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Diltiazem for nocturnal leg crampsSIRÐIn the prevention ofnocturnal leg cramps, quinine sulphate is the most frequently used drug; it has a modest effect [1, 2] but, because of toxicity associated with its use, an alternative is needed. Verapamil can relieve the leg cramps resistant to quinine [3]. Having properties of neuromuscular transmission inhibition [4] and calcium channel blockade in the sarcolemma [5±7], diltiazem hydrochloride may be worthy ofinvestigation.
We have carried out a double-blind, randomized, placebo-controlled, crossover trial on 13 patients (11 women; aged 64"10 years) with typical leg cramps two or more times per week. Subjects with clinically important electrolyte disorders, second- or third-degree atrioventricular block, sick sinus syndrome and uncon- trolled congestive cardiac failure were excluded. We prohibited concomitant use ofquinine sulphate, vitamins E and B complex and calcium-channel blockers.
This trial had four phases of observation, each lasting 2 weeks. Patients took a tablet containing 30 mg of diltiazem hydrochloride or a placebo tablet before going to bed. Placebo treatment was given during the run-in period (phase 1) and during the washout period (phase 3). We used a random numbers table to randomize the patients and neither the patients nor the investigators (except the assistant) knew to which subgroup the Division of Cardiology, Department of Internal Medicine, patients were randomized. Patients assigned an even Kaohsiung Medical University, Kaohsiung 807, Taiwan number took placebo during the second phase and diltiazem hydrochloride during the fourth phase, whereas those assigned an odd number took diltiazem hydro- chloride during the second phase and placebo during the 1. Man-Son-Hing M, Wells G. Meta-analysis of efficacy of fourth phase. A nightly diary was kept to record each leg quinine for treatment of nocturnal leg cramps in elderly cramp and an estimate ofits intensity from their own experience with a scale ofone (low) to three (high).
2. Man-Son-Hing M, Wells G, Lau A. Quinine for nocturnal The subjects tolerated diltiazem hydrochloride well leg cramps: a meta-analysis including unpublished data. J Gen and none reported side effects. As one patient took felodipine from another doctor to control her very high 3. Baltodano N, Gallo BV, Weidler DJ. Verapamil vs quinine in blood pressure, only 12 patients were included in the recumbent nocturnal leg cramps in the elderly. Arch Intern ®nal analyses. There was no signi®cant randomization group difference in the frequency [95% con®dence 4. Chang CC, Lin SO, Hong SJ, Chiou LC. Neuromuscular interval (CI), ±16.96 to 4.96 cramps per phase; block by verapamil and diltiazem and inhibition ofacetyl- P = 0.250)] and intensity (95% CI, ±0.709 to 0.142; choline release. Brain Res 1988; 454: 332±9.
P = 0.166) ofleg cramps. There was also no carryover 5. Rivet M, Cognard C, Rideau Y et al. Calcium currents in effect on the frequency (95% CI, ±14.85 to 9.52 cramps normal and dystrophic human skeletal muscle cells in culture.
per phase; P = 0.636) and intensity (95% CI, ±2.57 to 1.01; P = 0.352) ofleg cramps. Moreover, as for the 6. Triggle DJ. Calcium channel antagonists: mechanisms of frequency and intensity of leg cramps, there was neither action, vascular selectives, and clinical relevance. Cleve Clin signi®cant period effect between phases 2 and 4 (95% CI, ±4.51 to 4.51 cramps per phase; P = 1.000 and 95% 7. Arreola J, Calvo J, Garcia MC, Sanchez JA. Modulation of CI, ±0.42 to 0.77; P = 0.551, respectively) nor signi®cant calcium channels of twitch skeletal muscle fibres of the frog by sequence effect (95% CI, ±5.80 to 3.13 cramps per adrenaline and cyclic adenosine monophosphate. J Physiol phase; P = 0.542 and 95% CI, ±0.97 to 0.19; P = 0.175, respectively). The combined data ofphases 2 and 4 8. Keidar S, Binenboim C, Palant A. Muscle cramps during showed a statistically signi®cant difference (95% CI, treatment with nifedipine. Br Med J 1982; 285: 1241±2.
À5.84 to À0.16 cramps per phase; P = 0.040) in the 9. Grossman E, Messerli FH. Effect of calcium antagonists on frequency of leg cramps between those on diltiazem plasma norepinephrine levels, heart rate and blood pressure.
hydrochloride and those on placebo. There was no signi®cant difference (95% CI, ±0.30 to 0.11; P = 0.347) in the intensity ofleg cramps between those on diltiazem The mechanisms ofleg cramps are unknown. It is interesting that nifedipine [8] may induce but verapamil [3] and diltiazem may relieve leg cramps. Diltiazem and verapamil (but not nifedipine) can block neuromuscular transmission via inhibition ofneurotransmitter release [4]. Nifedipine, diltiazem and verapamil can block the L-type calcium channels in the sarcolemma [5, 6] and interfere with entry of calcium ions into the sarcoplasm via the T tubules, and with calcium-induced calcium release from the sarcoplasmic reticulum. Nifedipine may induce stronger re¯ex adrenergic stimulation than diltiazem and verapamil [9]. It will then enhance the entry ofcalcium ions through the dihydropyridine- insensitive T-type calcium channels [7] and thus nullify its net effect on calcium-channel blockade. Such dif- ferences either alone or in combination may explain the heterogeneous effects of calcium-channel blockers In conclusion, this small study suggests that diltiazem is effective and safe in the prevention of nocturnal leg

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