Opium

choi

(1) David Wainer, In Search of Opioid Alternatives; Vertex's clinical trials mark a step toward finding treatments for pain without the addiction risk. Wall Street Journal, Mar 2, 2024, at page B12 (section B is business, whose last page contains a half-page column "Heard from the Street" where Street alludes to Wall Street).
https://www.wsj.com/health/pharm ... on-the-way-61e3a359
*"For decades, the hunt for safe and effective pain treatments has eluded the pharma industry. It isn’t that researchers don’t know how to stop pain. Drugs can target receptors in the brain to reduce it, as opioids do quite well, but not without also triggering feelings of euphoria, or dulling mental acuity. Crucially, there is also the potential for addiction.   Pain can also be blocked at the source by local anesthetics. Dentists do it all the time during dental procedures. But * * *")

My comment:
(a) Just browse the article at a glance. Scientists have not been able to find a good alternative to opium as pain killer.
(b) The Vertex drug under clinical trial has only code name (assigned by the company) as VX-548, though the WSJ article did not mention it (code name). Understandably Vertex does not want to disclose its chemical composition, and no name is necessary unless and until it is approved by FDA.
(c) Feeling no pain (such as mutation of genes that provides blueprint for PROTEINS Nav1.7 or Nav1.8 are not good for health. Leprosy damages nerve and a patient feels no pain in infected area of the body; lacking reflex to withdraw that part of the body from harm quickly, the part get injuried easily.
(d) Addicts to opioids (such as fentanyl) in the United States are treated with a drug with the generic name methadone, a synthetic opioid agonist (which causes less addition and generates less euphoria).
--------------------------------Vertex
“We’re going to cure the world of its pain,” declared Richard Sackler (portrayed by Michael Stuhlbarg) in the Hulu miniseries “Dopesick,” which chronicled how Purdue Pharma used deceptive practices to make OxyContin a blockbuster. Opioids didn’t cure pain, but they led to a nationwide scourge that has killed hundreds of thousands of Americans.

These days, doctors no longer prescribe opioids as easily. Unfortunately for millions of Americans still suffering from debilitating pain, the alternatives aren’t great, leaving a gap in care that is in urgent need of a medical solution.

In recent months, Vertex Pharmaceuticals VRTX 2.86%increase; green up pointing triangle announced positive results from studies of its experimental nonopioid painkiller. The excitement has added about $20 billion to the company’s market capitalization in recent months, with some Wall Street analysts describing the pain market as the next big opportunity after obesity.

Yet the results, while encouraging, are far from being a home run. In two late-stage studies, the drug eased patients’ pain more than the placebo but failed to outperform Vicodin. In a bunion surgery trial, the opioid-based Vicodin outperformed Vertex’s drug on pain relief. The upshot is that while Vertex’s drug might not be a huge blockbuster, its success is likely to pave the way for better drugs down the line.

For decades, the hunt for safe and effective pain treatments has eluded the pharma industry. It isn’t that researchers don’t know how to stop pain. Drugs can target receptors in the brain to reduce it, as opioids do quite well, but not without also triggering feelings of euphoria, or dulling mental acuity. Crucially, there is also the potential for addiction.

Pain can also be blocked at the source by local anesthetics. Dentists do it all the time during dental procedures. But if you were to turn that into a pill, it would run the risk of blocking neuronal signaling within the brain, or affecting the heart’s rhythm, says Stephen Waxman, a Yale University neuroscientist. The challenge for drug developers has been how to create a highly selective pill that can target pain without compromising other bodily functions.

“We could block all pain, but we wouldn’t live very long,” says Thomas Buchheit, director of Duke University’s Regenerative Pain Therapies Program.

In recent decades, scientists identified genetic mutations that made people either feel too much pain or made them unable to sense it. A child in Pakistan with a genetic mutation entertained street crowds by walking on hot coals and sticking knives through his arms. The discovery of the mutated gene, which encodes sodium channels that regulate the transmission of pain signals to the brain, offered a tantalizing target because it represented a way to potentially block pain at its source with limited side effects.

But relieving pain by blocking these channels, known as Nav1.7 and Nav1.8, has proved difficult, and companies including Teva, Roche and Biogen have undertaken clinical trials that failed to demonstrate conclusive evidence of pain relief. One issue is that these sodium channels are similar to others that regulate functions in the heart and brain. Another challenge, Waxman says, is that unlike cancer, for example, where a clear marker in the blood can be measured after a treatment is given, assessing pain is more subjective, with results often based purely on patients’ responses.

Vertex’s success, then, should be viewed in the context of a long string of failures. Think of the opportunity less as the GLP-1 bonanza remaking the treatment of obesity and more like the slow, but promising, progress being made in fighting Alzheimer’s. While its drug didn’t beat opioid-based Vicodin in acute-pain studies and didn’t outperform Lyrica, an older drug, in a separate study with diabetic neuropathy patients, the results are likely to unleash more investment and research into this class of sodium channel blockers. And since Vertex will be able to claim its drug isn’t addictive, it should establish a decent-size market.

“This is an important step forward because it establishes proof of concept that this approach can reduce pain,” says Waxman. Latigo Biotherapeutics recently raised $135 million to focus on the same sodium channel as Vertex. Sean Harper, co-founding managing director at Westlake Village BioPartners, an investor behind Latigo, argues that so-called Nav inhibitors could follow a trajectory similar to that of statins. While the first drug wasn’t the most effective, it paved the way for subsequent ones with a better clinical profile. In the longer term, other approaches, such as gene therapies, could become available.

If approved, Vertex’s drug will initially be available for acute pain. That means it could be prescribed after surgery, when a patient needs a week or two of medication. While that is a multibillion-dollar market, the challenge is that doctors don’t mind prescribing opioids for short durations, says Myles Minter, an analyst at William Blair.

Price is a crucial factor. Opioid generics cost as little as 50 cents a pill, compared with an estimated $10 for Vertex’s drug, Minter says. Passage of the Nopain Act, legislation promoting the use of nonopioids, could help with the cost, but wouldn’t close the gap entirely. The bigger opportunity will be for neuropathic pain, which is treated chronically. After positive midstage results in people with painful diabetic peripheral neuropathy, Vertex is in talks with the Food and Drug Administration to conduct a broader study of people with neuropathic pain. Such chronic markets represent a much bigger opportunity because pills are taken for years and opioids aren’t as suitable because of their addictive nature, says Minter.

There is no arguing that pain, whether acute or chronic, is a huge market in desperate need of better drugs. In the ideal world, Vertex’s drug would be so effective that it would simply make opioids obsolete, but it won’t. In a field littered with failures and a dearth of options, though, it is a big step forward.

choi

(2) Tunku Varadarajan, Pipe Dreams of Empire. Opium transformed the Indian subcontinent and forced China to open its ports and markets to Britain. The story begins with tea. Wall Street Journal, Mar 2, 2024, at page C9, where section on Saturdays is "Review")
https://www.wsj.com/arts-culture ... arco-state-eb5d1789
(book review on Amitav Ghosh, Smoke and Ashes; Opium's hidden histories. FSG, Feb 13, 2024)

Note:
(a)
(i) FSG stans for Farrar, Straus and Giroux
https://en.wikipedia.org/wiki/Farrar,_Straus_and_Giroux
(founded in 1946 by the three)
(ii) Ghosh
https://en.wikipedia.org/wiki/Ghosh
(iii) Many facts and arguments in this book are not new.

(b) "Mr Ghosh also contends that opium begat an impoverishment of large swaths of north-central India—mostly the modern states of Bihar and Uttar Pradesh—that persists to this day in the form of chronic backwardness. If 21st-century Bihar is a basket case, says Mr. Ghosh, it’s because its peasants were coerced by the Brits to grow opium poppies in the 18th and 19th centuries, an operation that was overseen by the Opium Department (as it was called) of the East India Co."
(i) Bihar
https://en.wikipedia.org/wiki/Bihar
(ii) Uttar Pradesh
https://en.wikipedia.org/wiki/Uttar_Pradesh
(" lit. 'North Province'")

The noun masculine pradesh in Hindi means province.

(c) "Denied access to Indian opium, the Americans sourced their product [opium] in Smyrna (now Izmir), in Turkey, and the need to transport opium across the seas led to the development of the Baltimore Clipper, the best ship of its kind. Among the most salient pAmerican] East Coast opium profiteers was Warren Delano, a grandfather of FDR."
(i) Izmir
https://en.wikipedia.org/wiki/İzmir
is a seaport that handled and exported opium grown in Turkey.
(ii) Baltimore Clipper
https://en.wikipedia.org/wiki/Baltimore_Clipper

—----------------Opium War
Amitav Ghosh doesn’t mince words, especially when writing of British imperialism in India, the land of his birth, or of Britain’s role in China, the land of his moral obsessions. In “Smoke and Ashes”—an indignant and occasionally eccentric account of “opium’s hidden histories”—Mr. Ghosh characterizes Britain as an “imperial narco-state” whose model was perfected in India and whose methods were ruthlessly applied in China. He quotes with approval an academic who charges the British East India Co. with creating the “world’s first drug cartel.”

These are startling labels to attach to the long and complex British colonial project, one that can be said—if you’re even modestly objective—to have contributed much that was good to the lands where it was imposed. In the calculation of such writers as Nigel Biggar—the author of “Colonialism: A Moral Reckoning” (2023)—the undeniable negatives of the British Empire are outweighed by its positive effect on colonized peoples.

But Mr. Ghosh has no time for positives—perhaps inevitably, since his focus is exclusively on opium, a product whose unchecked trade had no obvious moral upside. In fact, opium had an effect on China so malign that it led to wars, widespread addiction and the systematic violation of Chinese sovereignty by Britain under the cynical guise of free trade.

Mr. Ghosh also contends that opium begat an impoverishment of large swaths of north-central India—mostly the modern states of Bihar and Uttar Pradesh—that persists to this day in the form of chronic backwardness. If 21st-century Bihar is a basket case, says Mr. Ghosh, it’s because its peasants were coerced by the Brits to grow opium poppies in the 18th and 19th centuries, an operation that was overseen by the Opium Department (as it was called) of the East India Co.

It was a criminal offense, no less, to grow anything other than poppies on land designated as falling under the Opium Department’s purview. No growing of food was permitted, nor any other sort of cash crop. The peasants cultivated poppies at a crippling loss and were compelled to sell it at a fixed price. The region, over time, became destitute and in thrall to criminal gangs and corrupt politicians.

Mr. Ghosh, among the finest novelists of Indian origin writing in the English language, is a social anthropologist by training. He studied the subject at Oxford, and his doctoral dissertation gave rise to his first published work of nonfiction—“In an Antique Land” (1992)—a centuries-long chronicle of two villages in the Nile Delta. In “Smoke and Ashes,” he returns to these academic roots. His book portrays the socioeconomic and cultural impact of opium on the societies that produced, transported, traded and consumed the stupefacient in the two centuries before World War II.

Since Mr. Ghosh’s politics are of the postcolonial left, his narrative ranges beyond straightforward imperial history and veers into critiques of modern capitalism, climate change and “structural racism.” With multiple citations, he reveals the influence of Priya Satia, a hyper-progressive Stanford historian who has made a career out of scorning the idea that Western imperialism led to any sort of progress anywhere.

But Mr. Ghosh’s research is rich enough to justify setting aside the leftist frills and fancies and dwelling instead on his main thrust—which is the corrosive legacy of opium on the two great lands of the East, China and India.

Opium, Mr. Ghosh states, was a “pillar of empire.” But its story begins with tea, which Britain imported at vast expense from China. The problem was that Britain had “nothing much to sell to China in return,” since the Chinese had “little interest in, and no need for, most Western goods.” This was irksome to the British, who found themselves having to pay for tea with silver. By the mid-18th century, this form of payment became onerous, and “finding a means of offsetting the drain of bullion now became a matter of increasing urgency.” And so Britain hit upon a solution, diabolical and lucrative: the large-scale export to China of opium from India.

Opium would pay for tea and much more, transforming the Indian subcontinent and forcing China to open its ports and markets to Britain. The narcotic, in short order, acquired “the status of a strategic resource,” Mr. Ghosh writes. The East India Co.’s “drug-pushing programme” was “astounding.” He cites eye-popping figures: In the century between 1729 and 1830, the company’s annual opium exports to China rose from 200 chests to 30,000 (with a single “chest” amounting to 140-160 pounds). From 1831 to 1840, China received as much opium from India as it had in the century preceding. After the two Opium Wars—in which China was humiliated—the British Empire’s opium exports peaked, reaching nearly 106,000 chests in 1880. Opium earnings amounted to 10 million pounds sterling in the 1880s (nearly $2 billion today).

“Quite possibly,” says Mr. Ghosh, “no single economic policy has ever been more successfully implemented than the British Empire’s opium scheme.” Within a few decades—“exactly as intended”—opium cured Britain’s balance of payments migraine. The flow of bullion to China was reversed, and wealth now coursed out of China and toward Britain. The knock-on effect on India was apparent. The immiseration of Bihar notwithstanding, the opium trade enriched a wide range of Indian mercantile castes and communities, in particular the Parsis, who set themselves up as adroit intermediaries, transporting opium to Hong Kong, Guangzhou and beyond. The city of Bombay, which had been the poorer cousin of Calcutta, grew rich on opium and its associated wealth and opportunities, becoming the country’s commercial capital—a status it continues to enjoy to this day.

Mr. Ghosh is enlightening on the much-neglected story of America’s hand in the opium trade, with East Coast shippers and traders following the East India Co. into China in a sort of Opium Rush. Denied access to Indian opium, the Americans sourced their product in Smyrna (now Izmir), in Turkey, and the need to transport opium across the seas led to the development of the Baltimore Clipper, the best ship of its kind. Among the most salient East Coast opium profiteers was Warren Delano, a grandfather of FDR.

Where Mr. Ghosh goes off the rails is in his ascription of personality—even smarts and acumen—to the poppy itself, “a Being whose vitality and power” the British were incapable of acknowledging. The poppy, he writes, is “a non-human entity whose intelligence, patience and longevity far exceed that of humans.” It is tempting, here, to ask what Mr. Ghosh is smoking and to ask, perhaps, for some of it ourselves. But to do so would be to make light of a project—and a period—that brought the British no credit. In totting up the balance books of empire, there’s no doubting where opium falls: on the debit side, an imperial sin for which there was no redemption.

Mr. Varadarajan, a Journal contributor, is a fellow at the American Enterprise Institute and at Columbia University’s Center on Capitalism and Society.