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.)

96 Comments | marketing, medications, psychiatry | Tagged: , , , , , , , | Permalink
Posted by stevebMD

Here’s A Disease. Do You Have It?

March 29, 2011

I serve as a consultant to a student organization at a nearby university.  These enterprising students produce patient-education materials (brochures, posters, handouts, etc) for several chronic diseases, and their mission—a noble one—is to distribute these materials to free clinics in underserved communities, with a goal to raise awareness of these conditions and educate patients on their proper management.

Because I work part-time in a community mental health clinic, I was, naturally, quite receptive to their offer to distribute some of their handiwork to my patients.  The group sent me several professional-looking flyers and brochures describing the key features of anxiety disorders, depression, PTSD, schizophrenia, and insomnia, and suggested that I distribute these materials to patients in my waiting room.

They do an excellent job at demystifying (and destigmatizing) mental illness, and describe, in layman’s terms, symptoms that may be suggestive of a significant psychiatric disorder (quoting from one, for example: “Certain neurotransmitters are out of balance when people are depressed.  They often feel sad, hopeless, helpless, lack energy, … If you think you may be depressed, talk to a doctor.”)  But just as I was about to print a stack of brochures and place them at the front door, I thought to myself, what exactly is our goal?

Experiencing symptoms of anxiety, depression, or insomnia doesn’t necessarily indicate mental illness or a need for medications or therapy; they might reflect a stressful period in one’s life or a difficult transition for which one might simply need some support or encouragement.  I feared that the questions posed in these materials may lead people to believe that there might be something “wrong” with them, when they are actually quite healthy.  (The target audience needs to be considered, too, but I’ll write more about that later.)

It led me to the question: when does “raising awareness” become “disease mongering”?

“Disease-mongering,” if you haven’t heard of it, is the (pejorative) term used to describe efforts to lead people to believe they have a disease when they most likely do not, or when the “disease” in question is so poorly defined as to be questionable in and of itself.  Accusations of disease-mongering have made in the area of bipolar disorder, fibromyalgia, restless legs syndrome, female sexual arousal disorder, “low testosterone,” and many others, and have mainly been directed toward pharmaceutical companies with a vested interest in getting people on their drugs.  (See this special issue of PLoS One for several articles on this topic.)

Psychiatric disorders are ripe for disease-mongering because they are essentially defined by subjective symptoms, rather than objective signs and tests.  In other words, if I simply recite the symptoms of depression to my doctor, he’ll probably prescribe me an antidepressant; but if I tell him I have an infection, he’ll check my temperature, my WBC count, maybe palpate some lymph nodes, and if all seems normal he probably won’t write me a script for an antibiotic.

It’s true that some patients might deliberately falsify or exaggerate symptoms in order to obtain a particular medication or diagnosis.  What’s far more likely, though, is that they are (unconsciously) led to believe they have some illness, simply on the basis of experiencing some symptoms that are, more or less, a slight deviation from “normal.”  This is problematic for a number of reasons.  Obviously, an improper diagnosis leads to the prescription of unnecessary medications (and to their undesirable side effects), driving up the cost of health care.  It may also harm the patient in other ways; it may prevent the patient from getting health insurance or a job, or—even more insidiously—lead them to believe they have less control over their thoughts or behaviors than they actually do.

When we educate the public about mental illness, and encourage people to seek help if they think they need it, we walk a fine line.  Some people who may truly benefit from professional help will ignore the message, saying they “feel fine,” while others with very minor symptoms which are simply part of everyday life may be drawn in.  (Here is another example, a flyer for childhood bipolar disorder, produced by the NIH; how many parents & kids might be “caught”?)  Mental health providers should never turn away someone who presents for an evaluation or assessment, but we also have an obligation to provide a fair and unbiased opinion of whether a person needs treatment or not.  After all, isn’t that our responsibility as professionals?  To provide our honest input as to whether someone is healthy or unhealthy?

I almost used the words “normal” and “abnormal” in the last sentence.  I try not to use these words (what’s “normal” anyway?), but keeping them in mind helps us to see things from the patient’s perspective.  When she hears constant messages touting “If you have symptom X then you might have disorder Y—talk to your doctor!” she goes to the doctor seeking guidance, not necessarily a diagnosis.

The democratization of medical and scientific knowledge is, in my opinion, a good thing.  Information about what we know (and what we don’t know) about mental illness should indeed be shared with the public.   But it should not be undertaken with the goal of prescribing more of a certain medication, bringing more patients into one’s practice, or doling out more diagnoses.  Prospective patients often can’t tell what the motives are behind the messages they see—magazine ads, internet sites, and waiting-room brochures may be produced by just about anyone —and this is where the responsibility and ethics of the professional are of utmost importance.

Because if the patient can’t trust us to tell them they’re okay, then are we really protecting and ensuring the public good?

(Thanks to altmentalities for the childhood bipolar flyer.)

13 Comments | diagnostics, mental health | Tagged: , , , , | Permalink
Posted by stevebMD

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