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Adults younger than age 50 treated with quinine for muscle cramps or restless leg syndrome had a threefold increased risk for death, according to results from a population-based study.

Treatment with quinine was associated with a less pronounced mortality increase in older adults, and there was a dose-response relationship, wrote Laurence Fardet, MD, PhD, of Frances' University Paris-Est Cretei, and colleagues in .

Last year, the FDA once again (quinine sulfate) for the treatment of night-time leg cramps, noting that the treatment can cause life-threatening bleeding. FDA officialsa decade earlier in a report associating 93 deaths and 665 adverse outcomes with quinine use for these indications.

A found "low quality evidence" that quinine treatment of 200 mg to 500 mg daily significantly reduces muscle cramp frequency, with "moderate quality evidence" that quinine reduces cramp intensity.

Fardet's group noted that despite the safety warnings and questionable efficacy, quinine is still prescribed for the treatment of restless leg syndrome and other muscle cramp disorders.

The researchers also expressed concern that the widely consumed alcohol mixer beverages bitter lemon and tonic water, which contain quinine, could pose a risk to people who consume the drinks daily, although they cited no clinical evidence to back up the concern.

They limited the exposed population in the study to people who had taken quinine salt at a dosage of 100 mg/day or more. By way of comparison, the FDA limits the quinine content of tonic water to 83 mg/L.

Data from The Health Improvements Network (THIN), a primary care database in the U.K., was used for the analysis, which compared mortality outcomes among adults who were and were not prescribed quinine salt for idiopathic muscle cramps or restless leg syndrome for at least 1 year from January 1990 through December 2014.

Three unexposed people with muscle cramps or restless leg syndrome from the database were included for every exposed person included in the analysis.

The study population included 175,195 people (median age 70, 58% women) followed for a median of 5.7 years (IQR, 3.1-8.9). Exposed participants took a median of 203 mg/day of quinine.

The authors reported that there were 11,598 deaths (4.2 per 100 person-years) among the 44,699 exposed participants versus 26,753 (3.2 per 100 person-years) among the 130,496 unexposed individuals (adjusted HR 1.24, 95% CI 1.21-1.27).

The increase in death risk was most pronounced in those younger than age 50 (adjusted HR 3.06, 95% CI,2.51-3.73), regardless of the indication for prescription.

A dose-effect was found for exposure of 200 to 299 mg/d (adjusted HR 1.25, 95% CI 1.20-1.30), 300 to 399 mg/d (adjusted HR 1.83, 95% CI 1.72-1.94), and 400 mg/d or more (adjusted HR 2.24, 95% CI 1.95-2.58) compared with less than 200 mg/d (P<0.001).

The researchers noted that unmeasured confounders, rather than quinine exposure, may explain the observed association. They also cited the lack of data on quinine beverage consumption and cause of mortality as significant study limitations.