Fog Facts: Side effects and re-positioning of drugs

Fog Facts: things that are known and yet not known —
[not known to the conventional wisdom, the general public, the media
but known to those (few) who are genuinely informed about the subject]

For that delightful term, Fog Facts, I’m grateful to Larry Beinhart who introduced me to it in his novel “The Librarian”. There it’s used in connection with political matters, but it’s entirely appropriate for the disconnect between “what everyone knows” about blood pressure, cholesterol, prescription drugs, and things of that ilk, and what the actual facts are in the technical literature.

For example, the popular shibboleth is that drug companies spend hundreds of millions of dollars in the development of a new drug, and that’s why they need to make such large profits to plough back into research. The truth of the matter is that most new drugs originate in academic research, conducted to a great extent at public expense; and drug companies spend more on advertising and marketing than they do on research. All that is known to anyone who cares to read material other than what the drug-company ads say and what the news media disseminate; and yet it’s not known because too few people read the right things, even books by former editors of medical journals and academic researchers at leading universities and published by mainstream publishers; see “What’s wrong with modern medicine”.

When it comes to drug “development”, the facts are all hidden in plain view. There’s even a whole journal about it, Nature Reviews — Drug Discovery, that began publication in 2002. I came to learn about this because Josh Nicholson had alerted me to an article in that journal, “Drug repositioning: identifying and developing new uses for existing drugs” (by Ted T. Ashburn and Karl B. Thor, 3 [2004] 673-82). I had never heard of “drug repositioning”. What could it mean?

Well, it means finding new uses for old drugs. And the basic reason for doing so is that it’s much easier and more profitable than trying to design or discover a new drug, because old drugs have already been approved as safe, and it’s already known how to manufacture them.

What seems obvious, however — albeit only as a Fog Fact — is that the very success of repositioning drugs should be a red flag warning against the drug-based medicine or drug-first medicine or drug-besotted medicine that has become standard practice in the United States. The rationale for prescribing a drug is that it will fix what needs attending to without seriously and adversely affecting anything else, in other words that there are no serious “side” effects. But repositioning a drug shows that it has a comparably powerful effect on something other than its original target. In other words, “side” effects may be as powerful and significant as the originally intended effect. Ashburn and Thor give a number of examples:

Cymbalta was originally prescribed to treat depression, anxiety, diabetic peripheral neuropathy, and fibromyalgia (all at about the same dosage, which might cause one to wonder how many different mechanisms or systems are actually being affected besides the intended one). The listed side effects do not include anything about urination, yet the drug has been repositioned as Duloxetine SUI to treat “stress urinary incontinence (SUI), a condition characterized by episodic loss of urine associated with sharp increases in intra-abdominal pressure (for example, when a person laughs, coughs or sneezes)”; and “Lilly is currently anticipating worldwide sales of Duloxetine SUI to approach US $800 million within four years of launch”.

Dapoxetine was not a success for analgesia or against depression, but came into its own to treat premature ejaculation.

Thalidomide was originally marketed to treat morning sickness, but it produced limb defects in babies. Later it was found effective against “erythema nodosum laprosum (ENL), an agonizing inflammatory condition of leprosy”. Moreover, since the birth defects may have been associated with blocking development of blood vessels, thalidomide might work against cancer; and indeed “Celgene recorded 2002 sales of US $119 million for Thalomid, 92% of which came from off-label use of the drug in treating cancer, primarily multiple myeloma . . . . Sales reached US $224 million in 2003 . . . . The lesson from the thalidomide story is that no drug is ever understood completely, and repositioning, no matter   how unlikely, often remains a possibility” [emphasis added: once the FDA has approved drug A to treat condition B, individual doctors are allowed to prescribe it for other conditions as well, although drug companies are not allowed to advertise it for those other uses. That legal restriction is far from always honored, as demonstrated by the dozens of settlements paid by drug companies for breaking the law.]

Perhaps the prize for repositioning (so far) goes to Pfizer, which turned sildenafil, an unsuccessful treatment for angina, into Viagra, a very successful treatment for “erectile dysfunction”: “By 2003, sildenafil had annual sales of US $1.88 billion and nearly 8 million men were taking sildenafil in the United States alone”.

At any rate, Ashburn and Thor could not be more clear: The whole principle behind repositioning is that it’s more profitable to see what existing drugs might do than to look for what might be biologically speaking the best treatment for a given ailment. So anti-depressants get approved and prescribed against smoking, premenstrual dysphoria, or obesity; a Parkinson’s drug and a hypertension drug are prescribed for ADHD; an anti-anxiety medication is prescribed for irritable bowel syndrome; Alzheimer’s, whose etiology is not understood, gets treated with Reminyl which, as Nivalin, (generic galantamine) is also supposed to treat polio and paralysis. Celebrex, a VIOXX-type anti-arthritic, can be prescribed against breast and colon cancer; treatment of enlarged prostate is by the same drug used to combat hair loss; the infamous “morning after” pill for pregnancy termination can treat “psychotic major depression”; Raloxifene to treat breast and prostate cancer is magically able also to treat osteoporosis.

And so on and so forth. This whole business of drug repositioning exposes the fallacy of the concept that it is possible to find “a silver bullet”, a chemical substance that can be introduced into the human body to accomplish just one desired thing. That concept ought to be recognized as absurd a priori, since we know that human physiology is an interlocking network of signals, feedback, attempted homeostasis, defenses against intruders.

It is one thing to use, for brief periods of time, toxins that can help the body clear infections — sulfa drugs, antibiotics. It is quite another conceit and ill-founded hubris to administer powerful chemicals to decrease blood pressure, lower cholesterol, and the like, in other words, to attempt to alter interlocking self-regulating systems as though one single aspect of them could be altered without doing God-only-knows-what-else elsewhere.

The editorial in the first issue (January 2002) of Nature Reviews Drug Discovery was actually clear about this: “drugs need to work in whole, living systems”.

But that editorial also gave the reason for the present-day emphasis on medicine by drugs: “Even with vastly increased R & D spending, the top 20 pharmaceutical companies still churn out only around 20 drugs per year between them, far short of the 4-5 new drugs that analysts say they each need to produce to justify their discovery and development costs”.

And the editorial also mentions one of the deleterious “side” effects of the rush to introduce new drugs: “off-target effects . . . have led to the vastly increased number of costly late-stage failures seen in recent years (approximately half the withdrawals in the past 20 years have occurred since 1997)” — “off-target effects” being a synonym for “side” effects.

It’s not only that new drugs are being rushed to market. As a number of people have pointed out, drug companies also create their own markets by inventing diseases like attention-deficit disorder, erectile dysfunction, generalized anxiety disorder, and so on and on. Any deviation of behavior from what might naively be described as “normal” offers the opportunity to discover a new disease and to re-position a drug.

The ability of drug companies to sell drugs for new diseases is helped by the common misconception about “risk factors”. Medication against hypertension or high cholesterol, for example, is based on the presumption that both those raise the risk of heart attack, stroke, and other undesirable contingencies because both are “risk factors” for such contingencies. But “risk factor” describes only an observed association, a correlation, not an identified causation. Correlation never proves causation. “Treating” hypertension or high cholesterol makes sense only if those things are causes, and they have not been shown to be that. On the other hand, lifelong ingestion of drugs is certainly known to have potentially dangerous consequences.

Modern drug-based, really drug-obsessed medical practice is as misguided as “Seeking Immortality”.

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