Restless Legs Syndrome Foundation Blog

Quinine Treatment for RLS or Leg Cramps is Associated with Increased Mortality

By Lynn Marie Trotti, MD, MSc

An excerpt from the Summer 2017 edition of NightWalkers, the Foundation's quarterly magazine

“Association Between Long-Term Quinine Exposure and All-Cause Mortality.” Fardet L, et al. JAMA, May 2017.

The Background:

Nocturnal leg cramps are common, affecting over one-third of adults over age 60 at least occasionally, and over half of adults over age 80. For many years, quinine was used for treatment of cramps, either as a prescription in pill form or through drinking tonic water for its high quinine content.

In 2006, the FDA recommended against the use of quinine for leg cramps because of the potential for serious side effects or death. Despite this warning, use of quinine for the treatment of leg cramps has not ceased.

The Research:

Researchers used a large healthcare database of primary care patients in the United Kingdom to evaluate quinine use and mortality across approximately 175,000 people from 1990 through 2015. Individuals who were prescribed a dose of at least 100 mg per day of quinine for at least one year were each compared to three people who were not prescribed quinine. Those who were prescribed quinine had either cramps (96 percent of the quinine-prescribed group) or restless legs syndrome (4 percent), so controls were chosen with these same diseases (96 percent had cramps and 4 percent had RLS).

People exposed to quinine were, on average, one year older than controls, and were prescribed an average quinine dose of 203 mg per day. There was a 24 percent increase in risk of dying during the study period in the group prescribed quinine. Considering only those people prescribed quinine for RLS, there was still a significant increase in mortality risk in those with a quinine prescription.

The Bottom Line:

Quinine pills are not recommended for the treatment of RLS or leg cramps. It is unclear whether daily use of tonic water, which generally contains less than 100 mg of quinine per liter, also increases mortality risk.

New Questions:

Although there are multiple proven treatments available for RLS, data is very limited on how best to treat nocturnal leg cramps. As quinine is to be avoided, what treatments are effective for nocturnal leg cramps?

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An excerpt from the Summer 2016 edition of NightWalkers the Foundation's quarterly magazine. This piece is from the reoccurring column "In the News" by Lynn Marie Trotti, MD, MSc

Restless legs syndrome & depression: effect mediation by disturbed sleep and periodic limb movements.

Koo BB, et al. American Journal of Geriatric Psychiatry. April 2016.

Background:

Prior studies have shown that RLS and depression are associated, such that people with RLS are twice as likely as people without RLS to have depression at some point in their lives. The reason behind this relationship is not known, but a number of theories have been proposed (which are not mutually exclusive): 1) RLS and depression could share a common underlying cause; 2) depression medications may trigger RLS symptoms (which, in a cross-sectional study, could explain an association between depression and RLS); 3) sleep disruption from RLS could cause depression; or 4) periodic limb movements in sleep (PLMS) could cause depression. This study was designed to evaluate the latter three possibilities.

Research:

The researchers used data from the large Osteoporotic Fractures in Men (MrOS) study of elderly men, which has been used in multiple prior RLS studies. Included participants were evaluated for RLS and depression. Measures of PLMS and estimates of sleep quality were performed with in-home sleep studies and wrist actigraphy (a measure of activity), respectively. RLS was present in 17 percent of the 982 men. Those with moderate to severe RLS were most likely to be depressed, took the longest amount of time to fall asleep, had the most disrupted sleep, and had the greatest PLMS. The presence of moderate to severe RLS increased the likelihood of depression by about three times. Disrupted sleep accounted for some, but far from all, of the relationship between RLS and depression. Periodic limb movements moderated the depression-RLS relationship, such that people with RLS and PLMS had more depressive symptoms than those without RLS, but this effect was not seen in those with RLS without PLMS. People with RLS who were taking antidepressants had fewer depressive symptoms than people with RLS and depression who were not on medications.

Bottom Line:

The relationship between depression and RLS is mediated, in part but not exclusively, by the sleep disruption that accompanies RLS. The relationship between RLS and depression is apparent in those with PLMS, but not in those without PLMS. In people who are depressed, antidepressants are associated with fewer depression symptoms despite the presence of RLS (that is, having RLS does not appear to prevent an antidepressant benefit of medications).

New Questions:

Given that sleep disruption only partially explains the RLS depression relationship, what other factors are important?