by Steve Balt
Gabapentin was first 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—seems to happen a lot these days). Gabapentin is 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 proportion of drug that enters 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 for a longer period of time.
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." (Specifically, GSK argued that the large number of pancreatic tumors found in rats taking Horizant may have occurred spontaneously, and human data don't show a compelling link between cancer and gabapentin use.)
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, and some people report an excellent response to
treatment. (Whether it 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.
However, the symptoms of RLS are rather nonspecific: "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 vague and common symptoms (who among us hasn't felt somewhat restless at times, with interrupted sleep?), a lot of people might get diagnosed with RLS when their symptoms are actually due to something else.
A while back, a fellow blogger directed me to the RLS "patient page" on the National Institutes of Health (NIH) web site, where RLS was—and still is—referred to as "akathisia." However, these may be two entirely different things. 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.)
What it means for patients and doctors is less clear. A new agent with apparently better availability and kinetics than gabapentin is now available, but it's approved for the treatment of something that may or may not exist (in most patients). It also may or may not be more effective than gabapentin itself, but it will most certainly have a heftier price tag. Ah, the wheels of psychopharmacology keep turning…
Steve Balt is psychiatrist at North Bay Psychiatric Associates in San Rafael, California and writes his own blog: Thought Broadcast.