Effect of Vitamin K2 in the Treatment of Nocturnal Leg Cramps in Older Population

Effect of Vitamin K2 in the Treatment of Nocturnal Leg Cramps in Older Population: Study Protocol of a Randomized, Double-blind, Controlled Trial

Nocturnal leg cramps (NLCs) are sudden contractions of the leg muscles, usually in the posterior calf muscles at night, affecting sleep quality. Because the precise pathophysiology of NCLs is unclear, different interventions have been proposed. There is conflicting evidence regarding the efficacy of conventional interventions in preventing cramps. Thus, the present study aims to investigate the effects of vitamin K2 for NLCs in a prospective randomized, double-blind, controlled trial.

Study Overview

• Status: Completed
• Conditions: Nocturnal Leg Cramps
• Intervention / Treatment: Drug: Placebo; Drug: Vitamin K2

Detailed Description

Nocturnal leg cramps (NLCs) are spontaneous contractions of muscles. The gastrocnemius is commonly involved, lasting from a few seconds to a few minutes. Patients might wake up with pain during attacks, making it difficult to sleep for a short period. It commonly occurs >60-year-old. The medical history and physical examination are usually sufficient to differentiate nocturnal leg cramps from other conditions, such as restless legs syndrome, claudication, myositis, and peripheral neuropathy. Factors that may lead to leg cramps attacks include hemodialysis, electrolyte imbalance, metabolic disorders, and congenital disorders. The cramps can be relieved by passive stretching of the gastrocnemius and deep tissue massage, but such prevention is limited, especially in patients with refractory muscle cramps. Quinine has been shown to be effective in treating NLCs but is not recommended by the US Food and Drug Administration due to severe side effects. Magnesium supplements are often used as a preventative treatment for NLCs; however, their effectiveness is controversial. Magnesium supplements are widely marketed for the prophylaxis of NLCs since a double-blind, placebo-controlled study proved their effectiveness in pregnant women. However, magnesium administration did not show significant benefits in NLCs in double-blind, placebo-controlled studies. Meta-analysis of some randomized control trials (RCTs) showed that magnesium therapy did not appear to be effective in the treatment of NLCs in the general population, but may have a negligible effect in pregnant women. Therefore, seeking new approaches to manage NLCs is imperative.

Vitamin K is a fat-soluble vitamin involved in carboxylation and activating several dependent proteins. It is found in two isoforms (phylloquinone (vitamin K1) and menaquinone (vitamin K2)) that differ in length and degree of saturation of the side chain. In addition to their role in coagulation, vitamin K-dependent proteins are involved in vascular calcification and osteoporosis physiology. Accumulating evidence has shown the beneficial effects of vitamin K2 supplementation on cardiovascular and bone health.

Another study revealed that vitamin K3 relieved muscle cramps by effectuating the voltage-dependent calcium channels to release the calcium stored in the cells, thus reducing the frequency of muscular contractions. To the best of our knowledge, no study has yet investigated the efficacy of vitamin K in NLCs. In addition, vitamin K2 has a good safety profile compared to other medications. Our pilot study demonstrated that vitamin K2 supplementation decreases the frequency, duration, and severity of muscle cramps in hemodialysis patients. To further investigate the efficacy and safety of vitamin K2 in NLCs, we designed this prospective, multicenter, randomized, double-blind trial.

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Sichuan
    • Chengdu, Sichuan, China, 610000
      • Chengdu Third People's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Unexplained cramps occurred two or more times in 2 weeks.
2. Age ≥65-year-old.

Exclusion criteria

1. Cramps caused by specific metabolic diseases and specific neuropathies (hypothyroidism, hemodialysis, hypoglycemia, alcoholism, amyotrophic lateral sclerosis, and poliomyelitis complications, lumbar spinal stenosis, Parkinson's disease, radiculopathies, and motor neuron diseases);
2. Suffering from malignant tumors (breast cancer, prostate cancer, lymphoma, and multiple myeloma);
3. Taking diuretics, or vitamin K antagonist;
4. Taking supplements with vitamin K2 within 2 months before enrollment;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: vitamin K2 arm; The vitamin K2 arm takes vitamin K2 180 μg/day at bedtime for 8 weeks.	Drug: Vitamin K2; Vitamin K2 is a fat-soluble and one of the body's indispensable vitamins. It is mainly synthesized by gut bacteria in the body and plays a role in the mitochondrial electron transport chain. It boosts calcium metabolism, acts on osteoblasts, and promotes bone tissue calcification. It also inhibits osteoclasts from causing bone resorption, thus increasing bone density, and preventing osteoporosis. Furthermore, it regulates the use of calcium and promotes the inhibition of vascular calcification by matrix Gla protein (MGP) activity. Vitamin K2 supplementation at recommended dosage does not affect vitamin K-dependent coagulation factors' activity. It does not enhance the carboxylation of prothrombin in healthy individuals. Vitamin K2 administration does not alter the hemostatic balance in healthy populations without anticoagulation treatment. Thus, vitamin K2 is deemed to have a good safety profile.
Placebo Comparator: Placebo; The placebo group takes a placebo at bedtime for 8 weeks.	Drug: Placebo; Similar-looking placebo tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The number of NLCs attacks	The mean number of NLC attacks per week	Comparing frequency differences between vitamin K2 and placebo treatment phases of NLCs in a 8 weeks investigation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The duration of NLCs	Duration of muscle cramps in minutes	During the 8 weeks of investigation, the differences in the duration during NLCs attacks will record in the trial compared to vitamin K2- and placebo-treated arms
The severity of NLCs	The severity of muscle cramps using a 1-10 analog scale（1-3 points, mild pain, tolerable, does not affect sleep; 4-6 points, moderate pain, affects sleep, also tolerable; 7-10 points, sharp pain, intolerable.）	During the 8 weeks of investigation, pain severity during NLCs attacks is recorded in the trial and compared to vitamin K2- and placebo-treated arms

Collaborators and Investigators

• Sponsor: The Third People's Hospital of Chengdu
• Collaborators: Affiliated Hospital of North Sichuan Medical College

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2022
• Primary Completion (Actual): December 31, 2023
• Study Completion (Actual): December 31, 2023

Study Registration Dates

• First Submitted: September 15, 2022
• First Submitted That Met QC Criteria: September 15, 2022
• First Posted (Actual): September 21, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 15, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Vitamin K2; Nocturnal Leg Cramps; older population
• Additional Relevant MeSH Terms: Neurologic Manifestations; Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Neuromuscular Manifestations; Mental Disorders; Sleep Wake Disorders; Parasomnias; Spasm; Muscle Cramp; Sleep-Wake Transition Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antifibrinolytic Agents; Fibrin Modulating Agents; Hemostatics; Coagulants; Micronutrients; Vitamins; Vitamin K; Vitamin K 2
• Other Study ID Numbers: 2022-S17

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No