. He heaved violently, gushing perhaps 250 cc of bright red blood onto the steel deck of the ship. Well-wishers gathered at his side, and began to blot at his profuse sweating. He vomited again, even more blood. The onlookers couldn’t not notice his complexion, once ruddy, had turned pallid.

The ship’s captain radioed to shore for emergency medical assistance. Even had he turned the vessel around and churned full steam ahead, the shoreline was more than two hours away. The EMS dispatcher pointed out that even with a medical chopper, which they didn’t have, the ship offered nowhere to land it…and that winching up an unstable man ever at risk for choking to death on his own bloody emesis on a gurney through mid-air just wouldn’t work. The ship of course had a medical kit with band-aids, wound salves, sunburn ointment and a syringe of epinephrine, but no iv kit, no bags of normal saline.

Again he retched. And again. He soaked towels with blood. Having vomited at least a liter of the essence of life, with who knows how much more blood already dumped in his stomach and headed downstream, he stooled in his pants urgently…..melena, black, like loose tar, with a profound odor that dared all onlookers to flee the nauseating stench engulfing them.

Colin exsanguinated aboard that vessel. Another naproxen casualty. Ostensibly acceptable to the FDA which still won’t blackbox-warn about its dangers. He’d never ailed, never been in a hospital, took no medications except prn naproxen, never had surgery….an outdoor-magazine cover guy portrait of robust health. In 2018 alone, Americans spent over $330M on brand-name Aleve, a trade name for naproxen.

What angers me about Colin’s death isn’t its non-necessity or its complete avoidability. I’m drawn more to the dysfunctionality of it; I think of miserable couples I saw in practice who’d been having the same argument weekly for 30 years because they were inherently incompatible but too lazy to depart the relationship. Imagine some paper airplane you’ve folded that you launch….and it just won’t stay airborne, ever. The American medical system is warped in an exuberance of ways, none more rococo than its dysfunctional relationship with NSAID painkillers. The system has an insufficiently ego-dystonic relationship with the fact that these agents are gastric ulcerogens (regardless of route of administration: iv Toradol is every bit as ulcer-causing as oral naproxen) and indeed roughly regards their analgesic efficacy as proportionate to their ulcerogenicity. Having said this, my own recent perusal of several dozen published reports on this topic shows gastroenterologic science to be ever a backwater, always the fall-short-of-expectations mess it’s long been, never living up to its peers in cardiology and oncology. To wit, no one can agree on what the most potent analgesic is among the NSAIDs or what the true rank order of NSAID ulcerogenicity is. Having said that, general consensus has it that naproxen has to be regarded probably as the uber-NSAID: the best pain killer and most ulcerogenic.

Why do NSAIDs cause ulcers? That question is stunningly complicated because in fact NSAID-induced stomach ulcers generally occur in only one region of the stomach, the  antrum, which also happens to be where proton-secreting (acid-making) cells reside. Despite this, NSAID ulcerogenicity and acid have nothing to do with each other. NSAIDs don’t make the gastric environment more acidic, and in fact shutting down the acid pump does not keep an NSAID from causing a gastric ulcer. Some practitioners feel that co-dosing NSAID users with proton pump inhibitors abates ulcer risk, but I regard this data as weak, its premise flimsy. PPI use may promote better gastric mucosal repair and thus ease ulcer risk, but PPI use has no direct effect on whether an ingested NSAID will cause an ulcer. NSAIDS may promote apoptosis of gastric lining cells in the antrum, and certainly they interfere with healing in this tetchy, high-turnover, epithelium.

The reason the pharma industry promulgated the NSAIDS, three decades ago is, of course, an irony: they are less insulting to the stomach mucosa than aspirin (ASA). ASA is absorbed directly from the stomach, and is highly ulcer-causing. People ingesting both ASA and an NSAID are, of course, at epic risk of getting stomach ulcers, but ulcers from all the available NSAIDS are known and well-described. Just how well-described? Well, that’s patchy; remember, the plural of “anecdote” is not data, and yet many gastrointestinal academic publications are premised on “the case series,” little more than a set of anecdotes flanked by the bookends of an investigator’s biases.

Some years ago when I was running a clinical trials unit, we were approached by a major NSAID manufacturer about doing a study of just how ulcerogenic the major NSAIDS are. The idea was that we’d select healthy volunteers, screen them endoscopically to confirm they had normal, ulcer-free stomachs, and then randomize them to one of three or four major NSAID products. They’d take the label full dose for one week at which point we’d do repeat EGD (esophagastroduodenoscopy) and studiously count how many ulcers now had taken up residence in their stomachs.

At first I refused to accept the study, refused to participate. It was a study  that potentially harmed people and from which no enrolled patient would be made healthier. But then I rethought things. First, they were offering to pay each participating patient $1500. Next, even I had to admit that the likelihood of developing a complication after merely a week of NSAID use (ulcer yes, complication no) was low (my cousin Colin’s naproxen ingestion was regarded as fairly chronic). Finally, if a given patient demonstrated ulcers, the trial sponsor would pay us a standard professional fee per EGD to repeat that EGD at intervals until ulcer healing was documented established. We stood to make considerable money from the study, but the sponsor also stated plans to publish a paper with the data (sorely needed) and use the data as a basis for claims in advertising about NSAID risk. I never saw a resulting publication and neither have I seen ads about NSAID risk….but I do clearly recall that every patient we had in the naproxen arm did far worse than any patient on any other NSAID. The degree of naproxen-induced ulceration we saw was consummate….commonly more than 100 ulcers per patient stomach.

The problem with ulcers is that they can erode downward into arteries in the stomach wall and bleed profusely. And they have a funny way  of doing that in the small hours of the morning.

The quotation below the opening photograph above, of a purulent ulcer crater mid-stomach with an artery eroded into and now pumping blood fervently, is in pirate-speak because of the quirky culture of clinical gastroenterology. Because the patient is sedated, endoscopic teams often bond with certain agreed-upon humor routines (never at the expense of the patient). Indeed, frankly, when you find yourself standing in a pool of freshly-retched blood scoping again at 4 am, chasing another NSAID ulcer, you can perhaps be forgiven a little punch-drunken frivolity. As I was suctioning (and suctioning and suctioning) yet another seemingly unclearable fundic pool of gastric blood, one or another endoscopy nurse would invariably shout out, “50 doubloons and a bucket o’ blood” to reflect that this was one very expensive middle-of-the-night procedure: special fees for the case being out-of-hours, special add-on charges levied for hemostatic interventions (epinephrine injections with sclerotherapy needles, gold-probe cautery, endoscopic clipping, and other techniques). Rooms where medical procedures are done behind closed doors tend to a predilection for gallows humor.

A smart gastroenterologist summons anesthesiology to a major upper gastrointestinal hemorrhage to endotracheally intubate the patient and provide outright general anesthesia. Why? Because waves of blood sluice UP the esophagus, whereupon patients easily aspirate them and get pneumonitis. Billing for a middle-of-night emergency EGD for GI bleeding generally begins at around $2500 and rises rapidly from there based on complexity and duration of the case. Involvement of anesthesiology adds mightily to the expense… the $2500 is just for the gastroenterology component.

At this point, it’s incumbent on the author to bludgeon you intellectually with how massive and outsize the problem is: how many bleeds, how much blood lost, how many urgent endoscopies, how many millions of NSAID rx’s versus how many millions of dollars spent chasing their complications (and those complications are many and not just confined to the GI bleeding arena). Here is a reference (https://www.ajmc.com/journals/supplement/2013/a467_nov13_nsaid/a467_nov13_fine_s267) that offers such for you, though I admit it’s verging on being out of date and a more contemporary edition hasn’t surfaced yet. Is what we’re discussing a big problem? Yes, surely it is.

During a vexing time of opioid overuse and addiction, we need our NSAIDs more than ever because let’s be clear: NSAIDs are extremely effective analgesics, rivalling entry-level narcotic analgesia, Acetaminophen will just never be much of a contender in this space because while it has modest analgesic and antipyretic properties, it isn’t anti-inflammatory in the slightest. The problem is, if you’ve experienced an NSAID-induced ulcer, most doctors are at a loss to tell you how to proceed….and certainly proceeding by using a PPI in tandem is NOT the answer. The specialty’s old answer to this question was invoking misoprostol (Cytotec), an agent actually invented by a distance relative of mine; but Cytotec is difficult to dose, difficult to tolerate, and often has a profound array of side effects including diarrhea. Almost no one stays on it. In more than two decades of practicing gastroenterology, I prescribed it fewer than ten times. The specialty’s new answer is: opioids (and addiction) for you.

Does it have to be this way? A small-cap start-up biotech in Toronto insists it doesn’t. That company is called Antibe and it trades as $ATBPF. We’ll be hearing from them in a conference call today at 12:30 pm. The company is completing trials developing a novel substituted rejiggered form of naproxen that kills pain better than the original agent but thus far has shown only an insignificant tendency to drive gastric ulcer formation. Antibe’s agent could become among the best selling drugs of all time, and could upend an entrenched set of vexing problems the clinic has faced since NSAIDs emerged.

Disclosure: The author has a long position in $ATBPF shares and will not trade in such shares for 7 days, reckoned in business days, after this column appears. This column should not be taken as advice or solicitation for you to trade in these shares, and particular diligence is due before investing in any small-cap biotech equity. Copyright 2019 by BioPubKSS.com and the author. All rights reserved. May not be reproduced without permission.

Corrigendum: the initial version of this column published at 0600 retained certain errors because of a failed server acceptance of an update. A corrected version was dispersed at 0850 on 1 March 2019.