By Dr. Emmanuel Mignot
A reply to "Bad medicine: restless legs syndrome," by Des Spence, general practitioner, Glasgow, as published in the British Medical Journal Dec. 19, 2013.
It is always sad to read unscientific articles in any medical journal, particularly when found in a reputable journal that boasts almost 200 years of history. On Dec. 19, 2013, the British Medical Journal published an opinion piece written by a general practitioner in Glasgow claiming that Restless Leg Syndrome (RLS) is rare (he never saw a patient with a primary complaint of RLS "in 20 years of practice").
More disturbingly, Dr. Spence claims that RLS is a "pharma classic" defined on the basis of subjective scales that are "pseudoscientifically converted to an illegitimate numerical rating" and that has an "implausible biological basis." Finally, the article claims that "the benefit of treatment is marginal, involving the usual suspects such as gabapentin derivatives (recently approved by the US Food and Drug Administration), strong opioids, and benzodiazepines."
We will not attempt to discuss the possible harm this article has done to patients with the condition, although RLS can be excruciating in its worst manifestations. Rather, this story illustrates a growing tendency for some journals to use lay opinions to stir controversy in hopes of increasing visibility and impact. I would also rather not blame Dr. Spence, as it is easy to find a doctor with unconventional opinions and without the needed expertise. Even as a sleep specialist myself, I would have hesitated to go against the prevailing opinion of those far more familiar with the topic of RLS. I do not believe blindly in what my colleagues publish and understand well that doctors are influenced consciously and unconsciously by the pharmaceutical companies, especially when consulting or working with these entities. However, I work hard to educate myself on the matters at hand before expressing opinions that can have damaging consequences. To do otherwise is hubris, and it is well known where that leads to, more often than not.
What is possibly the most disturbing is that a reputable journal would publish such rubbish. The editors are either incompetent, complicit, or both. Fact checking is the fundamentum inconcussum of professional journalism. Opinions are not facts, and thus have a limited place in a scientific journal that purportedly seeks to educate and inform physicians. In rare cases, opinion pieces are useful when addressing an issue that is agreed upon by most experts to be controversial, thus stimulating the intelligence of the readers. To publish otherwise treats physicians as if that are not able to create their own opinion based on facts alone. For the sake of experiment, let us attempt to debunk the major claims of this opinion piece, beginning with how rare is RLS and the suggestion the disease was made up by the pharmaceutical industry.
Firstly, RLS was first described far before the pharmaceutical industry in its currently prevailing form even existed, first by Willis in 1685, then by Ekbom in further detail in 1944. The claim that it is extremely rare and difficult to define also does not survive even the most cursory scrutiny. If this were the case, how could the author explain the thousands of articles published, some that include thousands of patients, and the fact that thousands of sleep clinics take care of these patients?
That being said, one of the primary challenges against RLS is that it usually manifests itself in patients in a relatively mild manner, making the determination of its status as a "true disease" relatively difficult to arrive upon. But this conundrum is not uncommon in medicine. Is depression a disease? Is diabetes a disease? A well-known solution to this dilemma is to define a pathological threshold either on the basis of the distress it causes (RLS, depression, and insomnia) or the invalidity it produces or predicts (high blood pressure and diabetes). Although the long-term consequences of RLS are still unknown, there are suggestions, but no proof (this would be a possible opinion piece) that it can have independent damaging health effects. Nevertheless, there is no doubt it can create a significant degree of distress. Among many studies that have found similar prevalence, Allen et al. (2011) recently found that approximately 1 to 4 percent of the population had clinically meaningful RLS, with at least 1/3 of this subsection experiencing severe symptoms with measurable effects on work and disability. Evidently this constitutes a substantially sizable portion of the population, one that Dr. Spence has elected to simply disregard.
The history of medicine abounds with incorrect "opinions" which makes our ability to prove or disprove our own feelings and intuitions on the basis of scientific methods all the more valuable. I would advise Dr. Spence to formulate a clearer hypothesis. Perhaps something more on the lines of: "How many of my patients have distressing symptoms of RLS?" Then, use a validated questionnaire to test it before making unsubstantiated statements based on his personal experience while dealing with his own population of patients. For years, the same types of stories have been said regarding sleep apnea, a disease that was largely unrecognized by doctors until the late 1980s, or narcolepsy, a rare disorder that one of my former classmates, a psychoanalyst by training (like myself), suggested was caused by a "flight response" (we now know it has a clear biological basis with the lack of a brain chemical).
The second claim, that it has an "implausible biological basis," is even more seriously flawed, as it not a matter of tautology and disease definition but of biology itself. Unlike many other subjectively defined disorders, RLS is strongly associated with polymorphisms in selected developmental genes, and those have reasonably strong effects on propensity (see Stefanson, Rye et al. 2007 and Winklemann et al., 2011). In addition, RLS is almost always associated with a large number of recurrent, stereotyped periodic leg movements during sleep that can be objectively measured (Stephanson, Rye et al., 1197). Finally, we know that it can be the sign of iron deficiency in at least some cases, and can be very bad in patients with kidney failure who are undergoing dialysis. There is no doubt that much remains to be learned about the condition but based on recent discoveries, I feel confident that there is a direct path to understanding the entire pathophysiology associated with RLS within the next 10 years.
What might possibly be the cherry on the cake, Dr. Spence (who has never seen a patient with RLS) finally claims that treatments simply do not work and that the high degree of responsiveness to placebo treatments makes them the "rational" recourse. Many other treatments for subjectively defined disorders exhibit strong placebo responses; this is in fact why placebos are needed to distinguish real effects, which typically are longer in duration, something that is often difficult and unnecessarily expensive to study. Dr. Spence proceeds to deny the numerous published studies on the matter of prevailing RLS treatments, and implies with great subtlety, though in no uncertain terms, that their existence is probably the result of biased experts who have been bought off. The vituperative claim that every relevant researcher and doctor in their respective fields has been bought off by the pharmaceutical industry is getting far too old for those who have dedicated their life's work to the betterment of the lives of RLS patients through assiduous and specialized research.
The fact that conflicts of interest exist is beyond contention, and as a physician at Stanford I am required to report all income derived from my arrangements with the pharmaceutical industry. I, however, believe these interactions are necessary, as I would myself not trust the industry to regulate itself while abstaining from receiving external opinion from Academia. Consultancy and funded research can indubitably taint judgment, and the unfortunate implications of this connection must always be taken into consideration. Furthermore, I am by nature most suspicious of holier-than-thou attitudes. "The road to Hell is paved with good intentions," say the wise, and reducing a disease and its treatment to a conflict of interest has never made the root problem disappear. On the other hand, research, medical progress, and drugs can. For the author to use emotionally charged terms like "the usual suspects" and "strong opioids" is highly suggestive of the metaphorical axe that the author might have to grind.
Sadly, this simplified view also obscures a genuine opportunity to educate physicians on how to treat RLS (as opposed to leaving the patient to suffer, without hope) and the controversies that exist among experts. As is the case in many areas of medicine, we simply don't know much about the long-term effects of these relatively new medications. Some cases show improvement with iron therapy. However, large studies have not been performed, partially because no one wants to pay for them (it is not of any use to the pharmaceutical industry) and due to fears of toxicity. Initially found to respond well to L-DOPA, many RLS patients were later found to develop "augmentation." Augmentation is a form of symptom exacerbation where RLS (which is normally worse in the evening) begins to manifest earlier and earlier during the day. This often leads to increasing dosage and dependence with negative consequences upon cessation of treatment. Many experts are worried that the same will also occur with widely used dopamine agonists such as ropinirole (Requip) and pramipexole (Mirapex), which act similarly to L-DOPA and have been touted not to have this problem. These drugs, normally used for Parkison's disease have been widely advertised for RLS. It is becoming evident that augmentation can occur with the administration of these medications as well, albeit at a slower pace and perhaps not ubiquitously. Thus, no one is entirely aware of the true magnitude of the problem. A conservative view may thus advocate an intermittent, low, and controlled dosage for these dopamine agonist medications. This could be most helpful in patients suffering from mild or intermittent symptoms.
Similar to other conditions, however, treating patients requires access to multiple medications, and successful treatment is often a question of trial and error and of finding the right combination. Augmentation does not occur with gabapentin-like drugs. Alternatively, opioids such as methadone can often be used as a stable dose in severe patients without any problems. As always, it is a matter of clinical experience on one side and objective studies on the other. Both are necessary. Experience is key because there is great patient heterogeneity and it is difficult to study all clinical and therapeutic variations. Objective studies are essential because even the best human mind can easily delude itself and the correct response to a question is not always what seems to be the most logical answer.
In conclusion, I invite the readers to reject mediocrity and insist that reputable journals publish intelligent, scientifically based, data-driven opinion pieces, if publish them they must. To accept otherwise is to believe we are all idiots, prone to conspiracy theories. Both doctors and patients deserve better. The publication of inferior papers results not only in "bad medicine," but is also "dangerous practice."
Willis T (1685). The London practice of physic, Bassett and Crooke, London, England
Ekbom KA (1944). Asthenia crurum paraesthetica ('Irritable legs'). New syndrome consisting of weakness, sensation of cold and nocturnal paresthesia in legs, responding to certain extent to treatment with Priscol and Doryl; note on paresthesia in general. Acta Med Scand, 118 pp. 197-209.
Allen RP, Bharmal M, Calloway M (2011). Prevalence and disease burden of primary restless legs syndrome: results of a general population survey in the United States. Mov Disord. 1:114-20. doi: 10.1002/mds.23430.
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Dr. Mignot is the director of the Stanford Center for Sleep Sciences and Medicine. This Center is the birthplace of sleep medicine and includes research, clinical, and educational programs that have advanced the field and improved patient care for decades. To learn more, visit us at: http://sleep.stanford.edu/.