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Don’t Believe The Hype: Cholinesterase Inhibitors As A Treatment For Dementia

Don’t Believe The Hype: Cholinesterase Inhibitors As A Treatment For Dementia
I distinctly remember the day I attended a “drug lunch” (as a PM&R resident in New York City) to learn about the value of donepezil (aricept) for the treatment of dementia. I was astonished by the drug’s lack of efficacy – the graph displayed in the PowerPoint show demonstrated a 2-point improvement on the Mini Mental State Exam (MMSE), an effect that began after 6 months of donepezil use, and persisted for only 6 months after that. A 2-point difference on the MMSE has no clinical relevance of which I’m aware. The drug’s common side effects include: nausea, vomiting, diarrhea, loss of appetite, tiredness, drowsiness, trouble sleeping, or muscle cramps. That day I vowed never to prescribe the drug to my elderly patients.
Nonetheless, I was dumbfounded by the number of patients who came to the hospital already on the medication. Over and over again I heard the same story: “mom is becoming forgetful so our doctor started her on this medication to help her memory.”
When I asked if the family if they thought the medicine helped, the response was equally predictable: a shrug and then “what else can we do?”
Here we have a classic example of a medical problem with no satisfactory treatment or cure – and a desperate desire on the part of patients and family members to do something – anything – about it. Many times people in these predicaments turn to alternative medicines, herbal supplements and faith –based remedies. And sometimes they turn to FDA-approved drugs.
The Cochrane Collaborative has reviewed the scientific literature on the use of cholinesterase inhibitors (like donepezil) in mild dementia, and has found:
There is no evidence to support the use of donepezil for patients with mild cognitive impairment (MCI). The putative benefits are minor, short lived and associated with significant side effects. http://www.cochrane.org/reviews/en/ab006104.html
So how did this drug get approved? Well, there do seem to be some small improvements (of dubious clinical significance in my opinion) in measures of cognitive impairment in patients with Alzheimer’s dementia in particular. http://www.cochrane.org/reviews/en/ab005593.html
AHRQ states:
The evidence is mixed, however, about the effects of cholinesterase inhibitors on functional measures such as instrumental activities of daily living (i.e., ability to use the telephone, mode of transportation, responsibility for medication, and ability to handle finances). In general, the studies show little or no effect on functional decline after 6 months of treatment and a small but statistically significant difference from placebo after 12 months of treatment.
Research has found no clinically important differences between people taking cholinesterase inhibitors and those taking placebo in the development of behavioral and psychological symptoms… Studies rarely addressed other important health outcomes such as utilization of health care services, injuries, and caregiver burden.
http://www.ahrq.gov/clinic/3rduspstf/dementia/dementsum.htm
Pfizer’s press release (when they received FDA approval to market Aricept in 1996) noted:
Alzheimer’s disease is a family tragedy. ARICEPT will benefit patients and families alike by improving or maintaining patient function, which in turn may help ease the burden for caregivers and help maintain personal dignity… “ARICEPT represents a significant step forward in addressing the therapeutic needs of the Alzheimer’s disease community…This therapy will help to change the approach to the management of Alzheimer’s disease.
http://www.pslgroup.com/dg/e2aa.htm
Global sales of Aricept were approximately $1.1 billion for 2008 alone.
Me-too cholinesterase inhibitors have seen similar global profits, with sales of namenda at about $1 billion as well in 2008. http://www.businessweek.com/magazine/content/04_14/b3877629_mz073.htm All this while the AHRQ can find no clinically relevant difference between the drugs in this class, and the effects they have are small and short lived.
There are pharmaceutical innovations that have changed the course of history (imagine where we’d be without the polio or smallpox vaccines), while others leverage the tiniest statistically-significant effects to drive global drug empires driven by public feelings of helplessness in the face of currently incurable diseases.
It’s no wonder that the public has a mistrust of pharma – their marketing engines drive sales of drugs that have vastly different clinical value. That means it’s up to physicians and scientists to tease out the legitimate enthusiasm from the marketing hype. And judging from all the patients with mild dementia that I see on cholinesterase inhibitors, I give us a failing grade.

I distinctly remember the day I attended a “drug lunch” (as a PM&R resident in New York City) to learn about the value of donepezil (Aricept) for the treatment of dementia. I was surprised by the drug’s lack of efficacy – the graph displayed in the PowerPoint show demonstrated a 2-point improvement on the Mini Mental State Exam (MMSE), an effect that began after 6 months of donepezil use, and persisted for only 6 months after that. A 2-point difference on the MMSE has no clinical relevance of which I’m aware. The drug’s common side effects include: nausea, vomiting, diarrhea, loss of appetite, tiredness, drowsiness, trouble sleeping, or muscle cramps. That day I realized that the risk-benefit profile did not support its use.

Nonetheless, I was perplexed by the number of patients who came to the hospital already on the medication. Over and over again I heard the same story: “Mom is becoming forgetful so our doctor started her on this medication to help her memory.” (more…)

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James Ray and testosterone replacement therapy (TRT)

For the last four years I have served in a volunteer capacity among a panel of pharmacotherapy experts queried regularly by the ABC News Medical Unit about breaking or upcoming news involving the efficacy and safety of drugs and supplements. Where appropriate, I provide background information that informs the story.

My incentive is largely to put my time where my mouth is when I say that scientists need to take a more active role in making sure medical stories are reported accurately. An additional dividend is paid to my students who then benefit from my presentation of the science behind timely medical developments.

On occasion, perhaps once or twice a year, I’ll be asked for an on-camera interview. Even when this occurs, the resulting story will contain no more than 15 seconds of the interview and some summary by the reporter of other issues we discussed. I take this responsibility very seriously and prepare as much as I can given the deadlines of the press and my daily education and research schedule.

But given airtime constraints, much of what I prepare would normally end up in the abyss of my files and come out in the classroom when I lecture about that particular topic. Blogging, however, now allows us to expand further on stories where we are consulted, giving us an opportunity to air, albeit to a smaller audience, the information we found important from our perspective. Authoring a blog, therefore, takes away the excuse some scientists and physicians have in not wanting to talk to the press: “There’s never enough airtime to tell the whole story the way I would tell it.”

This post was informed by one of those brief appearances, this time on ABC World News Sunday with Dan Harris. The interview was solicited last weekend following the release of information obtained during the execution of a search warrant in lodging occupied by the self-help guru, James Arthur Ray, who led an Arizona sweat lodge ceremony last October where three people ultimately died and almost two dozen were hospitalized. The segment was not archived to the World News website but some ABC affiliates subsequently aired truncated versions of the story.
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Posted in: Diagnostic tests & procedures, Pharmaceuticals, Science and the Media

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Osteoporosis Drugs: Good Medicine or Big Pharma Scam?

A recent story on NPR accused the drug manufacturer Merck of inventing a disease, osteopenia, in order to sell its drug Fosamax. It showed how the definition of what constitutes a disease evolves, and the role that drug companies can play in that evolution.

Osteoporosis is a reduction in bone mineral density that leads to fractures. The most serious are hip fractures, which require surgery, have complications like blood clots, and carry a high mortality. Many of those who survive never walk again. Vertebral fractures are common in the osteoporotic elderly and are responsible for dowager’s hump and loss of height. There is also an increased risk of wrist and rib fractures.

Bone density tends to decrease with age. Postmenopausal women are particularly susceptible to osteoporosis when their production of estrogen declines. The risk is increased in people taking corticosteroids and in people with certain diseases like rheumatoid arthritis. Other risk factors are European or Asian ancestry, smoking, excess alcohol, a family history of fractures, vitamin D deficiency, too much or too little exercise, malnutrition, and low body weight.

When a measurement like bone density varies widely in a population and decreases with age, how can we decide where to draw the line and call it abnormal? When does it become a disease requiring treatment? (more…)

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Recombinant Human Antithrombin – Milking Nanny Goats for Big Bucks

Antithrombin deficiency is a hereditary disease causing low levels or defects of antithrombin, a blood protein required for controlling clot formation. Patients are at risk of blood clots, organ damage, and death. They usually have to take oral anticoagulant drugs like warfarin for life.

During high-risk procedures like surgery or childbirth, oral anticoagulants must be discontinued to minimize the chance of bleeding complications. While patients are off oral anticoagulants, they are given preventive treatment with antithrombin derived from pooled human blood. With any human blood product there is a small risk of infection with diseases like hepatitis C. And human antithrombin supplies are not plentiful.

Clever researchers found an ingenious solution. Put a human antithrombin gene in goats, milk them, isolate the human antithrombin protein from the milk, and voila! An udderly safe and plentiful source. A Brit might call it bleatin’ brilliant. (more…)

Posted in: Pharmaceuticals, Science and Medicine

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All Medicines Are Poison!

That’s the title of a new book  by Melvin H. Kirschner, M.D. When I first saw the title, I expected a polemic against conventional medicine. The first line of the Preface reassured me: “Everything we do has a risk-benefit ratio.” Dr. Kirschner took the title from his first pharmacology lecture in medical school. The professor said “I am here to teach you how to poison people.” After a pause, he added, “without killing them, of course.” 

He meant that any medicine that has effects has side effects, that the poison is in the dose, and that we must weigh the benefits of any treatment against the risks. Dr. Kirschner has no beef with scientific medicine. He does have a lot of other beefs, mainly with the health insurance industry, the pharmaceutical industry, and alternative medicine. (more…)

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An open letter to Dr. J. Douglas Bremner

Peter Lipson wrote a post last week entitled Before You Trust That Blog…, which was a criticism of Dr. J. Douglas Bremner’s blog Before You Take That Pill. Dr. Bremner was not pleased, and posted a rebuttal entitled Response to Peter Lipson MD of “Science” Based Blogs, My Blog Does Not Suck, Yours Does. Given the kerfuffle and my role as managing editor of SBM, I felt the need to put my two cents in, which is why I’m posting this open letter to Dr. Bremner. This letter started as a much briefer response that I was going to e-mail to Dr. Bremner, but as I wrote it grew and grew to the point where I decided that, given the public nature of the disagreement between Dr. Lipson and Dr. Bremner, I might as well make my commentary public too. Consider it a bonus post from me. I still plan a post for my usual slot on Monday. In the meantime, here’s my open letter:
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Posted in: Medical Academia, Pharmaceuticals, Public Health, Science and the Media, Vaccines

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“Oh, come on, Superman!”: Bill Maher versus “Western medicine”

I realize that I’ve spent a fair amount of verbiage (to put it mildly) expressing my frustration with celebrities whose support for pseudoscience and even outright quackery endanger public health. The two most frequent targets of the wrath, sarcasm, frustration, and puzzlement of me and my partners in crime at SBM have been Jenny McCarthy and her boyfriend Jim Carrey for their having emerged over the last two years as the most vocal celebrity faces of the anti-vaccine movement in general and the anti-vaccine organization Generation Rescue in particular and Oprah Winfrey for her promotion of pseudoscience, quackery, and mysticism on her show. That doesn’t even count Oprah’s inking of a development deal with Jenny McCarthy to do her own weekday talk show, which has poised McCarthy to walk in the footsteps of previous Oprah proteges, such as Dr. Phil McGraw and Dr. Mehmet Oz. I’ve also lamented how celebrity physicians like Dr. Jay Gordon, Robert “Bob” Sears, and the hosts of the daytime TV show The Doctors have promoted, through the mantra of “balance,” anti-vaccine views in particular and pseudoscience about health in general.

As bad as celebrities such as Oprah, Jim Carrey, and Jenny McCarthy are, though, no one views them as skeptics, at least no one I know and no one in the skeptical movement. Even the reporters and newscasters who credulously interview them, I suspect, realize that Oprah, Jim, and Jenny are not exactly the most scientific of people. Unfortunately, if there’s one thing I’ve learned over the years since I became more involved with the skeptical movement, it’s that being an agnostic, atheist, or skeptic is no guarantee against falling for pseudoscience. The problem is that when someone becomes associated with the skeptic movement for another reason, even if that person is a total woo-meister when it comes to medicine, they tend to be given a pass. I don’t give such people a pass because of their anti-religion views because I consider myself a skeptic and don’t really care much about religion, except when it intersects issues of science and health, such as Jehovah’s Witnesses refusing blood transfusions, faith healers offering prayer instead of medicine, and fundamentalists undermining the teaching of evolution. If someone who promotes pseudoscience is a prominent critic of religion, to me that makes it even worse when they spout nonsense.

I’m referring to Bill Maher, comedian and host of the HBO show Real Time With Bill Maher. Thanks to an anti-religion movie (Religulous) and his frequent stance as a “skeptic,” many of my fellow skeptics consider him one of our own, even to the point of giving him an award named after Richard Dawkins. Yet, when it comes to medicine, nothing could be further from the truth. Maher’s own words show that he has anti-vaccine views, flirts with germ theory denialism and HIV/AIDS denialism, buys into extreme conspiracy theories about big pharma, and promotes animal rights pseudoscience. That’s not a skeptic or a supporter of science-based medicine.
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Posted in: Pharmaceuticals, Public Health, Science and the Media, Vaccines

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Off-Label Use of Prescription Drugs

A recent survey of 599 primary care physicians and 600 psychiatrists found that:

The adjusted response rate was 47%, respondents were similar to non-respondents, and physicians commonly prescribed the drugs examined. The average respondent accurately identified the FDA-approval status of just over half of the drug-indication pairs queried (mean 55%; median 57%). Accuracy increased modestly (mean 60%, median 63%) when limited to drugs the respondent reported having prescribed during the previous 12 months. There was a strong association between physicians’ belief that an indication was FDA-approved and greater evidence supporting efficacy for that use (Spearman’s 0.74, p < 0.001). However, 41% of physicians believed at least one drug-indication pair with uncertain or no supporting evidence (e.g., quetiapine [Seroquel®] for dementia with agitation) was FDA approved.

These results are interesting, but deserve to be dissected a bit further. Taken at face value they indicate that physicians need better education regarding the FDA indications and (more importantly) the evidence-base for commonly prescribed drugs. This is an uncontroversial recommendation, and I personally strongly advocate more thorough physician continuing medical education.

Of course, at SBM we have to also dissect the weaknesses of any study we examine. This was a voluntary survey with a 47% response rate, which opens the door for significant responder bias. The survey does not broadly represent different specialties and therefore its relevance beyond primary care and psychiatry is uncertain. The details of the study may also have greatly influenced the outcome.

For example, one of the drug-indication pairs was gabapentin for diabetic peripheral neuropathy. Gabapentin is not specifically indicated for diabetic neuropathy, but it is indicated for post-herpetic neuralgia. Both conditions are forms of neuropathic pain, and it is highly scientifically plausible for a treatment of one condition to also be effective for the other. In fact, there is strong evidence that gabapentin is effective for diabetic neuropathy, and it is commonly prescribed for this condition (in fact insurance companies often require that it is first line treatment as it is now available generically and is therefore less expensive than newer drugs that are indicated specifically for diabetic neuropathy). In other words, this was one of the easiest mistakes to make.

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Is Tylenol Safe?

Tylenol (acetaminophen, also known as paracetamol outside the US) has been in the news recently. Most of the stories I’ve seen have been accurate, but I’ve run across a couple of people who misunderstood what they read. I thought I’d try to put the record straight.

An FDA advisory panel has recommended reducing the maximum allowed single dose from 1000 mg to 650 mg in over-the-counter acetaminophen products. The 1000 mg dose would be available by prescription only. They also recommended eliminating painkillers like Percocet and Vicodin that contain a combination of a narcotic and acetaminophen. They did not recommend removing acetaminophen from over-the-counter cold remedies, cough medicines and similar products that combine acetaminophen with other drugs. Advisory panel recommendations are not binding, but the FDA usually follows them.

Some people got the impression that the FDA had just discovered that acetaminophen can be dangerous. No, we always knew that. The danger is when you take too much: it can damage the liver. The “new” information is just that acetaminophen overdose is now the leading cause of liver damage, causing an estimated 1600 cases of liver failure each year. (more…)

Posted in: Pharmaceuticals, Politics and Regulation

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Naturopathic Prescribing: The Dark Side Beckons

I am a terrible Oregon chauvinist.  I think there is no better place to live on the planet. Period.  Great natural beauty, not a lot of people, best beer ever and no pro football team. Oregon is both casual and tolerant.  It is safe to say that dressing up in the Pacific NW means tucking your t shirt into your jeans.  And the citizens of the NW, especially in the Portland metro area, are tolerant of  a diverse number of alternative life styles. What more could you want?

No good deed goes unpunished. The downside of toleration is the proliferation of alternative medicine.  Portland has  a school of chiropractic, a college of oriental medicine and  the country’s oldest school of naturopathy, established in 1956.  It is a year older than me. There are about 850 ND’s in Oregon.  To judge from the number of alternative practitioner offices around my hospital,  most of the graduates stay in Portland.

There are five health care systems in Portland.   Three of the five have hired naturopaths as part of their complementary medicine programs.   My system, as of yet, does not have a scam practitioner on staff, a fact of which I am most proud.  Yet,  I suppose it will come some day. However, if you wonder if a hospital practices evidence and science based medicine, see if they have a naturopath, a chiropractor or an acupuncturist on staff.  If they do, they may be interested in issues other than providing quality health care.

Oregon has had a Board of Naturopathic physicians since 1929 to oversee naturopathic practice.  There has been a long tradition of legislative oversight of naturopathy in Oregon, but they have been able, until recently, to only prescribe medications that are naturally derived.  None of that synthetic nonsense for naturopaths. Natural products only.  Until this month.

In Oregon, naturopaths are no longer limited to natural, herbal and homeopathic concoctions, they can also prescribe substances that actually work.  Recently House Bill 327  was passed by the Oregon legislature to expand the prescriptive privileges of naturopaths.  Drugs can now be added to the naturopathic  formulary just by asking.  The bill was passed by the Senate 22-7 and the House unanimously.  Bummer. If you live in Oregon and want to pester your representative on their profound stupidity, a list is at  http://gov.oregonlive.com/bill/SB327/. Send them a link to this post.

As a shill for big pharma and a tool of the medical-industrial complex, I suggest this may not be such a  good idea.  Naturopaths do not have the training, experience  or understanding of medicine to safely prescribe medications. Their understanding of disease and the various therapies taught at naturopathic schools are antithetical to what is required to safely and knowledgeably  prescribe modern medications.
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