What are the common causes and pathophysiologic mechanisms of muscle cramps?

Why Muscle Cramps Happen

Muscle cramps occur due to hyperexcitability of intramuscular terminal motor axons, firing at abnormally high frequencies (200-300 Hz), triggered primarily by electrolyte imbalances (sodium, potassium, magnesium deficiencies), dehydration, muscle fatigue, and disturbances in proprioceptive feedback from muscle spindles and Golgi tendon organs. 1, 2, 3

Primary Pathophysiologic Mechanisms

Neurophysiologic Basis

• Muscle cramps are characterized by involuntary, painful, visible contractions caused by irregular repetitive firing of motor unit action potentials at 200-300 Hz, originating from hyperexcitable intramuscular terminal motor axons 2, 4
• The motor neuron activity is subject to multiple influences: peripheral receptor sensory input, spinal reflexes, inhibitory interneurons, synaptic modulation, and descending CNS input 3
• Disturbances in muscle spindle and Golgi tendon organ proprioceptors—which control muscle length, tone, and posture—lead to increased motor neuron activity and excessive motor unit recruitment 3

Electrolyte and Metabolic Triggers

• Sodium, potassium, and magnesium deficiencies are the primary electrolyte triggers, disrupting normal muscle membrane excitability and neuromuscular transmission 1
• Diuretic medications (such as hydrochlorothiazide) commonly cause electrolyte imbalances leading to cramping 1
• Inadequate fluid intake throughout the day leads to fluid and electrolyte losses that manifest as cramping 1
• Hypercalcemia can also cause muscle cramps along with irritability and constipation 1

Exercise-Related Mechanisms

• Intense exercise and exercise to fatigue disturb proprioceptor activity, resulting in increased motor neuron activity 3
• The relaxation phase of muscle contraction is prolonged in fatigued muscle, raising the likelihood of fused summation of action potentials when motor neurons deliver sustained high firing frequencies 3
• Faulty posture and shortened muscle length contribute to disturbances in receptor activity 3

Circadian and Vascular Factors

• A circadian variation exists, with most episodes occurring in early morning hours, reflecting reduced parasympathetic tone and enhanced alpha-adrenergic vascular receptor reactivity 1
• Vascular stiffness and arteriopathy can contribute to cramping symptoms 1

Common Clinical Contexts

Physiologic (Benign) Cramps

• Occur in 50% of people after age 65 years 2
• Common in young people during pregnancy and exercise 2
• Part of the spectrum of normal human physiology 4

Secondary Causes to Exclude

• Drug-induced: Diuretics, corticosteroids, RAAS inhibitors are frequent culprits 5
• Metabolic disorders: Thyroid dysfunction, electrolyte abnormalities 5
• Neuromuscular diseases: Neuropathy, radiculopathy, plexopathy, neuromyotonia, cramp-fasciculation syndrome (which can precede ALS), motor neuron diseases 2, 6
• Myopathies: Metabolic myopathies may present with muscle pain during or after exhausting exercise, or cramps during exercise (myoadenylate deaminase deficiency) 6
• Liver disease: Patients with decompensated cirrhosis frequently experience incapacitating muscle cramps 6

Important Clinical Pitfalls

• Do not confuse cramps with contractures: Contractures are myogenic shortenings of muscle resulting in inability to relax normally, distinct from neurogenic cramps 4
• Distinguish true cramps from mimics: True cramps originate from peripheral nerves; other muscle pain or spasm has different origins 7
• Isolated cramps don't need treatment: Only severe, frequent, or symptomatic cramps warrant intervention 2
• ENMG and biological tests are needed only in cases of severe symptoms (severity and frequency) and/or abnormal examination findings 2