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.)


EMRs and Zombie Psychiatry

April 5, 2011

I consider myself to be a fairly tech-savvy guy.  I grew up in the 80s and computers have been a part of my leisure time, my academic life, and my work environment for as long as I can remember.  But using an electronic medical record (EMR) is testing my patience.

More importantly, it’s yet another example of an external influence which is changing the practice of psychiatry.  And not for the better.

I learned how to practice medicine from teachers who valued the essence of the interpersonal relationship between patient and doctor.  What attracted me to psychiatry in particular was the fact that in this field, these unspoken and unquantifiable aspects of the doctor-patient dyad are paramount, much more so than in any other medical specialty.  The patient’s subjective feelings about the therapeutic relationship—the patient’s unconscious transference of experience from past relationships into the present, for example—are as much a part of the therapeutic process as his or her verbal reports or directly measurable behavioral symptoms.  The “soul” of psychiatry lies in this nonverbal interaction.

Moreover, this relationship transcends time.  For as much as we like to bemoan the “15-minute med check” appointment, the truth is that fifteen minutes is plenty of time for an expert clinician to get an overall feeling for a patient—the “Gestalt” impression that informs the treatment process.  By the same token, a one-hour session by a poorly trained clinician is nothing more than data gathering.

EMRs are changing how we document information.  One could argue, correctly, that documentation has always been an important part of clinical care, and not directly related to the doctor-patient relationship.  However, a well-written note (not to mention the exquisitely detailed psychodynamic case formulations from years past) can convey a rich trove of information about a patient’s history, symptoms, underlying pathology, and future goals.

The type of information we document in an EMR, however, is different.  I’ve commented elsewhere that the ideal EMR for a psychiatrist would be a word processor and an encrypted hard drive.  Nothing more.  Just let me enter all the information that I think is relevant in a given session and save it for next time.

But EMRs weren’t designed for the psychiatrist or the patient.  They were designed for administrators, billing experts, lawyers, insurance companies, and others who care more about the quantifiable aspects of the interaction (the diagnosis, the medication prescribed, the presence/absence of discrete symptoms) than about the patterns of symptoms, the clinician’s subjective assessment, and the hypotheses underlying the patient’s behavior which are being actively tested in the therapeutic relationship.

The amount of time it takes me to document everything that is required for “correct billing” of my appointments (and to double-check everything, lest I get a call from my administrator the next day to “fix the chart”) takes up virtually the entire scheduled appointment time.

But my concern here is not about the time it takes, or even about the nuisance of having to click on a few dozen boxes during each patient encounter, or open six different documents—in different formats, in non-overlapping windows—to see what’s happened since a patient’s last visit.  (I like to think that I’m a quick enough learner to do all of that.)  My concern instead is with how I’m now starting to think of patients not as human beings with interesting and complicated histories which inform my care, but rather as collections of symptoms which change from visit to visit.

EMRs demand measurement and assessment of patients on scales that are, for the most part, arbitrary, and which may be completely “off the mark” vis-à-vis what’s really happening in a person’s life.  They ask us to quantify things that cannot be quantified, and distract our attention from what might be truly significant in the patient’s life at the time of the encounter.

Hey, maybe that’s okay.  After all, it’s the monthly visits by patient 2010-00224, dx code 296.34, that pay the bills.  And as long as I’ve checked the boxes next to “depressed mood” or “insomnia” or “feelings of guilt” (not to mention the other two-dozen boxes I need to check for his mental status exam and review of systems), and updated his problem list, and made sure I checked the box indicating he isn’t suicidal (never mind whether I actually asked him or not), that counts as “good” care.

But by this time, I’m not a psychiatrist.  Heck, I’m not even a human, I’m entranced, soulless, and following someone else’s commands.  A zombie.  And patient 2010-00224 deserves more than that.


The Power Of No

April 3, 2011

Why is it that when someone tells us we can’t have something, we just want it more?  Marketers (those masters of neuropsychology) use this to their great advantage.  “Call now!  Offer expires in ten minutes!”  “Only one more available at this price!”  “Limited edition—Act now!”  Talk about incentive salience!!!

This phenomenon is known as the Scarcity Effect—a psychological principle saying that individuals don’t want to be left alone without an item—particularly something they believe they cannot have.  We’ve all experienced this in our personal lives.  Tight budgets often invite wasteful expenditures.  Obsession over “forbidden foods” has ruined many a diet.  Saying “no” to a child is frequently a trigger for constant begs and pleas.

Given the apparent universality of this concept, it’s surprising that we fall victim to it in medicine as often as we do, particularly at times when we want to motivate behavior change.  Saying “no” to a patient usually doesn’t work—it’s human nature.  In fact, if anything, the outcome is usually the opposite.  Reciting the dangers of cigarette smoking or obesity, for example, or admonishing a patient for these behaviors, rarely eliminates them.  The patient instead experiences shame or guilt that, paradoxically, strengthens his resistance to change.

But if we understand the Scarcity Effect, we doctors can outsmart it and use it to our advantage.  This can be important when we prescribe medications which are likely to be misused or abused, like sleep medications or benzodiazepines (Valium, Xanax, and others).  These drugs are remarkably effective for management of insomnia and anxiety, but their overuse has led to great morbidity, mortality, and increased health costs.  Similarly, narcotic pain medications are also effective but may be used excessively, with unfortunate results.  We discourage excessive use of these drugs because of side effects, the development of physical dependence, and something I call “psychological dependence”: the self-defeating belief I see in many patients that taking a pill is absolutely necessary to do what the patient should be able to do by him- or herself.

If I give a patient a prescription and say something like “Here’s a script for 15 pills, but I’m not giving you a refill until next month,” I’m almost inviting failure.  Just as expected by the Scarcity Effect, the patient’s first thought is usually “but what if I need 16?”

(I’ve worked extensively in addiction medicine, and the same principle is at work here, too.  When an alcoholic in early recovery is told that he can never have a drink again, he immediately starts to crave one.  Now I know that most alcoholics in early recovery are not in the position to say “no” to a drink, but this is the ultimate goal.  Their ability and willingness to say “no” is far more effective for long-term sobriety than someone else saying “no” for them.)

So why exactly does inaccessibility lead to craving?  Because even when it’s clear that we cannot have something, our repeated efforts to get it sometimes pay off.  And here’s where another psychological principle—that of intermittent reinforcement—comes in to play.  People who play the lottery are victims of this.  They know (most of them!!) that the odds of their winning are vanishingly low.  Most people never win, and those who play regularly are almost always losers.  However, every once in a while they’ll get lucky and win a $5 scratcher (and see the news stories about the $80 million jackpot winner just like them!) and this is incredibly reinforcing.

Similarly, if a doctor tells a patient that she should use only 10 Ambien tablets in 30 days– and that no refills will be allowed– but she calls the doctor on day #12 and asks for a refill anyway, getting the refill is incredibly reinforcing.  In the drug and alcohol treatment center where I used to work, if someone’s withdrawal symptoms did not require an additional Valium according to a very clear detox protocol, he might beg to a nurse or staff member, and occasionally get one—precisely what we do not want to do to an addict trying to get clean.

The danger is not so much in the reinforcement per se, but in the fact that the patient is led to believe (for very therapeutic reasons) that there will be no reinforcement, and yet he or she receives it anyway.  This, in my view, potentially thwarts the whole therapeutic alliance.  It permits the patient’s unhealthy behaviors to prevail over the strict limits that were originally set, despite great efforts (by patient and doctor alike) to adhere to these limits.  As a result, the unhealthy behaviors override conscious, healthy decisions that the patient is often perfectly capable of making.

One solution is, paradoxically, to give more control back to the patient.  For example, prescribing 30 Ambien per month but encouraging the patient to use only 10.  If she uses 12 or 15, no big deal—but it’s fodder for discussion at the next visit.  Similarly, instead of making a statement that “no narcotic refills will be given,” we can give some rough guidelines in the beginning but let the patient know that requests will be evaluated if and when they occur.  Recovering addicts, too, need to know that relapses and craving are not only common, but expected, and instead of seeing them as failures of treatment (the big “no”), they are a natural part of recovery and worthy of discussion and understanding.

In medicine, as in all sciences dealing with human behavior, ambivalence is common.  Preserving and respecting the patient’s ability to make decisions, even those which might be unhealthy, may seem like giving in to weakness.  I disagree.  Instead, it teaches patients to make more thoughtful choices for themselves (both good and bad)—exactly what we want to encourage for optimal health.


The FDA Should Really Look Into This Drug

April 1, 2011

The Food and Drug Administration (FDA) regulates and approves medications for use in humans.  Their approval process is rigorous, and they do extensive monitoring of drugs they’ve already approved (“postmarketing surveillance”) to ensure their continued safety and efficacy.

As a psychiatrist, I see one particular drug used very frequently by my patients, usually prescribed by another physician for management of a physical or mental disorder.  In certain cases, however, I wonder whether it might actually worsen the symptoms I’m treating.  Furthermore, I’ve seen several recent references in the medical literature describing how this particular drug can increase the risk of psychotic symptoms and might even cause schizophrenia, a lifelong condition with high morbidity and mortality.

This month’s British Medical Journal, for instance, contains an article showing that users of this drug are more than twice as likely to have psychotic symptoms than nonusers; it “significantly increased the risk of psychotic experiences” over a 10-year period, and “adjustment for other psychiatric diagnoses did not change the results.”  Similarly, a meta-analysis published last month in the Archives of General Psychiatry showed that “the age at onset of psychosis for users [of this drug] was 2.70 years younger than for nonusers,” and that exposure to this drug “is associated with a decline in cognitive performance in young people.”  Finally, an article in the August 2010 American Journal of Psychiatry reported that use of this drug “is associated with an adverse course of psychotic symptoms, even after taking into account other clinical, substance use, and demographic variables.”

Given all this bad news, it’s surprising that this drug is still on the market—particularly in light of the FDA’s recent decisions to pull the plug on other medications with potentially dangerous side effects:  heart rhythm abnormalities (in the case of Darvon), coronary heart disease (Vioxx), increased risk of myocardial infarction (Avandia), fainting and non-cancerous ovarian cysts (Zelnorm), and so on.  So what gives?

And what is this horrible drug anyway?

It’s medical marijuana.

To be fair, asking why the FDA hasn’t withdrawn medical marijuana from the market is not exactly a reasonable question because, technically, it has never been on the market.  The DEA labels it a schedule I drug, which means, according to their definition, that it has a high potential for abuse, no recognized medical use, and no “accepted safety profile.”  However, several states (sixteen at last count, including my home state of California) have approved its use, and annual sales are around $1.7 billion, rivaling the annual sales of Viagra.

Let me point out that I have no official position on medical cannabis.  (See my previous post on the subject.)  I do not prescribe it, but that’s a professional decision, not a personal or moral one.  As noted above, I’ve seen some of my patients benefit from it, and others harmed by it.

Many other substances that are readily available to my patients—whether legal or not—have the potential for both benefit and harm.  People “self-medicate” in all kinds of ways, and we physicians have a responsibility to ensure that they’re doing so in a way that doesn’t cause long-term damage.  We encourage people to stop smoking cigarettes, for instance, and make sure that patients use alcohol in moderation.  (Alcohol and nicotine, of course, are legal but not “prescribed” as medications.)

But once we (i.e., the medical profession and the government) designate a drug as a “medication,” this should imply a whole new level of scientific rigor and safety.  This designation communicates to patients that the substance will provide some sort of measurable benefit and the relative lack of adverse effects when used as prescribed.  I’m not sure medical marijuana passes this test.  Not only have its benefits not been rigorously proven (a fact that is probably due to the reluctance of the NIH to fund such research), but, as demonstrated in the research above, it’s not really “safe” enough to meet criteria for an FDA-approved medication.

As a result, we have a situation where the “medical” label is being used to describe a product that is used for “medicinal” use (although, in my experience, patients often use it for recreational purposes only), but which also has the potential to exacerbate existing conditions or cause new ones.  Medications shouldn’t do this.  Medical cannabis, if subjected to the FDA approval process in its current form, would go nowhere.

Don’t get me wrong:  I understand the potential benefit of cannabis and the compounds in the natural marijuana product, and I support any measure to bring more effective treatments to our patients.  But the current awkward “medicalization” of marijuana imposes too much cognitive dissonance on prescribers and users.  We believe intuitively that it may “help” but also know its potential risks, and that’s hard for any honest physician to endorse.

I see two solutions to this dilemma:  Perform the rigorous, controlled studies to prove its efficacy and safety; or just do away with the whole “medical” façade and legalize it already.


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