Restless Legs Syndrome: Overdiagnosed and Overtreated

Every now and then, like most people, you probably feel restless at night and have trouble falling asleep. But if your restlessness specifically involves an uncontrollable urge to move one or more of your limbs, you may be diagnosed with a condition known as restless legs syndrome (RLS).

Only recently has RLS been formally recognized as a medical condition, and that designation has been controversial. The diagnosis is based solely on vague, subjective symptoms often also seen in some psychiatric and physical disorders, and the cause in most patients remains unknown.

In addition, the introduction of RLS as a disease coincided with an extensive promotional campaign by the pharmaceutical industry to exploit uncertainty and lack of knowledge about the condition to expand the market for the industry’s lucrative drugs. Some have therefore questioned whether most patients with RLS, especially those with mild symptoms, are truly afflicted with a disease.

This is particularly relevant when considering treatment options. The medications approved by the Food and Drug Administration (FDA) to treat RLS have been proven somewhat effective only in the short term and have several serious side effects, including, in many cases, worsening of the symptoms they are intended to treat.

About RLS

According to the National Institutes of Health (NIH), RLS “is a neurological disorder characterized by throbbing, pulling, creeping, or other unpleasant sensations in the legs and an uncontrollable, and sometimes overwhelming, urge to move them.”[1] Symptoms of RLS:[2]

• Are worse at night and improve in the morning.
• Are triggered by rest, relaxation or sleep.
• Get better, and stay better, with movement.

An estimated 5 to 10 percent of adults meet these criteria for RLS, but at least half of these experience only mild or infrequent symptoms.[3]

Some evidence suggests that the disorder stems from a dysfunction in the area of the brain responsible for coordinating muscle movements.[4] Iron deficiency and, specifically, low levels of iron in certain areas of the brain have also been associated with RLS.[5],[6]

The National Sleep Foundation classifies RLS into two types.[7] Primary RLS is diagnosed in those with a suspected genetic cause or in whom the cause is unknown, while secondary RLS is diagnosed when an identifiable and potentially reversible cause is thought to be responsible. Patients displaying RLS symptoms before age 40 are more likely to have a family history of, and therefore a possible genetic component to, the disease.[8]

Secondary RLS has been associated with conditions such as chronic kidney disease, diabetes and peripheral neuropathy (a disorder linked to nerve damage). Women in their last trimester of pregnancy also may be at higher risk for secondary RLS.[9] Certain medications have been implicated in the occurrence or aggravation of secondary RLS. These include drugs to treat nausea, antipsychotic drugs, antidepressants, and cold or allergy medications that contain antihistamines.[10]

Lifestyle and psychological factors likely play a major role in the development or severity of all forms of RLS. Consumption of alcohol and caffeine, sleep deprivation or irregular sleep schedules, and mood disorders such as depression and anxiety all have been associated with RLS symptoms.[11],[12]

Managing and treating RLS

Patients diagnosed with RLS are generally evaluated for secondary causes. Patients’ medications should be carefully scrutinized to determine whether the symptoms are drug-induced. If no underlying cause of the symptoms is found, the patient probably has primary RLS.

Patients with mild or moderate RLS can often reduce or resolve their symptoms with changes to their lifestyle or daily routine. Strategies recommended by NIH to reduce RLS symptoms include:[13]

• Cutting down on caffeine, alcohol and tobacco consumption.
• Improving sleep hygiene, including maintaining a regular sleep pattern.
• Exercising regularly.
• Applying leg care measures such as massaging the legs, taking a hot bath or using a heating pad or ice pack.

It is also recommended that RLS patients with low iron blood levels be treated with iron replacement therapy.[14]

Drug therapy should be pursued only when RLS symptoms persist despite lifestyle changes and in severe, incapacitating cases. There are currently four drugs approved for treating RLS: the dopamine agonists pramipexole (MIRAPEX), ropinirole (REQUIP) and rotigotine transdermal system (NEUPRO), as well as extended-release gabapentin enacarbil (HORIZANT).[15] All four drugs are approved only for moderate to severe cases of primary RLS.[16]

Other drugs not approved by the FDA to treat RLS nevertheless may be prescribed for the condition by some physicians on an “off-label” basis. These medications, such as anti-epileptics, benzodiazepine sedatives and other dopamine-acting drugs, have severe and sometimes fatal side effects and have never successfully undergone any FDA review of their effectiveness for RLS.

Limitations of drug therapies

Unfortunately, all currently approved RLS medications have been proven effective only in the short-term treatment of RLS. A 2012 review of all randomized clinical trials of dopamine agonists for the treatment of RLS, including those that are not FDA-approved for the condition, found that the trials treated subjects for an average of only 10 weeks, with no trial lasting longer than seven months.[17] The only non-dopamine agonist approved to treat RLS, extended-release gabapentin enacarbil, was approved based on two trials lasting just 12 weeks each.[18]

One of the major long-term complications of dopamine agonist therapy in RLS is the potential for patients to become physically dependent on the medications and require higher doses over time.[19] Known as augmentation, this phenomenon is thought to occur in 7 percent of all treated patients with each year of treatment.[20] Patients who develop augmentation from dopamine agonists are generally taken off the drugs, but many then experience even worse RLS symptoms than they had before being treated.[21] This outcome raises questions as to whether dopamine agonists do more harm than good when used on a chronic basis.

Other side effects of the three dopamine agonists approved for RLS include dangerously low blood pressure when standing up, hallucinations and psychosis. A recent study that analyzed hundreds of adverse event reports sent to the FDA concluded that pathological gambling, hypersexuality and compulsive shopping are likely side effects of dopamine agonist use in some patients with RLS and Parkinson’s disease.[22] In 2012, the FDA warned that pramipexole may lead to a slightly increased risk of congestive heart failure.[23] Extended-release gabapentin enacarbil can result in suicidal thoughts.[24] All four drugs can lead to excessive and sudden daytime sleepiness, potentially resulting in dangerous driving impairment.[25]

What You Can Do

If you have symptoms of RLS, such as leg discomfort or restlessness at night, consult your doctor on whether you have a condition or are taking a medication that might be causing the symptoms.

If your symptoms are not incapacitating, try making the few suggested changes to your diet and daily routine recommended in this article before pursuing medication.

If you and your doctor decide that a drug is necessary to treat the condition, be sure to review the side effects of each treatment and keep in mind that all FDA-approved drugs to treat RLS have been proven to improve symptoms only in the short term. Never treat the condition with a drug that has not been approved by the FDA to treat RLS.

References

[1] National Institutes of Health. Restless Legs Syndrome Fact Sheet. http://www.ninds.nih.gov/disorders/restless_legs/detail_restless_legs.htm. Accessed October 8, 2014.

[2] Ibid.

[3] Ohayon MM, O'Hara R, Vitiello MV. Epidemiology of restless legs syndrome: a synthesis of the literature. Sleep Med Rev. August 2012;16(4):283-95.

[4] National Institutes of Health. Restless Legs Syndrome Fact Sheet. http://www.ninds.nih.gov/disorders/restless_legs/detail_restless_legs.htm. Accessed October 8, 2014.

[5] Ibid.

[6] National Sleep Foundation. Restless Legs Syndrome (RLS) and Sleep. http://sleepfoundation.org/sleep-disorders-problems/restless-legs-syndrome. Accessed October 8, 2014.

[7] Ibid.

[8] National Institutes of Health. Restless Legs Syndrome Fact Sheet. http://www.ninds.nih.gov/disorders/restless_legs/detail_restless_legs.htm. Accessed October 8, 2014.

[9] Ibid.

[10] Ibid.

[11] Ibid.

[12] Becker PM, Sharon D. Mood disorders in restless legs syndrome (Willis-Ekbom disease). J Clin Psychiatry. July 2014;75(7):e679-694.

[13] National Institutes of Health. Restless Legs Syndrome Fact Sheet. http://www.ninds.nih.gov/disorders/restless_legs/detail_restless_legs.htm. Accessed October 8, 2014.

[14] Ibid.

[15] For drugs approved through 2012, see: Drug for Parkinson’s Disease and Restless Leg Syndrome May Increase Heart Failure Risk. Worst Pills Best Pills News. February 2013 /newsletters/view/833. Accessed October 8, 2014.
For drugs approved since 2012, see: Food and Drug Administration. New Drugs at FDA: CDER’s New Molecular Entities and New Therapeutic Biological Products. Available by year. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/default.htm. Accessed October 8, 2014.

[16] FDA-approved labels for: Gabapentin enacarbil (HORIZANT), May 2013; pramipexole (MIRAPEX), March 2013; ropinirole (REQUIP), August 2014; and rotigotine transdermal system (NEUPRO), April 2012.

[17] Hornyak M, Trenkwalder C, Kohnen R, Scholz H. Efficacy and safety of dopamine agonists in restless legs syndrome. Sleep Med. March 2012;13(3):228-36.

[18] FDA-approved label (May 2013). Gabapentin enacarbil (HORIZANT). Section 14: Clinical Studies.

[19] Johns Hopkins Medicine. Department of Neurology and Neurosurgery. Dopamine Drugs and Possible Side Effects. http://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/restless-legs-syndrome/what-is-rls/problems.html. Accessed October 8, 2014.

[20] Ibid.

[21] Ibid.

[22] Moore TJ, Glenmullen J, Mattison DR. Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs. JAMA Intern Med. October 20, 2014. doi: 10.1001/jamainternmed.2014.5262. [Epub ahead of print]

[23] Food and Drug Administration Drug Safety Communication: Ongoing safety review of Parkinson’s drug Mirapex (pramipexole) and possible risk of heart failure. Sept. 19, 2012. http://www.fda.gov/Drugs/DrugSafety/ucm319779.htm. Accessed October 14, 2014.

[24] FDA-approved label for: Gabapentin enacarbil (HORIZANT).

[25] FDA-approved labels for: Gabapentin enacarbil (HORIZANT), May 2013; pramipexole (MIRAPEX), March 2013; ropinirole (REQUIP), August 2014; and rotigotine transdermal system (NEUPRO), April 2012.