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


Letters

Quinine for nocturnal leg cramps

ACP J Club. 1995 Nov-Dec;123:86. doi:10.7326/ACPJC-1995-123-3-086



To the Editor

We believe that your readers should be aware of the following information, which reflects a finding contrary to that contained in an abstract recently published in ACP Journal Club (1).

Quinine has been removed from the over-the-counter (OTC) market in the United States, and no quinine prescription products are allowed to be labeled for this use. On 22 August 1994, the U.S. Food and Drug Administration (FDA) issued a final regulation (2) containing the agency's detailed analysis and decision that OTC quinine drug products are not safe and effective for treatment or prevention of nocturnal leg muscle cramps.

Quinine was removed from the OTC market for this use because of 1) the failure of the clinical studies to show effectiveness of quinine in this condition in doses ranging between 260 and 325 mg/d, 2) the evidence of symptoms of quinine toxicity at the OTC doses used for leg cramps in a proportion of the target population, and 3) the potential for serious, life-threatening, and fatal hypersensitivity reactions to quinine. The FDA stated in the final rule that even if quinine were effective for this condition, the safety risk in its use would require that a prescribing physician participate in the decision to use the drug by assuring the diagnosis, considering alternative treatment options, evaluating concurrent medical problems and medications, and monitoring patient safety throughout treatment.

The decision on OTC quinine sulfate was part of the FDA's ongoing review of OTC drug products. The review process is a public one that is formalized in the agency's regulations. In this case, as in all cases, before a final decision was made, there were specified stages where the preliminary findings on safety and effectiveness were published and public comments and data solicited and reviewed (3, 4).

Subsequently, the agency notified manufacturers in January 1995 that the FDA has no record of an approved new drug application or abbreviated new drug application for any prescription quinine sulfate products indicated for nocturnal leg muscle cramps and that prescription quinine drug products should no longer be labeled for this use. Thus, prescription products for this use need to be relabeled because effectiveness has not been established by clinical studies.

Following publication of the final rule, initial introduction or initial delivery for introduction into interstate commerce of OTC quinine sulfate for the treatment and prevention of nocturnal leg muscle cramps was to cease effective 22 February 1995 (existing stocks in the marketplace were allowed to be used up).

Stuart L. Nightingale, MD
FDA Office of Health Affairs
Rockville, Maryland

Response

The FDA's action of August 1994 to stop the use of quinine sulfate for the prevention and treatment of nocturnal leg cramps is not based on complete information.

The FDA's 12-year process to review this OTC medication was poorly structured for incorporating new information. As indicated in the 22 August 1994 Federal Register (5), "new data could have been submitted until November 10, 1986" and "comments on these data until January 8, 1987." Since 1987, numerous clinical trials evaluating the efficacy of quinine in this condition have been published. In particular, the FDA did not consider 3 well-designed randomized controlled trials (6-8) that showed a statistically and, most likely, clinically significant benefit for quinine compared with placebo for nocturnal leg cramps. Other well-designed and well-executed trials were done (9, 10) that show a strong trend toward benefit for quinine, although statistical significance was not reached. The results of these trials appeared to be attributable to the small number of patients that were enrolled. Therefore, the FDA's conclusion that available data are not sufficient to establish the effectiveness of quinine sulfate for the treatment and prevention of nocturnal leg cramps is based on incomplete information and needs to be re-evaluated. Given the above, their 1994 decision to no longer allow labeling of quinine for use in nocturnal leg cramps also needs to be re-assessed.

The FDA also has implied that nocturnal leg cramps is not a serious health condition (11). Although not life-threatening, nocturnal leg cramps can seriously affect the quality of life. Given quinine's potentially serious side effects, however, the FDA's decision to restrict its OTC use is appropriate.

One study (12) suggests that a nonpharmacologic therapy, passive stretching, can help relieve nocturnal leg cramps. Thus, a rational approach to treatment of this prevalent condition is to first try passive stretching. If this fails, then a trial of quinine is warranted in patients whose quality of life is seriously affected. As with all potentially harmful medications, it is important that physicians prescribing quinine monitor its benefits and risks in individual patients.

Malcolm Man-Son-Hing, MD
George Wells, PhD
Ottawa Civic Hosptial
Ottawa, Ontario, Canada

Response

Although it is helpful to receive clarification from the FDA on its deliberations to remove quinine from OTC preparations, it is important to recall the underlying tenet of evidence-based medicine: Clinicians should be aware of the quality of evidence that informs their medical decisions. After wading through the most recent Federal Register report about quinine (13), it becomes apparent that the FDA based their decision on evidence submitted by various interested parties. Unfortunately, the evidence available for the FDA to consider derived predominantly from unpublished data or published clinical trials from the early 1980s.

Regarding the safety of quinine, the FDA concluded that an unacceptable incidence of side effects exists (8% to 43%), although serious reactions were relatively uncommon. This seemed to be an important factor in their decision to remove quinine from unsupervised OTC use, a move that most clinicians would deem as prudent. As the FDA pondered the evidence submitted to them to substantiate claims of quinine effectiveness, they correctly identified the many threats to validity in the unpublished studies. Based solely on that evidence, I also would have concluded that adequate evidence does not exist regarding the effectiveness of quinine in treating leg cramps.

Fortunately, the busy clinician can turn to ACP Journal Club or the original meta-analysis by Man-Son-Hing and Wells that concludes, based on the best available evidence (including 3 randomized controlled trials from the 1990s), that quinine appears to decrease the number of nocturnal leg cramps. So, should you consider the unlabeled use (i.e., not FDA approved) of quinine in your patients who complain of frequent, painful nocturnal leg cramps? My answer remains the same as when I wrote the ACP Journal Club commentary. Good evidence does exist that quinine can decrease the number of leg cramps on a short-term basis, and the decision to use quinine for individual patients should involve close monitoring during a therapeutic trial or even doing an n-of-1 trial.

Mark C. Wilson, MD
Bowman Gray School of Medicine
Winston-Salem, North Carolina


References

1. 1. Quinine is effective for preventing nocturnal leg cramps. ACP J Club. 1995 Jul-Aug;123:11. Abstract of: Man-Son-Hing M, Wells G. Meta-analysis of efficacy of quinine for treatment of nocturnal leg cramps in elderly people. BMJ. 1995;310:13-7.

2. 2. Drug products for the treatment and/or prevention of nocturnal leg muscle cramps for over-the-counter human use. Federal Register. 1994 Aug 22;59:43234-52.

3. 3. Quinine for the treatment of nocturnal leg muscle cramps for over-the-counter human use. Federal Register. 1982 Oct 1;47:43562-4.

4. 4. Tentative final monograph for drug products for the treatment and/or prevention of nocturnal leg muscle cramps. Federal Register. 1985 Nov 8; 50:46588-94.

5. Drug products for the treatment and/or prevention of nocturnal leg muscle cramps for over-the-counter human use. Federal Register. Aug 22 1994;59:43234-52.

6. Fung MD, Holbrook JH. Placebo-controlled trial of quinine therapy for nocturnal leg cramps. West J Med. 1989; 151:42-4.

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

8. Gorlich HD, von Gablenz E, Steinberg HW. Treatment of nocturnal leg cramps. A multi-center, double blind, placebo controlled comparison between the combination of quinine and theophylline ethylene diamine with quinine. Arzneimittelforschung. 1991;41:167-75.

9. Warburton A, Royston JP, O'Neill CJ, et al. A quinine a day keeps the leg cramps away? Br J Clin Pharmacol. 1987;23:459-65.

10. Sidorov J. Quinine sulfate for leg cramps: does it work? J Am Geriatr Soc. 1993; 41: 498-500.

11. FDA Consumer. July-August 1995.

12. Daniell HW. A simple cure for nocturnal leg cramps. N Engl J Med. 1979;301:216.

13. Drug products for the treatment and/or prevention of nocturnal leg muscle cramps for over-the-counter human use. Federal Register. 1994 Aug 22;59:43234-52.