primary outcome:
Quinine for muscle cramps
Absolute difference in number of cramps (occurring day or night) during a two‐week treatment period.The number of cramps was selected as the primary outcome on the grounds that it is the most commonly used outcome in clinical trials. For trials that involved treatment periods greater than two weeks, the results were standardised to provide comparable data for combined analysis at two weeks. For example, studies with treatment periods of four weeks had the reported number of cramps divided by two.Eighteen placebo‐controlled trials reported the absolute number of cramps occurring over their study period. To allow the results to be combined in a meta‐analysis, we standardised the data to the number of cramps occurring over two weeks.Four trials could not be entered into the meta‐analysis for the reasons given above (Bottner 1984; Kaji 1976; Maule 1990; Smith 1985). The 14 trials (n = 982) entered into the meta‐analysis all investigated idiopathic muscle cramps except one (Lee 1991), which investigated cramps in people with liver cirrhosis. The results of the Lee 1991 trial were comparable with the rest. When the 14 trials were entered into the meta‐analysis, the combined mean change in the number of cramps was ‐1.81 (95% CI ‐2.20 to ‐1.42) (See Analysis 1.1).Significant heterogeneity was detected in the meta‐analysis (I² = 89%). Inspection of the included trials identified potential causes in two trials. The small trial of Woodfield 2005 contained large standard errors for the primary outcome and Connolly 1992 was the only trial to use 500 mg quinine and included only men. The exclusion of Woodfield 2005 did not reduce the heterogeneity but excluding Connolly 1992 reduced the I² index to 71%. We performed further sensitivity analyses excluding all trials at a high or unclear risk of bias for adequate sequence generation, allocation concealment, and blinding; the heterogeneity index changed to 50%, 67% and 91% respectively. Quinine remained significantly effective compared to placebo in all these sensitivity analyses. After discussion, we excluded Connolly 1992 only because of its unique participant selection and quinine dose, and used a random‐effects model. Quinine resulted in a significant decrease in cramp number (‐2.45 cramps, 95% CI ‐3.54 to ‐1.36, random‐effects), equivalent to a 28% (95% CI 15% to 40%) reduction over placebo (see Analysis 1.2, Figure 2). It is worth noting the persistent heterogeneity (I² = 71%) associated with this result.The inclusion of Connolly 1992 resulted in significant heterogeneity (I² = 94%, reduced to 29% on exclusion), so it was removed on the basis of its unique selection of participants and dose. With this persisting heterogeneity (I² = 29%), we used the random‐effects model and there was no significant difference between quinine and vitamin E in reducing cramps; ‐0.24 cramps (95% CI ‐1.29 to 0.81) (see Analysis 2.1, Figure 7).Three unpublished studies (n = 510) compared quinine with a combination of quinine and vitamin E (Q‐Vel); two of these trials claimed superiority of the quinine‐vitamin E combination over quinine alone (BioDesign 1984; Leo Winter 1986), whilst one reported no significant difference (CIBA 1988). The BioDesign 1984 study did not report data that could be included in the meta‐analysis. We identified significant heterogeneity in the meta‐analysis of the remaining two studies (CIBA 1988; Leo Winter 1986). This could not be explained, so we used a random‐effects model (I² = 49%); there was a nonsignificant difference in cramp number when quinine alone was compared to the quinine‐vitamin E combination (1.07 cramps, 95% CI ‐1.08 to 3.23) (see Analysis 3.1, Figure 8).A single parallel‐group study conducted by a pharmaceutical company (Gorlich 1991, n = 77 excluding placebo group) compared quinine to a quinine‐theophylline combination known as Limptar®. Standardised results from the second treatment week showed quinine was at a significant disadvantage compared to the quinine‐theophylline combination, giving 3.8 more cramps (95% CI 1.08 to 6.52) over two weeks, representing a 136% (95% CI 39% to 233%) difference.