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"Muscle spasms"
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Randomized double-blind personalized N-of-1 clinical trial to test the safety and potential efficacy of TJ-68 for treating muscle cramps in amyotrophic lateral sclerosis (ALS): study protocol for a TJ-68 trial
by
Fernandes, Joseph Americo
,
McElhiney, Martin
,
Cheung, Ken
in
Amyotrophic lateral sclerosis
,
Amyotrophic Lateral Sclerosis - complications
,
Amyotrophic Lateral Sclerosis - diagnosis
2023
Introduction/aims
Muscle cramps are a common and often disabling symptom in amyotrophic lateral sclerosis (ALS), a devastating and incurable neurodegenerative disorder. To date, there are no medications specifically approved for the treatment of muscle cramps. Ameliorating muscle cramps in ALS may improve and sustain quality of life. A widely prescribed traditional Japanese (Kampo) medicine against muscle cramps, shakuyakukanzoto (TJ-68), has been studied in advanced liver disease, spinal stenosis, kidney failure, and diabetic neuropathy. The Japanese ALS Management Guideline mentions TJ-68 for difficult muscle cramps in ALS. Therefore, the rationale of our trial is to investigate the safety and effectiveness of TJ-68 in treating painful and disabling muscle cramps in people with ALS outside of Japan. Accordingly, we are conducting a randomized clinical trial to test the safety and efficacy of TJ-68 in participants with ALS reporting frequent muscle cramps using an innovative, personalized N-of-1 design. If successful, TJ-68 may be used for muscle cramps in a broader population of people with ALS.
Methods
This is a two-site, double-blind, randomized personalized N-of-1 early clinical trial with TJ-68. At least 22 participants with ALS and daily muscle cramps will receive drug or placebo for 2 weeks (one treatment period) followed by a 1-week washout in a four-period cross-over design. While the primary objective is to evaluate the safety of TJ-68, the study has 85% power to detect a one-point shift on the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity of the Columbia Muscle Cramp Scale (MCS). Secondary outcomes include the full MCS score, a Cramp Diary, Clinical Global Impression of Changes, Goal Attainment Scale, quality of life scale and ALS functional rating scale-revised (ALSFRS-R).
Discussion
The study is underway. A personalized N-of-1 trial design is an efficient approach to testing medications that alleviate muscle cramps in rare disorders. If TJ-68 proves safe and efficacious then it may be used to treat cramps in ALS, and help to improve and sustain quality of life.
Trial registration
This clinical trial has been registered with ClinicalTrials.gov (NCT04998305), 8/9/2021.
Journal Article
Pickle Juice Intervention for Cirrhotic Cramps Reduction: The PICCLES Randomized Controlled Trial
2022
Muscle cramps are common among persons with cirrhosis and associated with poor health-related quality of life. Treatment options are limited. We sought to determine whether pickle juice can improve muscle cramp severity.
We enrolled 82 patients with cirrhosis and a history of >4 muscle cramps in the previous month from December 2020 to December 2021. Patients were randomized 1:1 to sips of pickle juice vs tap water at cramp onset. Our primary outcome assessed at 28 days was the change in cramp severity measured by the visual analog scale for cramps (VAS-cramps, scaled 0-10). Cramps were assessed 10 times over 28 days using interactive text messages. Secondary outcomes included the proportion of days with VAS-cramps <5, change in sleep quality, and global health-related quality of life measured using the EQ-5D.
Overall, 74 patients completed the trial, aged 56.6 ± 11.5 years, 54% male, 41% with ascites, 38% with encephalopathy, and model for end-stage liver disease-sodium score 11.2 ± 4.9. Many patients were receiving other cramp therapies at baseline. The baseline VAS for cramps was 4.2 ± 3.4, the EQ-5D was 0.80 ± 0.10, and 43% rated sleep as poor. At trial completion, the respective values for the pickle juice and control arms were -2.25 ± 3.61 points on the VAS for cramps, compared with control tap water (-0.36 ± 2.87), P = 0.03; a proportion of cramp-days with VAS-cramps <5 were 46% vs 35% (P = 0.2); and the change in sleep quality was not different (P = 0.1). The end-of-trial EQ-5D was 0.78 ± 0.10 vs 0.80 ± 0.10 (P = 0.3). No differences in weight change were observed for those with and without ascites.
In a randomized trial, sips of pickle brine consumed at cramp onset improve cramp severity without adverse events.
Journal Article
Vitamin K2 as a potential therapeutic candidate for the prevention of muscle cramps in hemodialysis patients: A prospective multicenter, randomized, controlled, crossover pilot trial
2022
[Display omitted]
•Vitamin K2 supplementation decreased the frequency, duration, and severity of refractory muscle cramps in hemodialysis patients.•Vitamin K2 might be a safe, inexpensive, and effective management for muscle cramps in patients with dialysis.•Intracellular calcium regulation mechanism might be the theoretical rationale for vitamin K2 suppressing muscle cramps.
Muscle cramps occur in 33% to 78% of patients with dialysis. The etiology of muscle cramps is poorly understood, and no clear evidence-based prevention or treatment strategies exist. Improved interventions are urgently needed. The aim of this study was to investigate the effect of vitamin K2 in reducing the frequency and severity of muscle cramps in hemodialysis (HD) patients.
This multicenter, randomized, placebo-controlled, crossover clinical trial was conducted from June 2019 to May 2020. Each participant received vitamin K2 (360 µg/d) or placebo for two 4-wk phases, and then crossed to the alternative arm for two 4-wk phases after a 2-wk washout. The primary endpoint was the frequency of muscle cramps during HD. The secondary endpoints were severity and duration of muscle cramps during HD.
A total of 523 patients with maintenance HD were screened for muscle cramps, including 41 patients with muscle cramps refractory to conventional interventions, were enrolled. Nineteen patients in the vitamin K2-initial group and 20 in the placebo-initial group completed the protocol, and were included in the final analysis. Vitamin K2 reduced the frequency, duration, and severity of muscle cramps in HD patients (all P < 0.05). The frequency, duration, and severity of muscle cramps in HD patients increased again after crossing over to the placebo. There were no serious adverse events. One patient experienced gastrointestinal discomfort when taking vitamin K2.
This pilot trial demonstrated that vitamin K2 supplementation could decrease the frequency, duration, and severity of muscle cramps in HD patients.
Journal Article
Programmed vs. Thirst-Driven Drinking during Prolonged Cycling in a Warm Environment
by
Hoffman, Martin D.
,
Gendron, Philippe
,
Claveau, Pascale
in
Adult
,
Athletes
,
Athletic Performance - physiology
2021
We compared the effect of programmed (PFI) and thirst-driven (TDFI) fluid intake on prolonged cycling performance and exercise associated muscle cramps (EAMC). Eight male endurance athletes (26 ± 6 years) completed two trials consisting of 5 h of cycling at 61% V˙O2peak followed by a 20 km time-trial (TT) in a randomized crossover sequence at 30 °C, 35% relative humidity. EAMC was assessed after the TT with maximal voluntary isometric contractions of the shortened right plantar flexors. Water intake was either programmed to limit body mass loss to 1% (PFI) or consumed based on perceived thirst (TDFI). Body mass loss reached 1.5 ± 1.0% for PFI and 2.5 ± 0.9% for TDFI (p = 0.10). Power output during the 20 km TT was higher (p < 0.05) for PFI (278 ± 41 W) than TDFI (263 ± 39 W), but the total performance time, including the breaks to urinate, was similar (p = 0.48) between conditions. The prevalence of EAMC of the plantar flexors was similar between the drinking conditions. Cyclists competing in the heat for over 5 h may benefit from PFI aiming to limit body mass loss to <2% when a high intensity effort is required in the later phase of the race and when time lost for urination is not a consideration.
Journal Article
Acute Passive Static Stretching and Cramp Threshold Frequency
2017
Exercise-associated muscle cramps are a common clinical problem for athletes.
To determine whether acute passive static stretching altered cramp threshold frequency (CTF) of electrically induced muscle cramps.
Crossover study.
Laboratory.
Seventeen healthy college-aged individuals.
Stretching or no stretching.
The independent variable was the static stretch versus the no-stretch condition, and the dependent variable was the CTF.
The CTF increased in both the control (pretest: 18.12 ± 6.46 Hz, posttest: 19.65 ± 7.25 Hz; P = .033) and stretching (pretest: 18.94 ± 5.96 Hz, posttest: 20.47 ± 7.12 Hz; P = .049) groups. No difference between the groups was found (t
= 0.035, P = .97).
Acute passive static stretching did not seem to increase the CTF.
Journal Article
Effect of oral rehydration solution versus spring water intake during exercise in the heat on muscle cramp susceptibility of young men
by
Lau, Wing Yin
,
Kato, Haruyasu
,
Nosaka, Kazunori
in
analysis of variance
,
blood serum
,
body weight
2021
Background
Muscle cramp is a painful, involuntary muscle contraction, and that occurs during or following exercise is referred to as exercise-associated muscle cramp (EAMC). The causes of EAMC are likely to be multifactorial, but dehydration and electrolytes deficits are considered to be factors. This study tested the hypothesis that post-exercise muscle cramp susceptibility would be increased with spring water ingestion, but reduced with oral rehydration solution (ORS) ingestion during exercise.
Methods
Ten men performed downhill running (DHR) in the heat (35–36 °C
)
for 40–60 min to reduce 1.5–2% of their body mass in two conditions (spring water vs ORS) in a cross-over design. The body mass was measured at 20 min and every 10 min thereafter during DHR, and 30 min post-DHR. The participants ingested either spring water or ORS for the body mass loss in each period. The two conditions were counter-balanced among the participants and separated by a week. Calf muscle cramp susceptibility was assessed by a threshold frequency (TF) of an electrical train stimulation to induce cramp before, immediately after, 30 and 65 min post-DHR. Blood samples were taken before, immediately after and 65 min after DHR to measure serum sodium, potassium, magnesium and chroride concentrations, hematocrit (Hct), hemoglobin (Hb), and serum osmolarity. Changes in these varaibles over time were compared between conditions by two-way repeated measures of analysis of variance.
Results
The average (±SD) baseline TF (25.6 ± 0.7 Hz) was the same between conditions. TF decreased 3.8 ± 2.7 to 4.5 ± 1.7 Hz from the baseline value immediately to 65 min post-DHR for the spring water condition, but increased 6.5 ± 4.9 to 13.6 ± 6.0 Hz in the same time period for the ORS condition (
P
< 0.05). Hct and Hb did not change significantly (
P
> 0.05) for both conditions, but osmolarity decreased (
P
< 0.05) only for the spring water condition. Serum sodium and chloride concentrations decreased (< 2%) at immediately post-DHR for the spring water condition only (
P
< 0.05).
Conclusions
These results suggest that ORS intake during exercise decreased muscle cramp susceptibility. It was concluded that ingesting ORS appeared to be effective for preventing EAMC.
Journal Article
Treatment of insomnia, restless legs, cramps, and pain associated with chronic kidney disease: results from a multinational survey of kidney supportive care practice
by
Snead, Charlotte M.
,
Stallworthy, Elizabeth
,
Agarwal, Neeru
in
Agonists
,
Australia - epidemiology
,
Chronic kidney disease
2025
Background
Kidney failure is associated with a high symptom burden, yet few studies describe real-world management approaches.
Methods
Kidney care units in Australia, New Zealand (NZ) and the United Kingdom (UK) were surveyed regarding their pharmacological treatment of a range of common symptoms affecting those with kidney failure. The present report describes the results for insomnia, restless legs syndrome (RLS), cramps, and pain. Variation in responses was described using normalised generalised variance (NGV), resulting in a score from 1 (most diverse) to 0 (least diverse).
Results
One hundred and twelve (of 171 contacted) kidney units responded, including 56 units in Australia (50%), 7 in NZ (6%), and 49 in the UK (44%). Diversity of practice was highest for insomnia (mean NGV 0.95, range 0.93–0.98), where melatonin was the leading first-line agent (38%), followed by zolpidem and zopiclone (29%). Diversity of practice was lowest for RLS (mean NGV 0.66, range 0.30–0.99), owing to widespread use of iron replacement as first line (69%), gabapentinoids (45%), and dopamine agonists (37%). Diversity of practice was moderate for neuropathic pain (mean NGV 0.71, range 0.44–0.93), cramps (mean NGV 0.72, range 0.48–0.97), and opioids (mean NGV 0.88, range 0.75–0.97). Numerous significant between-country differences in treatment preferences were noted.
Conclusions
There is wide variation in treatment approaches to common symptoms affecting people living with advanced CKD or kidney failure, both within and between countries, indicating a need for evidence-based guidelines and further randomised studies to inform practice.
Clinical trial number
Not applicable.
Journal Article
Prevention of leg cramps by using compression stockings or magnesium supplements in the 50–84 age group: study protocol for a randomised controlled trial
2021
Background
Leg cramps are painful sensations of tightening in the muscles of the legs that commonly appear during the night and are often associated with secondary insomnia. They are common especially in older age. There is no evidence that any method of prevention of nocturnal leg cramps is both safe and effective. There are no previous trials concerning cramp prevention by using compression stockings. The objective of this study is to assess in a prospective randomised controlled trial whether leg cramps can be prevented by the daily use of knee-length compression stockings or magnesium supplements.
Methods
The study will be set in Finland, and 50–84-year-old volunteers will be recruited through Google Ads, the Finnish health library website and Finnish primary health care centres. The participants must have a minimum of two episodes of leg cramps per week for the past 4 weeks to be included in the study. The participants (
n
= 225) will be allocated to three equal groups: the compression stocking arm, the magnesium supplement arm and the placebo arm. The participants will go through 4 weeks of follow-up without intervention and then another 4 weeks of follow-up with the assigned intervention. The material for the study will be collected through electronic questionnaires.
Discussion
This protocol describes a study that compares compression stockings, magnesium supplements and placebo for the prevention of leg cramps. The results of this study can significantly improve knowledge on the methods of preventing leg cramps.
Trial registration
ClinicalTrials.gov
NCT04694417. Registered on Jan 4, 2021.
Journal Article
Effect of l-carnitine supplementation on muscle cramps induced by stroke: A case report
by
Hanai, Tatsunori
,
Katsumura, Naoki
,
Shimizu, Masahito
in
acyl coenzyme A
,
Adenosine triphosphate
,
Aged
2020
•l-carnitine is reported to reduce muscle cramps in patients with liver cirrhosis, diabetes, and those on dialysis.•The present patient, diagnosed with cerebral infarction, experienced nocturnal leg cramps in the affected side with sleep disturbance.•l-carnitine supplementation reduced the number of nocturnal leg cramps and alleviated sleep disturbance.•This case suggests that stroke may cause localized carnitine deficiency, and l-carnitine supplementation might be effective for muscle cramps induced by stroke.
l-carnitine, a compound responsible for transportation of acyl groups across cell membranes and modulating intracellular acyl-coenzyme A levels, is reported to reduce muscle cramps in patients with liver cirrhosis and diabetes and those on dialysis. A 79-y-old man with right-sided paralysis was admitted to our hospital and diagnosed with cerebral infarction. Nocturnal leg cramps appeared in the affected side and caused sleep disturbance. Supplementation with l-carnitine reduced the number of nocturnal leg cramps and alleviated sleep disturbance. It also plays an important role in nerve protection and treatment for carnitine deficiency. Patients with stroke-induced paralysis experience muscle wasting, which might reduce pooled carnitine in the affected side. This case suggests that stroke may cause localized carnitine deficiency, and l-carnitine supplementation might be effective for muscle cramps induced by stroke. To the best of our knowledge, this is the first case of l-carnitine supplementation for muscle cramps triggered by cerebral infarction.
Journal Article