Current issues of ACP Journal Club are published in Annals of Internal Medicine


Quinine was more effective than Vitamin E for nocturnal leg cramps in men

ACP J Club. 1993 Mar-April;118:36. doi:10.7326/ACPJC-1993-118-2-036

Source Citation

Connolly PS, Shirley EA, Wasson JH, Nierenberg DW. Treatment of nocturnal leg cramps. A crossover trial of quinine vs vitamin E. Arch Intern Med. 1992 Sep;152:1877-80.



To compare the efficacy and safety of quinine sulfate and vitamin E for nocturnal leg cramps in men.


Randomized, double-blind, placebo-controlled, crossover trial with 28-week follow-up.


A Veterans Affairs hospital.


Men were included if they had ≥ 6 nocturnal cramps per month and no known intolerance of quinine or vitamin E. Exclusion criteria were concomitant use of quinidine sulfate or warfarin, thrombocytopenia, hypokalemia, hypocalcemia, unstable angina, uncontrolled congestive heart failure, creatinine clearance < 0.67 mL/s, liver dysfunction, inability to keep a diary, alcoholism, or terminal illness. 55 men were screened, 30 were enrolled, and 27 completed the study. Mean age was 59 years (range 38 to 73 y).


All participants had a 4-week run-in period with no medication and received 4 weeks of each drug (quinine sulfate, 200 mg at suppertime and 300 g at bedtime; placebo at suppertime and vitamin E, 800 U at bedtime; or double placebo at suppertime and bedtime) in randomized order. Each drug period was separated by a 4-week wash-out period.

Main outcome measures

Prestudy questionnaires and daily diaries gathered data on frequency and severity of nocturnal leg cramps and sleep disturbances. Nocturnal cramps were defined as muscle cramps in the foot, lower leg, or thigh after participants went to bed. A severity index was calculated by adding total severity scores on nights with cramps (4-point scales) divided by the number of nights with cramps.

Main results

Within the 4-week period, quinine reduced the number of cramps, number of nights with cramps, and sleep disturbances relative to placebo (P ≤ 0.005), whereas vitamin E did not. For quinine, vitamin E, and placebo, respectively, the mean numbers of cramps for the 4-week period were 19, 32, and 37; mean numbers of nights with cramps were 9, 14, and 15; sleep disturbance scores were 21, 33, and 37; and cramp severity scores were 21, 38, and 39. The groups did not differ in severity-index score changes or in documented side effects for placebo or vitamin E. Quinine showed a slight increase in side effects over placebo (P = 0.05). 63% of patients had ≥ 80% compliance by pill count.


Quinine compared with placebo was more effective than vitamin E compared with placebo in treating nocturnal leg cramps in men. Persons taking quinine had more side effects.

Source of funding: Hitchcock Foundation.

For article reprint: Not available.


Cramps are a frequent patient complaint. They are spasmodic contractions of muscle that are painful, sustained, and involuntary. Their cause is not well understood. Although physicians have argued for years over whether quinine actually helps relieve leg cramps during sleep, it has remained the standard treatment for lack of anything better (1). The study by Connolly and colleagues is a well-designed, placebo-controlled, double-blinded, clinical trial and a valuable addition to the literature on nocturnal leg cramps. Problems with the study include the small number of patients involved, unmeasured serum quinine levels, and reduced generalizability from selecting male veterans from only 1 hospital.

The authors have shown that quinine sulfate is an effective treatment modality for this group of patients; it is, however, difficult to project these results to all patients with nocturnal leg cramps. The quinine sulfate dose used in this study (200 mg at supper with an additional 300 mg at bedtime) is higher than the commonly prescribed 200-mg dose at bedtime. At this higher dose, risks for side effects increase. It is important to keep in mind the serious and potentially fatal hypersensitivity reactions and liver injury occasionally caused by quinine (2, 3). Patients may also become refractory to quinine after 2 to 3 months of therapy. A longer study with a broader-based population would be needed to address these issues.

In the meantime, for patients with leg cramps we should prescribe quinine cautiously in addition to before-bedtime massage and prophylactic leg stretching.

Abdulrazak Abyad, MD, MPH
University of Arizona Tucson, Arizona, USA