The Balance of Information

May 19, 2011

How do doctors learn about the drugs they prescribe?  It’s an important question, but one without a straightforward answer.  For doctors like me—who have been in practice for more than a few years—the information we learned in medical school may have already been replaced by something new.  We find ourselves prescribing drugs we’ve never heard of before.  How do we know whether they work?  And whom do we trust to give us this information?

I started to think about this question as I wrote my recent post on Nuedexta, a new drug for the treatment of pseudobulbar affect.  I knew nothing about the drug, so I had to do some research.  One of my internet searches led me to an active discussion on a site called studentdoctor.net (SDN).  SDN is a website for medical students, residents, and other medical professionals, and it features objective discussions of interesting cases, new medications, and career issues.  There, I found a thread devoted to Nuedexta; this thread contained several posts by someone calling himself “Doogie Howser”—and he seemed to have a lot of detailed information about this brand-new drug.

Further internet sleuthing led me to a message board on Yahoo Finance for Avanir Pharmaceuticals, the company which makes Nuedexta.  In one of the threads on this board, it was suggested that the “Doogie Howser” posts were actually written by someone I’ll call “TS.”  Judging by the other posts by this person, “TS” clearly owns stock in Avanir.  While “TS” never admitted to writing the SDN posts, there was much gloating that someone had been able to post pro-Nuedexta information on a healthcare website in a manner that sounded authoritative.

Within 24 hours of posting my article, someone posted a link to my article on the same Yahoo Finance website. I received several hundred “hits” directly from that link.  Simultaneously (and ever since), I’ve received numerous comments on that article, some of which include detailed information about Nuedexta, reminiscent of the posts written by “Doogie Howser.” Others appear to be written by “satisfied patients” taking this drug.  But I’m skeptical. I don’t know whether these were actual patients or Avanir investors (or employees); the IP address of one of the pro-Nuedexta commenters was registered to a public-relations firm in Arizona. Nevertheless, I have kept the majority of the posts on the blog, except those that contained personal attacks (and yes, I received those, too).

The interesting thing is, nothing “TS”/”Doogie Howser” said about Nuedexta was factually incorrect.  And most of the posts I received were not “wrong” either (although they have been opinionated and one-sided).  But that’s precisely what concerns me. The information was convincing, even though—if my hunch is correct—the comments were written for the sake of establishing market share, not for the sake of improving patient care.

The more worrisome issue is this: access to information seems to be lopsided.  Industry analysts (and even everyday investors) can have an extremely sophisticated understanding of new drugs on the market, more sophisticated, at times, than many physicians.  And they can use this sophistication to their advantage. Some financial websites and investor publications can read like medical journals.  Apparently, money is a good motivator to obtain such information and use it convincingly.  Quality patient outcomes? Not so much.

So what about the doctor who doesn’t have this information but must decide whether to prescribe a new medication?  Well, there are a few objective, unbiased sources of information about new drugs (The Medical Letter and The Carlat Report among them).  Doctors can also ask manufacturers for the Prescribing Information (“PI”) or do their own due diligence to learn about new treatments.  But they often don’t have the time to do this, and other resources (like the internet) are far more accessible.

However, they’re more accessible for everyone.  When the balance of information about new treatments is tipped in favor of drug manufacturers, salespeople, and investors—all of whom have financial gain as their top priority—and not in favor of doctors and patients (whose lives may be at stake), an interesting “battle of wits” is bound to ensue.  When people talk a good game, and sound very much like they know what they’re talking about, their motives must always be questioned.  Unfortunately—and especially under the anonymity of the internet—those motives can sometimes be hard to determine.  In response, we clinicians must be even more critical and objective, and not necessarily believe everything we hear.


Horizant: The Second Coming of Gabapentin

April 8, 2011

Like the religious notion of reincarnation, apparently some drugs are destined to be reborn as newly designed and re-packaged drugs for brand new indications.  I’ve written about Contrave and Silenor, for instance—two drugs with generic equivalents that have been re-tweaked, re-packaged, and renamed, for newer (and larger) markets.

This week, the FDA granted its approval to yet another “new” agent (that’s “new” with an asterisk, mind you), Horizant, developed by GlaxoSmithKline (GSK) and Xenoport.  Horizant is a name-brand version of gabapentin, which is also known as Neurontin.  While on the surface this appears to be an attempt to re-brand an existing drug, it may actually provide some advantages over the already-available alternative.  But the question is, at what cost?  And for what exactly?

Gabapentin was approved in 1994 and is marketed as Neurontin.  It’s approved for the treatment of partial seizures and post-herpetic neuralgia (although its manufacturer, Pfizer, got into some serious trouble for extensive off-label marketing of this compound—so what else is new?).  These days, it’s actually quite widely used by neurologists and psychiatrists, not just for seizures, but also for  chronic pain syndromes, anxiety, mood stabilization (where it’s not particularly effective), and even for alcohol dependence.

Gabapentin’s bioavailability—the ability of the drug to enter the bloodstream when taken as an oral dose—is rather low (and, paradoxically, decreases as the dose is increased) and the duration of its action is quite short, which means that users need to take this drug three or four times daily.  The key advantage of Horizant is that it is a “pro-drug.”  Technically it’s gabapentin enacarbil, and the “enacarbil” refers to a molecule added to the drug which allows it to be absorbed along the entire GI tract, resulting in greater blood levels.

(Interestingly, in early 2010 the FDA rejected Horizant’s first request for approval, citing a small but significant risk of cancer.  They relented, however, and approved it this year after “reconsidering the risks and benefits.”  Sound fishy?  No, I’m sure it’s all good.)

So who might use Horizant?  Well, you can bet that GSK and Xenoport hope that anyone who currently uses Neurontin (and there are a lot of them) is a potential customer patient.  Officially, though, it was approved for the treatment of restless legs syndrome (RLS).

Now, RLS is one of those “diseases that may not be diseases”—or “diseases that you didn’t know you had.”  (See the articles here and here for accusations of “disease mongering” by GSK [hey! GSK! Coincidence? I don’t think so!] when it introduced Requip, the first “treatment” for RLS.)  Hopefully it goes without saying that when you see headlines like “Disease X may affect  7-10% of the population” when, in fact, no one had even heard of Disease X ten years ago, you have to be somewhat suspect.

Nevertheless, like much else in psychiatry, there may be some reality to RLS; it may in fact be a true pathophysiological entity that responds to medication.  (Whether this entity afflicts 10% of the population is another story.)  Current treatment strategies involve dopamine replacement, in the form of Requip (ropinirole) or Mirapex (pramipexole) so maybe dopamine insufficiency is part of the process.

The symptoms of RLS are “an urge to move the limbs, which improves with activity and worsens with rest.”  That’s about it.  Which leads to yet another problem (a problem that GSK and Xenoport don’t see as a problem, that’s for sure): with such nonspecific and common symptoms (who among us hasn’t felt somewhat restless, with interrupted sleep?), a lot of people might get diagnosed with RLS when their symptoms are actually due to something else.

I thought of this a few weeks ago, when I saw that the RLS “patient page” on the National Institutes of Health (NIH) web site referred to RLS as “akathisia” (thanks to altmentalities for the link).  Akathisia (from the Greek for “not sitting still”) has long been recognized as a side effect of some—perhaps most—psychiatric medications, from antipsychotics to antidepressants.  It is often described as an “inner restlessness,” a “need to keep moving.”  Sometimes it’s associated with extreme emotional distress.  In terms of severity, it can range from a mild nuisance to—in some cases—aggressive tendencies.  (Indeed, the psychiatrist David Healy has even linked psychotropic-induced akathisia to suicide attempts and violent behavior.)

Psychiatrists really don’t know exactly what causes akathisia, and disagree on how to treat it.  It may have something to do with dopamine blockade, or something completely independent.  Treatment might consist of benzodiazepines (like Ativan or Valium), beta blockers (like propranolol), or discontinuing the drug that caused it in the first place.

Unlike RLS, which seems to bother people most when they are lying down (hence its tendency to disrupt sleep), drug-induced akathisia is worse when people are awake and moving around.  Sounds like a simple distinction.  But nothing is quite this simple, particularly when psychiatric drugs—and real people—are involved.   In fact, many psychiatric meds can cause other motor side effects, too, involving (theoretically) yet other neural pathways, such as “parkinsonian” side effects like rigidity and tremor.  (In fact, some antipsychotic drug trials show “restlessness” and “akathisia” as entirely separate side effects, and when I’ve tried to ask experts to explain the difference, I have never received a straightforward answer.)

So what does this all mean for Horizant?  I could be cynical and simply remark that GSK/Xenoport are capitalizing on the nonspecificity of symptoms, the tremendous diagnostic overlap, and the fact that motor side effects, in general, are common side effects of antipsychotics (one of the most widely prescribed drug classes worldwide).  In other words, they know that there are a lot of people out there with “restless legs” for all kinds of reasons, and lots of psychiatrists who will misdiagnose akathisia as RLS and prescribe Horizant for this purpose.  But in reality, that remark would not be all that cynical.  Remember, there is this pesky little thing called “return on investment.”

What it means for the patient (or should I say “customer”) is more confusing.  A new agent with apparently better availability and kinetics than gabapentin is now available, but approved for the treatment of something that may or may not exist (in most patients), and may or may not be more effective than gabapentin itself.  Oh, and a hefty price tag, too.  Ah, the wheels of psychopharmacology keep turning….

(NB: altmentalities has also written her point of view on the Horizant story… I suggest you check it out, too.)


Thank You, Somaxon Pharmaceuticals!

March 18, 2011

One year ago today, the pharmaceutical company Somaxon introduced Silenor, a new medication for the treatment of insomnia, and today I wish to say “thanks.”  Not because I think Silenor represented a bold new entry into the insomnia marketplace, but because Somaxon’s R&D and marketing departments have successfully re-introduced doctors to a cheap, old medication for a very common clinical complaint.

You see, Silenor is a branded version of a generic drug, doxepin, which has been around since the 1970s.  Doxepin is classified as a tricyclic antidepressant, even though it’s not used much for depression anymore because of its side effects, mainly sedation.  Of course, in psychiatry we sometimes exploit the side effects of certain drugs to treat entirely different conditions, so it’s not surprising that doxepin—which has been generic (i.e., cheap) for the last few decades—has been used occasionally for the treatment of insomnia.  However, this is an “off-label” use, and while that doesn’t prevent doctors from prescribing it, it may make us less likely to consider its use.

Somaxon spent several years, and millions of dollars, developing Silenor, a low-dose formulation of doxepin.  Stephen Stahl (paid by Somaxon) even publicized low-dose doxepin in his CNS Spectrums column.  Generic doxepin is currently available in comparatively high doses (10, 25, 50, 75, 100, and 150 mg), but Somaxon found that lower doses (6 and 3 mg, even 1 mg) can be used to treat insomnia.  Silenor is sold at 3 and 6 mg per tablet.

The obvious question here (to both expert and layman alike) is, what’s so special about the 3 or 6 mg dose?  Why can’t I just take a generic 10 mg pill and cut it in half (or thereabouts), for a homemade 5-mg dose?  Well, for one thing, the 10 mg dose is a capsule, so it can’t be split.  (There is a generic 10 mg/ml doxepin solution available, which would allow for very accurate dosing, but I’ll ignore that for now.)

Okay, so there’s the practical issue: pill vs. capsule.  But is 6 mg any better than 10 mg?  For any drug, there’s always variability in how people will respond.  The relative difference between 6 and 10 is large, but when you consider that people have been taking doses of up to 300 mg/day (the maximum approved dose for depression) for decades, it becomes relatively meaningless.  So what gives?

It’s natural to ask these questions.  Maybe Somaxon was hoping that doctors and patients simply assume that they’ve done all the necessary studies to prove that, no, doxepin is an entirely different drug at lower doses, and far more effective for sleep at 3 or 6 mg than at any other dose, even 10 mg.  Indeed, a few papers have been published (by authors affiliated with Somaxon) showing that 3 and 6 mg are both effective doses.  But they still don’t answer:  how are those different from higher doses?

I contacted the Medical Affairs department at Somaxon and asked this very question.  How is 3 or 6 mg different from 10 mg or higher?  The woman on the other end of the line, who (one would think) must have heard this question before, politely responded, “Doxepin’s not approved for insomnia at doses of 10 mg or higher, and the 3 and 6 mg doses are available in tablet form, not capsule.”

I knew that already; it’s on their web site.  I would like to think that no psychiatrist asking my question would settle for this answer.  So I asked if she had some additional information.  She sent me a six-page document entitled “Is the 10 mg Doxepin Capsule a Suitable Substitute for the Silenor® 6 mg tablet?”  (If you’re interested in reading it, please email me.)

After reading the document, my response to this question is, “well, yes, it probably is.”  The document explains that doxepin hasn’t been studied as an insomnia agent at higher doses (in other words, nobody has tried to get FDA approval for doxepin in insomnia), and the contents of the tablet are absorbed at a different rate than the capsule.

But what really caught my eye was the following figure, which traces plasma concentration of doxepin over a 12-hour period.  The lower curve is for 6 mg of Silenor.  The higher curve is for “estimated” 10 mg doxepin.

Huh?  “Estimated”?  Yes, that’s right, the upper curve was actually obtained by giving people 50 mg doxepin capsules and then “estimating” the plasma concentrations that would result if the person had actually been given 10 mg capsules.  (I know, I had to read it twice myself.)  I don’t know how they did the estimation.  Did they divide the plasma concentration by 5?  Use some other equation involving fancy things like logarithms or integrals?  I don’t know, and they don’t say.  Which only begs the question: why didn’t they just use 10 mg capsules for this study???

That seems a little fishy.  At any rate, their take-home message is the fact that with the lower dose, there’s less doxepin left over in the bloodstream after 8 hours, so there’s less of a “hangover” effect the next morning.  But this just raises even more questions for me.  If this is the case, then what about all those people who took 75-150 mg each day for depression?  Wouldn’t that result in a constant “hangover” effect?  I didn’t practice in the 1970s and 1980s, but I’m guessing that depressed people on doxepin weren’t in bed 24 hours a day, 7 days a week.  (I know, the serotonergic and noradrenergic effects “kick in” at higher doses, but the histamine and alpha-1 adrenergic receptors are already saturated.)  A related question is, what plasma concentration of doxepin is required to induce sleep anyway?  What plasma concentration accounts for a “hangover” effect?  0.5?  1.0?  2.0?  Does anyone know?

The Somaxon document states that “clinical trials demonstrated only a modest increase in mean sleep maintenance efficacy when the dose is increased from 3 mg to 6 mg.”  But according to the graph above, the 3 mg curve would be expected to look quite different, as it’s a 50% reduction in dose.  (And I can’t even begin to think what the 1 mg curve would look like, but that apparently works, too.)

We all know (or should know) that tables, charts, and graphs can be used to convey just about any message.  It’s important to look at which data are presented, but also which data are not presented, in order to draw any conclusions.  We must also ask what the data actually mean (i.e., the importance of a plasma concentration—what does it actually mean for a clinical effect?).  In the end, Somaxon’s “explanation” seems like a pretty flimsy explanation for using a very expensive name-brand drug.

That said, I do have to say “thank you” to Somaxon for reminding me of yet another medication that I can use to help treat insomnia.  Not Silenor, but low-dose generic doxepin (10 mg).  It’s a shame they had to spend the millions of dollars on R&D, clinical trials, and marketing, to convince me to prescribe the generic version of their drug, which costs only pennies a pill, but then again, you pays your money, you takes your chances.

(Postscript:  Speaking of money, Somaxon stock closed at $2.70/share today, down from a high of $10.01 on the day Silenor was approved, a loss of $258 million of market capitalization.  Imagine all the soft pillows, soothing music CDs, and OTC sleep aids that money could have bought…)


Off-Label Meds: Caveat Prescriptor

March 13, 2011

In medicine we say that a drug is “indicated” for a given disorder when it has gone through rigorous testing for that condition. Typically, a drug company will perform clinical trials in which they select patients with the condition, give them the new drug, and compare them with similar patients who are given a placebo (or an established drug which is already used to treat the disease). In the US, when the FDA approves a drug, the drug company is then permitted to advertise it in magazines, journals, TV, the internet, and directly to doctors, but they must specify its “approved” use.

In the past few years, several drug companies have found themselves in trouble after accusations of marketing their drugs for off-label indications. Total fines have reached into the billions, and many companies have vowed to change their marketing practices in response.

It should be emphasized, however, that doctors use drugs off-label very frequently. This is particularly true in psychiatry, where an estimated 31% of all prescriptions are off-label. Some familiar examples include trazodone (an antidepressant) for insomnia or beta blockers (originally approved for hypertension and heart failure) for anxiety. Furthermore, some very common symptoms and conditions, such as personality disorders, impulsivity, nightmares, eating disorders, and PTSD, have no (or few) “indicated” medications, and yet we often treat them with medications, sometimes with great success. And since the FDA restricts its approvals to medications and devices, even psychotherapy—something we routinely recommend and “prescribe” to patients—is, technically, off-label.

One colleague took this one step further and explained that virtually any psychiatric drug which has been prescribed for more than 8 or 12 weeks is being used “off-label” since the studies to obtain FDA approval are generally no longer than that. Admittedly, that’s nitpicking, but it does demonstrate how the FDA approval process works with a very limited amount of clinical data.

Drug companies that deliberately market their drugs for off-label indications are indeed guilty of misrepresenting their products and deceiving doctors and consumers. But to blame them for bad patient outcomes conveniently ignores the one missing link in the process: the doctor who decided to prescribe the drug in the first place. Whether we like it or not, drug companies are businesses, they sell products, and as with everything else in our consumerist society, the buyer (in this case the doctor) must beware.

Here’s an example. A new drug came to market in February called Latuda, which has been FDA approved for the treatment of schizophrenia. Before a few months ago, most community psychiatrists (like me) knew absolutely nothing about this drug.

If a sales rep visits my office tomorrow and tells me that it’s approved for schizophrenia and for bipolar disorder, she is obviously giving me false information. This is not good. But how I choose to use the drug is up to me. It’s my responsibility—and my duty, frankly—to look at the data for schizophrenia (which exists, and which is available on the Latuda web site and in a few articles in the literature). If I look for data on bipolar disorder, I’ll find that it doesn’t exist.

That’s just due diligence. After reviewing the data, I may conclude that Latuda looks like a lousy drug for schizophrenia (I’ll save those comments for later). However, I might find that it may have some benefit in bipolar disorder, maybe on particular symptoms or in a certain subgroup of patients. Or, I might find some completely unrelated condition in which it might be effective. If so, I should be able to go ahead and use it—assuming I’ve exhausted the established, accepted, and less costly treatments already. Convincing my patient’s insurance company to pay for it would be another story… but I digress.

I don’t mean to imply that marketing has no place in medicine and that all decisions should be made by the physician with the “purity” of data alone. In fact, for a new drug like Latuda, sales reps and advertising materials are effective vehicles for disseminating information to physicians, and most of the time it is done responsibly. I just think doctors need to evaluate the messages more critically (isn’t that something we all learned to do in med school?). Fortunately, most sales reps are willing to engage doctors in that dialogue and help us to obtain hard data if we request it.

The bottom line is this: psychiatric disorders are complicated entities, and medications may have potential far beyond their “approved” indications. While I agree that pharmaceutical marketing should stick to proven data and not anecdotal evidence or hearsay, doctors should be permitted to use drugs in the ways they see fit, regardless of marketing. But—and this is critical—doctors have a responsibility to evaluate the data for both unapproved and approved indications, and should be able to defend their treatment decisions. Pleading ignorance, or crying “the rep told me so,” is just thoughtless medicine.


Levitra Ads Yanked From TV

January 25, 2011

Well, this is unfortunate news.  Drug maker GlaxoSmithKline is pulling its TV ads for Levitra.

No more awkward notices about “erections lasting longer than four hours” on the evening news.  No more of those suggestive glances between a couple out for a relaxing hike or enjoying a glass of wine on the back porch of their house (after their grown children have moved out, of course). No more reminders of how a simple pill can add that “spark” back in your relationship when you’d otherwise be worring about your retirement account, your mortgage, or which color of convertible to buy to satisfy your craving for youth.

In all seriousness, Glaxo sees erectile dysfunction as a “legitimate medical condition,” and while they’re committed to their product, they are pulling their direct-to-consumer Levitra ads “to be more respectful of patients.”  Says Dierdre Connelly, president of their North America pharmaceuticals unit, “when we walk into your home through television, we have to do it in a respectful way.”

That’s funny, when my friends walk into my home, they almost always ask me questions about my sex life and ask me indirect questions about whether I’m “ready.”

I have to admit, though, their German advertising is more entertaining:

 


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