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 have a condition known as restless legs syndrome (RLS), also called Willis-Ekbom disease.[1]

The formal recognition of RLS as a medical condition has been controversial. The diagnosis of RLS is based solely on vague, subjective symptoms that also are seen in some psychiatric and physical disorders, and the cause of the disorder in most patients remains unknown.

In addition, widespread public awareness of RLS as a disease coincided with an extensive promotional campaign by the pharmaceutical industry to exploit the uncertainty and lack of knowledge about the condition to expand the “market” for the industry’s lucrative drugs (see text box, below). Some have therefore questioned whether many patients diagnosed 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 adverse effects, including potentially worsening the symptoms they are intended to treat.

About RLS

According to the National Institute of Neurological Disorders and Stroke (NINDS) — part of the National Institutes of Health — RLS is a condition that “causes unpleasant or uncomfortable sensations in the legs and an irresistible urge to move them.”[2] These sensations may be described as aching, throbbing, pulling, itching, crawling or creeping.[3] The symptoms typically occur during the late afternoon or evening and are most severe at night when a person is resting or lying in bed.[4] Moving the legs relieves the discomfort, which leads patients to pace the floor, constantly move their legs while sitting and toss and turn in bed.[5]

An estimated 5% to 10% of adults meet the criteria for RLS,[6] but clinically significant RLS symptoms occur only in approximately 2% to 3% of adults.[7]

Some evidence suggests that the disorder in some patients stems from a dysfunction in the area of the brain responsible for coordinating muscle movements that produce dopamine.[8] Iron deficiency and, specifically, low levels of iron in certain areas of the brain also have been associated with RLS.[9],[10] Additionally, certain genetic factors are associated with RLS.[11]

RLS is classified into two types.[12] Primary RLS is diagnosed in those with a suspected genetic cause or in whom the cause is unknown, whereas secondary RLS is diagnosed when an identifiable and, in some cases, 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 disorder.[13]

Secondary RLS has been associated with conditions such as end-stage kidney disease requiring hemodialysis, diabetes and peripheral neuropathy (nerve damage).[14] Women in their last trimester of pregnancy also may develop secondary RLS, which usually resolves within four weeks after delivery.[15] Certain medications have been implicated in the occurrence or aggravation of RLS. These include drugs to treat nausea (such as prochlorperazine [COMPRO, PROCOMP] and metoclopramide [REGLAN]), antipsychotic drugs (such as haloperidol [HALDOL]), antidepressants (such as fluoxetine [PROZAC, SARAFEM, SELFEMRA] and sertraline [ZOLOFT]) and older antihistamines (such as diphenhydramine [BENADRYL]).[16]

Lifestyle and psychological factors can 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 have all been associated with RLS symptoms.[17],[18]

Managing and treating RLS

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

Patients with mild or moderate RLS often can reduce or resolve their symptoms with changes to their lifestyle or daily routine. Strategies recommended by NINDS to reduce RLS symptoms include the following:[19]

• Decreasing 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

NINDS also recommends that RLS patients with low blood iron levels be treated with a trial of iron supplementation.[20]

Drug therapy should be pursued only when RLS symptoms are moderate and persist despite lifestyle changes or are severe and incapacitating. There are currently four drugs approved for treating RLS: the dopamine agonists pramipexole (MIRAPEX),[21] ropinirole (REQUIP)[22] and rotigotine (NEUPRO),[23] and extended-release gabapentin enacarbil (HORIZANT).[24] All four drugs are approved only for moderate to severe cases of primary RLS.

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 antiseizure drugs and benzodiazepine sedatives, have severe and sometimes fatal adverse effects and have never successfully undergone any FDA review of their effectiveness for treating RLS. Such drugs should not be used for RLS.

Limitations of drug therapies

Importantly, all currently approved RLS medications have been proven effective only in short-term clinical trials that showed moderate improvement in RLS symptoms. 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.[25] The only non-dopamine agonist approved to treat RLS, extended-release gabapentin enacarbil, was approved based on two trials lasting just 12 weeks each.[26]

An FDA medical reviewer initially recommended against approving extended-release gabapentin enacarbil because it caused pancreatic cancer in rats at doses relatively close to those used in humans, thereby outweighing its potential benefit for RLS. We therefore have designated this drug as Do Not Use for treating RLS.

One of the major long-term complications of dopamine agonist therapy for RLS is the potential for patients to become physically dependent on the medications and require higher doses over time.[27] Known as augmentation, this phenomenon is thought to occur in 7% of all treated patients with each year of treatment.[28] 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 they were treated.[29] This outcome raises the larger question as to whether dopamine agonists do more harm than good when used on a chronic basis for treating RLS.

Other adverse effects of the dopamine agonists include dangerously low blood pressure when standing up, hallucinations (or even psychosis) and uncontrollable impulsive behaviors (including pathological gambling, hypersexuality and compulsive shopping). Pramipexole may lead to a slightly increased risk of heart failure.[30] These drugs also can lead to excessive and sudden daytime sleepiness, potentially resulting in dangerous driving impairment.

What You Can Do

If you have symptoms of RLS, consult your doctor about 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 lifestyle changes recommended in this article before pursuing medication therapy.

If you and your doctor decide that a drug is necessary to treat your condition, you should use one of the dopamine agonists approved for RLS but not gabapentin enacarbil or any drug that has not been approved by the FDA to treat RLS.

If you are prescribed a dopamine agonist, be sure to review the drug’s adverse effects and keep in mind that all FDA-approved drugs to treat RLS have been proven to improve symptoms only in the short term.

‘Disease Mongering’ and RLS

The history of RLS as a disease offers yet another fascinating instance of how the pharmaceutical industry exploits common symptoms in otherwise healthy people for the purposes of expanding the market for its products.

In 2005, the FDA approved ropinirole (REQUIP) as the first drug treatment for RLS.[31] Shortly after this approval, Public Citizen’s May 2006 issue of Health Letter reported the results of a study that examined how RLS was being discussed in the media and by certain drug companies before the first drug had even been approved for the condition.[32] The study’s authors, physicians Steven Woloshin and Lisa Schwartz from Geisel School of Medicine at Dartmouth, found that beginning in 2003, two years before ropinirole was approved for RLS, the drug’s maker, GlaxoSmithKline, “launched a campaign to promote awareness about restless legs syndrome” and issued press releases on studies that it claimed demonstrated the effectiveness of ropinirole for RLS.[33]

By failing to question the scientific basis for these claims, exaggerating the extent and severity of RLS, associating it with an array of common sleep and psychiatric disorders, and minimizing adverse effects of potential drug treatments, “the media seemed to have been co-opted into the diseasemongering process,” in the view of Drs. Woloshin and Schwartz.[34]

However valid its biological basis ultimately proves to be, RLS is all too real for many patients with truly debilitating forms of the disease. But, for all other patients, including those with milder symptoms who have been led to believe that their everyday symptoms are a disease and not simply variations on the norm, dangerous overuse of the potent drugs approved (and not approved) to treat RLS has ensued.

References

[1] National Institute of Neurological Disorders and Stroke. Restless Legs Syndrome Fact Sheet. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Restless-Legs-Syndrome-Fact-Sheet. Accessed March 30, 2020.

[2] Ibid.

[3] Ibid.

[4] Ibid.

[5] Ibid.

[6] Ohayon MM, O'Hara R, Vitiello MV. Epidemiology of restless legs syndrome: a synthesis of the literature. Sleep Med Rev. August 2012;16(4):283-295.

[7] Ondo WG. Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adult. UpToDate. March 6, 2020.

[8] National Institute of Neurological Disorders and Stroke. Restless Legs Syndrome Fact Sheet. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Restless-Legs-Syndrome-Fact-Sheet. Accessed March 30, 2020.

[9] Ibid.

[10] Ondo WG. Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adult. UpToDate. March 6, 2020.

[11] Ibid.

[12] Ibid.

[13] National Institute of Neurological Disorders and Stroke. Restless Legs Syndrome Fact Sheet. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Restless-Legs-Syndrome-Fact-Sheet. Accessed March 30, 2020.

[14] Ibid.

[15] Ibid.

[16] Ibid.

[17] Ibid.

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

[19] National Institute of Neurological Disorders and Stroke. Restless Legs Syndrome Fact Sheet. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Restless-Legs-Syndrome-Fact-Sheet. Accessed March 30, 2020.

[20] Ibid.

[21] Boehringer Ingelheim Pharmaceuticals. Label: pramipexole (MIRAPEX). January 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=688fa4d7-de12-4930-8bc5-0169297c1da6&type=display. Accessed March 30, 2020.

[22] GlaxoSmithKline. Label: ropinirole (REQUIP). May 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020658s034lbl.pdf. Accessed March 30, 2020.

[23] UCB. Label: rotigotine transdermal system (NEUPRO). January 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021829s016lbl.pdf. Accessed March 30, 2020.

[24] Arbor Pharmaceuticals. Label: gabapentin enacarbil (HORIZANT). October 2016. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=4c486fc7-c8c4-4c6c-b30c-366dabaeaadd&type=display. Accessed March 30, 2020.

[25] Hornyak M, Trenkwalder C, Kohnen R, Scholz H. Efficacy and safety of dopamine agonists in restless legs syndrome. Sleep Med. 2012;13(3):228-236.

[26] Arbor Pharmaceuticals. Label: gabapentin enacarbil (HORIZANT). October 2016. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=4c486fc7-c8c4-4c6c-b30c-366dabaeaadd&type=display. Accessed March 30, 2020.

[27] 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 March 30, 2020.

[28] Ibid.

[29] Ibid.

[30] Food and Drug Administration Drug safety communication: Ongoing safety review of Parkinson’s drug Mirapex (pramipexole) and possible risk of heart failure. September 19, 2012. http://www.fda.gov/Drugs/DrugSafety/ucm319779.htm. Accessed March 30, 2020.

[31] Woloshin S, Schwartz LM. Giving legs to restless legs: A case study of how the media helps make people sick. PLoS Med. 2006;3(4):e170.

[32] Public Citizen. Blurring the boundaries between health and illness. Health Letter. May 2006. /newsletters/view/465. Accessed March 30, 2020.

[33] Woloshin S, Schwartz LM. Giving legs to restless legs: A case study of how the media helps make people sick. PLoS Med. 2006;3(4):e170.

[34] Ibid.