Nocturnal muscle cramps

INTRODUCTION — 

Nocturnal muscle cramps, also termed nocturnal leg cramps and sleep-related leg cramps, are a common lower extremity condition that produces pain and can disrupt sleep. Symptoms result from involuntary muscle contractions, which are sudden in onset, usually affecting the calf or foot.

Nocturnal muscle cramps are reviewed here. Other nighttime disorders of leg discomfort or movement, including restless legs syndrome (RLS), periodic limb movements of sleep (PLMS), and muscle cramps associated with pregnancy, are discussed separately. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults" and "Maternal adaptations to pregnancy: Musculoskeletal changes and pain", section on 'Leg and foot pain/cramps'.)

EPIDEMIOLOGY — 

Nocturnal muscle cramps are common and frequently unreported to clinicians [1,2]. In the general population, they are present in 40 percent of those over the age of 50, have an increased frequency with age, show no sex preference, and are associated with sleep disturbance and overall poor health [3].

Nocturnal muscle cramps have been reported in approximately 7 percent of children and adolescents [4]. Peak occurrence in this population was at 16 to 18 years of age, with no cases reported less than eight years of age. Pediatric nocturnal leg cramps are typically benign, self-limited, and infrequent [4,5].

PATHOPHYSIOLOGY — 

Patients with chronic nocturnal muscle cramps exhibit nonperiodic bursts of gastrocnemius electromyographic activity. These episodes occur during sleep without preceding physiologic changes. A typical episode occurs in three phases:

●Predisposition – A variety of underlying pathologies can result in hyperexcitability of motor axons, leading to muscle cramps. Such hyperexcitability is often the result of increased Na+ and/or reduced K+ conductance [6].

●Initiation – Most commonly, patients with idiopathic nocturnal muscle cramps have an increased frequency of muscle action potentials in the affected muscles due to motor neuron hyperactivity [7]. On electromyography (EMG), the involuntary contraction of the muscle is associated with repetitive firing of motor unit action potentials at much higher rates than those seen with voluntary muscle contraction [8].

●Propagation – As the cramp develops, there is a gradual increase in the number of motor units activated and their discharge frequency. This results in depletion of muscle adenosine triphosphate; cytosolic accumulation of calcium then prevents muscle relaxation.

●Resolution – As the cramp resolves, there is a gradual decrease in the number of activated motor units and the discharge frequency becomes irregular.

RISK FACTORS AND ETIOLOGY — 

There is a long list of risk factors and conditions reported to be associated with nocturnal muscle cramps; however, many of these reports are anecdotal and thus may be coincidental given the high prevalence of this symptom, particularly in those with medical comorbidities. The majority of patients with leg cramps have no known underlying cause.

Repetitive lower extremity stress — Activities that stress the muscles of the lower extremities have been associated with an increased risk of nocturnal muscle cramps. Examples include prolonged sitting, positioning that places prolonged pressure on the leg, and walking or running on concrete floors.

Medications — Multiple medications have been associated with an increased risk of nocturnal muscle cramps, including the following:

●Long-acting beta agonists and thiazide/potassium-sparing diuretics – Medications that are most strongly associated with nocturnal leg cramps include inhaled long-acting beta agonists (LABA) and diuretics (both potassium-sparing and thiazide) [9].

A study of 24,417 patients older than 50 years used prescriptions for quinine as a surrogate marker for nocturnal muscle cramps [9]; historically, quinine has been used for the treatment of nocturnal muscle cramps, although this practice has become more controversial. (See 'Limited role for quinine' below.)

This study made the following observations:

•Patients who received a prescription for LABA, a potassium-sparing diuretic, or a thiazide diuretic were more likely to receive a prescription for quinine during the subsequent year.

•This sequence implies that LABA, potassium-sparing diuretics, and thiazide diuretics are all associated with an increased risk of nocturnal muscle cramps.

•Loop diuretics and statins were associated only with a small increased risk.

This analysis did not identify patients with nocturnal muscle cramps who did not receive a prescription for quinine, which likely included patients with mild symptoms and patients with contraindications to quinine.

●Other medications – Other medications that have been associated with cramps include [9-15]:

•Beta agonists

•Angiotensin II receptor antagonists

•Benzodiazepines

•Teriparatide

•Pyrazinamide

•Raloxifene

•Donepezil

•Neostigmine

•Tolcapone

•Clofibrate

•Cisplatin

•Vincristine

•Oral contraceptives

•Intravenous iron sucrose

Other factors — Some experts distinguish idiopathic nocturnal muscle cramps from secondary nocturnal muscle cramps that occur in association with the conditions listed below. Whether these diagnoses represent risk factors or a secondary form of nocturnal muscle cramps is not entirely clear.

●Sleep disorder – Sleep disturbance (eg, restless legs syndrome [RLS], periodic limb movements of sleep [PLMS], and obstructive sleep apnea) have also been associated with nocturnal muscle cramps, although a causal relationship has not been proven. These conditions are described briefly (see "Classification of sleep disorders") and in more detail in separate topic reviews [16].

●Peripheral vascular disease – Peripheral vascular disease and venous insufficiency have also been associated with nocturnal muscle cramps. Additionally, severe peripheral vascular disease may cause claudication, which may be mistaken for nocturnal muscle cramps. (See 'Differential diagnosis' below.)

●Fluid imbalance – Leg cramps may result from extracellular volume depletion (eg, due to diuretics, excessive sweating without sufficient salt replacement, or fluid removal during hemodialysis) and the dialysis disequilibrium syndrome. (See "Dialysis disequilibrium syndrome".)

●Pregnancy related – Pregnancy-related leg cramps tend to occur during the latter half of pregnancy; the exact etiology is unknown. These are discussed in greater detail elsewhere. (See "Maternal adaptations to pregnancy: Musculoskeletal changes and pain", section on 'Leg and foot pain/cramps'.)

●Metabolic disorders – Other metabolic disorders associated with leg cramps include diabetes, hypoglycemia, hypocalcemia, alcoholism, and hypothyroidism [10].

●Specific neurologic disorders – Neurologic disorders, including motor neuron disorders and polyneuropathy, may have muscle cramps as symptoms at some point in their course. These diagnoses are discussed in detail elsewhere. (See "Clinical manifestations of Parkinson disease", section on 'Pain and sensory disturbances' and "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease", section on 'Clinical symptoms and signs'.)

●Exercise-associated muscle cramping – Exercise-associated muscle cramping ("heat cramps") is defined as an involuntary, painful contraction of skeletal muscle during or after exercise [17]. There are a number of pathophysiological theories as to its origin, including dehydration, electrolyte imbalances, and imbalances of afferent and efferent control at the motor axon [18].

Exercise-associated muscle cramping is discussed elsewhere. (See "Exertional heat illness in adolescents and adults: Epidemiology, thermoregulation, risk factors, and diagnosis", section on '"Heat cramps" (exercise-associated muscle cramps)'.)

●Radiculopathy – Patients with lumbar radiculopathy due to disc herniation or spinal stenosis often report leg cramps, most commonly at night.

●Other risk factors – Less commonly, nocturnal muscle cramps have also been associated with anemia, Raynaud phenomenon, opioid withdrawal, nonalcoholic cirrhosis, and bariatric surgery [2,15,19,20].

CLINICAL FEATURES — 

Nocturnal muscle cramps generally share the following characteristics [21,22]:

●Symptoms – Nocturnal muscle cramps are characterized by sudden muscle tightness, usually painful, and most commonly in the calf, foot, or thigh [8,15,21]. Calf cramping may induce extreme plantar flexion of the foot and toes [21].

●Duration – Nocturnal muscle cramps typically last from seconds to many minutes and are relieved by forceful stretching of the affected muscles. The average duration of nocturnal muscle cramps is nine minutes [2].

●Timing – Nocturnal muscle cramps typically occur while in bed, but patients may be awake or asleep.

Most individuals have such cramps only at night. In one study, cramps occurred exclusively at night in most (73 percent), but they occurred both during the day and night in 20 percent of patients and only during the daytime in 7 percent [2].

●Residual soreness – Following resolution of the acute cramp, there may be persistent soreness that typically lasts for several hours. However, discomfort for up to 48 to 72 hours following resolution of the muscle cramp has been described. Nocturnal muscle cramps affecting the thigh are more commonly associated with prolonged soreness than cramps affecting the calf and foot [8,21].

●Frequency – Roughly 40 percent of those with nocturnal muscle cramps report having such symptoms at least three times per week, and 5 to 10 percent report nightly cramping [3].

●Sleep disturbance – Nocturnal muscle cramps are associated with sleep disturbance, and patients may present to their clinician with a complaint of insomnia. Daytime fatigue is sometimes reported [22].

●Seasonal variation – Nocturnal muscle cramps are more common in winter than in summer. This seasonal variation was suggested by an analysis of the frequencies of new quinine prescriptions and of internet searches related to leg cramps, both of which doubled in winter compared with summer [23]. The basis for these observations is not known.

EVALUATION — 

A detailed assessment is generally conducted only for patients with recurrent symptoms despite initial preventative therapies. (See 'Initial preventive therapies' below.)

Physical examination — Nocturnal muscle cramps cannot be diagnosed based on physical examination. The role of the physical examination is to identify findings that may suggest an underlying cause or alternative diagnosis.

●Excluding alternate causes of symptoms – In a patient with nocturnal muscle cramps, physical examination of the muscles should be unrevealing. Therefore, the lower extremities should be examined carefully for areas of tenderness, induration, or other abnormalities that might indicate the presence of an alternate diagnosis. (See "Approach to the patient with myalgia", section on 'Muscle examination'.)

A careful neurologic examination should also be completed, including an assessment of motor strength and sensation, to look for evidence of a neurologic disorder that might be associated with or mistaken for leg cramps. (See 'Differential diagnosis' below.)

The patient should be asked specifically about symptoms consistent with restless leg syndrome (RLS; eg, an urge to move the legs at night) or obstructive sleep apnea (eg, daytime somnolence, snoring), which may be associated with muscle cramps. (See 'When to refer' below.)

●Identifying risk factors associated with nocturnal muscle cramps – The physical examination should also be used to identify the presence of risk factors associated with nocturnal muscle cramps (eg, pes planus, genu recurvatum, hypermobility). (See 'Pathophysiology' above.)

Laboratory evaluation — Laboratory tests are not necessary to establish a diagnosis of nocturnal muscle cramps. However, laboratory testing may be indicated for patients in whom the history and physical examination suggests an alternative diagnosis (eg, iron deficiency in patients suspected of RLS or periodic limb movement disorder). (See 'Differential diagnosis' below.)

Specific testing may also reveal an underlying cause of nocturnal muscle cramps in specific scenarios; examples include:

●Hypokalemia in patients receiving diuretics

●Electrolyte abnormalities in patients on dialysis

●Hypomagnesemia during pregnancy

●Hypocalcemia in a patient with diffuse, recurrent, or severe muscle cramping (see "Clinical manifestations of hypocalcemia")

●Elevated thyroid-stimulating hormone in patients with hypothyroidism

DIAGNOSIS — 

The diagnosis of nocturnal muscle cramps is established clinically. To be diagnosed with nocturnal muscle cramps, patients should meet all three of the following criteria [22]:

●A painful sensation in the leg or foot associated with sudden, involuntary muscle hardness or tightness, indicating a strong muscle contraction.

●The painful muscle contractions occur during the time in bed, although they may arise from either wakefulness or sleep.

●The pain is relieved by forceful stretching of the affected muscles, thus releasing the contraction.

DIFFERENTIAL DIAGNOSIS — 

Patients may describe numerous types of leg discomfort as cramps. A careful history and physical examination can exclude the majority of disorders in the differential diagnosis. Some of these conditions are also risk factors for muscle cramps while at the same time producing symptoms that are distinct from muscle cramps. These diagnoses include the following [7,11,24]:

●Sleep disorders – Sleep disorders are risk factors for nocturnal muscle cramps. However, sleep disorders can also mimic nocturnal muscle cramps.

•Restless legs syndrome – Like nocturnal muscle cramps, restless legs syndrome (RLS) also occurs at rest, predominantly in the evening or at night, and is sometimes painful. Patients sometimes complain of a cramping sensation.

Unlike nocturnal muscle cramps, RLS is characterized by more continuous discomfort, a need to move the affected limb, and involuntary brief (generally one- to two-second) movements. An important distinguishing feature is that RLS does not involve sustained contraction of muscles.

RLS is discussed in detail elsewhere. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults", section on 'Restless legs syndrome'.)

•Periodic limb movements – Like nocturnal muscle cramps, periodic limb movements of sleep (PLMS), also termed nocturnal myoclonus, occur at night.

Unlike nocturnal muscle cramps, PLMS are not associated with the muscle tightening, pain, or relief with stretching.

PLMS are involuntary, jerking (lasting 0.5 to 10 seconds) movements of the legs that occur during sleep. Patients have stereotyped dorsiflexion of the toes and feet, sometimes with flexion of the knees and hips, occurring roughly every 10 to 30 seconds.

PLMS may occur as an independent phenomenon or maybe associated with sleep fragmentation and excessive daytime sleepiness (periodic limb movement disorder). PLMS commonly occur in patients with RLS and are frequently present as well in the general population, especially with increasing age.

PLMS are discussed in detail elsewhere. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults", section on 'Periodic limb movements of sleep'.)

•Hypnic jerks – Like nocturnal muscle cramps, hypnic jerks, also termed benign hypnic myoclonus or sleep starts, commonly occur at night.

Unlike nocturnal muscle cramps, hypnic jerks are not associated with a prolonged or painful muscle contraction.

Hypnic jerks are sudden jerking contractures of the limbs that occur during the transition to, or very shortly after, falling asleep [25]. Hypnic jerks may awaken the patient, and the severity of the movement can be frightening, but they seldom recur after falling back to sleep.

Hypnic jerks are discussed in detail elsewhere. (See "Nonepileptic paroxysmal disorders in adolescents and adults", section on 'Hypnic jerks'.)

●Other mimics of muscle cramps

•Peripheral neuropathy – Like nocturnal muscle cramps, peripheral neuropathy produces pain and discomfort primarily affecting the lower extremities. While the signs and symptoms of peripheral neuropathy are distinct from those of leg cramps, many patients with peripheral neuropathy also suffer from leg cramps [26].

Unlike nocturnal muscle cramps, peripheral neuropathy is not associated with nighttime or sustained muscle contractions. Patients will often complain of persistent lower extremity discomfort, aching, electrical sensations, or coldness, which is often more common at night.

Patients with peripheral neuropathy may also have an abnormal sensory examination; however, some patients with small fiber neuropathy have a normal sensory examination.

The clinical presentation of peripheral neuropathy is discussed in detail elsewhere. (See "Overview of lower extremity peripheral nerve syndromes", section on 'Clinical presentation'.)

•Myopathies – Myopathies, including drug-related myalgia (eg, from statins, cimetidine, or cholestyramine), may produce muscle pain which does not occur in the form of a muscle contraction; such patients also typically have proximal muscle weakness. (See "Statin muscle-related adverse events", section on 'Neuromuscular disorders'.)

•Compartment syndrome – Compartment syndromes in the lower extremity, which may very infrequently occur after excessive running, produce acute-onset pain that is sustained. (See "Acute compartment syndrome of the extremities", section on 'Clinical features'.)

•Peripheral vascular disease – Peripheral vascular disease may result in cramp-like leg pain in a pattern of intermittent claudication.

Unlike nocturnal muscle cramps, these symptoms occur during limb use and are relieved by rest. On examination, decreased pulses and other signs of atherosclerotic vascular disease (eg, loss of hair on legs) may be present.

The clinical features of peripheral vascular disease are discussed in detail elsewhere. (See "Lower extremity peripheral artery disease: Clinical features and diagnosis".)

Peripheral vascular disease is also a risk factor for nocturnal muscle cramps; thus, patients may have clinical features of claudication and muscle cramps. (See 'Other factors' above.)

●Other forms of sustained muscle contraction – These diagnoses are associated with sustained muscle contraction, rather than the brief episodes of muscle contraction that characterize muscle cramps. These diagnoses are also not associated with sleep and are not relieved by stretching.

•Dystonias – Like nocturnal muscle cramps, dystonias (particularly focal dystonias affecting the feet) may cause lower extremity muscle contractions.

Unlike nocturnal muscle cramps, dystonias involve simultaneous contraction of agonist and antagonist muscles. In contrast to muscle cramps, dystonia is typically absent or markedly reduced during sleep. Dystonias can be distinguished formally from nocturnal muscle cramps electrophysiologically.

Some focal dystonias are associated with specific activities such as "writer’s cramp," which affects the hand. Other dystonias are segmental or generalized with movements that occur spontaneously such as dystonias related to dopamine antagonists (eg, antipsychotic medications or antiemetics).

Dystonias are discussed in detail elsewhere. (See "Etiology, clinical features, and diagnostic evaluation of dystonia", section on 'Clinical features'.)

•Tetany – Tetany refers to severe, intermittent muscle spasms, which have several causes, including hypocalcemia, hypomagnesemia, and metabolic acidosis. (See "Clinical manifestations of hypocalcemia", section on 'Tetany' and "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Neuromuscular manifestations'.)

•Myokymia – This refers to undulating, continuous muscle movements appearing like a "bag of worms" under the skin, which can appear in the face, limb, or in a more generalized distribution. It can appear in the context of an primary neurologic disorders, cancer, toxin exposure, or mono- or polyneuropathy [27].

•Myotonia – Delayed relaxation of muscle following voluntary activation is referred to as myotonia. It can affect a variety of muscles. Repetitive activation of muscles can limit the sustained contractions, known as "warm-up phenomena."

MANAGEMENT

Treatment of acute leg cramps

●Stretching – Patients with an acute leg cramp should forcefully contract the opposing muscle group to stretch the affected muscle (eg, calf cramps are treated by dorsiflexing the foot with the knee extended). This widely recommended approach typically provides rapid relief of the acute cramp [8,15,22].

Some patients may also find relief from passive stretching (eg, calf cramps may be treated by standing with the foot flat on the floor, then leaning forward). However, active dorsiflexion of the foot may be more effective [28].

In our experience, stretching of the affected muscle reduces the duration and severity of the cramping and subsequent discomfort.

●Alternate therapies – If stretching is ineffectual, other measures that may offer relief from the acute cramp include:

•Walking or leg jiggling followed by leg elevation

•A hot shower with the water directed towards the area of the cramp (usually for five minutes) or a warm bath

•Ice massage

Prevention of recurrent nocturnal muscle cramps — Patients who experience recurrent nocturnal muscle cramps (eg, weekly) may wish to engage in preventative strategies, such as those listed below.

Initial preventive therapies

●Stretching exercises for all patients – We suggest that all patients with recurrent nocturnal muscle cramps perform posterior leg muscle stretching exercises. These stretches are performed as follows (picture 1):

•The posterior leg stretches are performed while standing

•The patient leans forward with the legs kept straight and the feet kept flat on the floor

•The position is held for 10 to 20 seconds

For the first week, the patient should complete four sets of three to five stretches [29]. Afterwards, the patient should complete three sets daily (twice in the evening and once at bedtime). Some patients may need to continue these stretching exercises indefinitely, but stretching just once at bedtime may be enough to maintain benefit.

Evidence supporting the efficacy of stretching has been mixed [30]:

•One trial recruited 80 patients over 55 years of age with a mean of 3.2 to 3.4 cramps nightly [31]. In the trial, a six-week program of calf and hamstring muscle stretching before sleep significantly decreased the frequency of nocturnal muscle cramps compared with not stretching (mean difference of -1.2 cramps nightly, 95% CI -0.6 to -1.8). Additionally, cramp severity was decreased in the treatment group but not in the controls.

•Another clinical trial failed to confirm the benefit of this approach. However, all of the trial patients were on quinine at baseline, and many continued the drug during the trial [32]. The use of quinine may have reduced the ability of this trial to detect a difference between the two groups.

●Additional interventions for select patients – Patients who have a partial response to stretching exercises may wish to add some of the interventions listed below:

•Increase exercise – Increasing exercise may reduce nocturnal leg cramps. A large French study demonstrated an association between a sedentary lifestyle and nocturnal leg cramps, controlling for a variety of covariates, in those >60 years of age [33].

•Using long-countered shoes (ie, with a rigid piece of material that supports the hindfoot) and other proper foot gear (to support the musculature of the lower extremities during activities). (See "Joint protection program for the lower limb".)

•Keeping the bed covers at the foot of the bed loose and not tucked in (to prevent plantar flexion of the gastrocnemius, which may stimulate nocturnal muscle cramps).

•Avoidance of drugs, alcohol, caffeine, exercise in extreme heat or on concrete floors (all of which have been associated with nocturnal muscle cramps).

Resistant to initial preventive therapies — For patients who continue to experience nocturnal muscle cramps with a frequency or an intensity they find unacceptable, despite the initial preventative therapies, we use the following approach:

Evaluation for treatable risk factors and disease mimics — Nocturnal muscle cramps are common, and most patients will have an adequate response to the initial preventive therapies described above. Therefore, a detailed evaluation is unnecessary for most patients. (See 'Initial preventive therapies' above.)

However, when the muscle cramps are recurrent and resistant to initial preventive therapies, we complete an evaluation for potentially treatable risk factors and disease mimics prior to starting drug therapy. (See 'Evaluation' above.)

This evaluation should include tests for fasting blood glucose, calcium, phosphate, potassium, magnesium, creatine phosphokinase, creatinine, liver enzymes, and thyroid function. Any electrolyte abnormalities or iron deficiency should be corrected. An elevated fasting blood glucose, creatine kinase, liver enzymes, or thyroid-stimulating hormone may require evaluation for diabetes, metabolic myopathy, hepatic disease, or hypothyroidism, respectively. (See 'Laboratory evaluation' above and "Etiology, clinical manifestations, and diagnosis of volume depletion in adults".)

Medications (including alcohol) that are potentially associated with muscle cramping should be eliminated, if possible. (See 'Evaluation' above.)

For those with lumbar disc disease or spinal stenosis and nocturnal leg cramps, intervention for the radiculopathy itself will be based on those circumstances. However, studies have assessed treatment outcomes for nocturnal leg cramps. Blockade of the medial branch of the deep peroneal nerve produced a 50 percent reduction in 80 percent of patients [34]. In another study, varying intensities of unilateral stimulation of the gastrocnemius twice per week for four weeks were associated with a reduction in daytime, but not nighttime cramps, versus sham stimulation [35].

Initial drug therapies — For patients who fail to respond to nonpharmacologic measures or modification of risk factors (as described above), we use a stepwise approach to drug therapy.

For each drug, a four-week trial should be adequate to determine response. Patients with no (or suboptimal) response should stop the drug and try the next agent. We do not typically combine agents. Patients may need to continue these drugs indefinitely, although other factors (eg, cost, patient preference) may need to be considered (algorithm 1). (See 'Limited role for other interventions' below.)

●Supplements – We recommend mineral and vitamin supplementation before using prescription medications.

We suggest vitamin B complex (three times daily, containing 30 mg of vitamin B6) or vitamin E (800 international units before bed). Patients who do not improve with one supplement after a two-month trial may be cycled to the other supplement. In older adults, vitamin K₂ supplementation may also be a reasonable alternative.

Limited data support the use of vitamin B complex and vitamin E for nocturnal muscle cramps. Vitamin B complex (containing fursultiamine 50 mg, hydroxocobalamin 250 micrograms, pyridoxal phosphate 30 mg, and riboflavin 5 mg) showed benefit in one randomized trial [36]. Vitamin E was beneficial in some small studies but not others [37,38]. Vitamin K₂ 180 micrograms was also effective in one large randomized trial of adults ≥65 years old [39].

●Calcium channel blocker – In patients in whom the measures above are ineffective, we prescribe a calcium channel blocker, either diltiazem (30 mg) or verapamil (120 to 180 mg), taken nightly. Limited evidence from small randomized trials with each agent supports their use [40,41]. We do not use nifedipine, which can cause muscle cramps as a side effect.

●Gabapentin – Gabapentin 300 to 900 mg or pregabalin 50 to 150 mg (both before bed) can be attempted if the above measures have failed. These medications must be used cautiously in older patients or those who have impaired kidney function, both of whom have an increased risk of side effects. Gabapentin was efficacious for nocturnal muscle cramps in an open-label trial in which the electrically induced cramp threshold normalized [42]. A randomized comparative trial of gabapentin (300 to 800 mg) and baclofen (5 to 10 mg), given at bedtime, in patients with spinal stenosis demonstrated equal efficacy of the two treatments in reducing leg cramps [43]. Pregabalin (75 to 150 mg twice daily) demonstrated efficacy for nearly exclusively daytime leg cramps in patients with liver cirrhosis [44].

●Baclofen – Baclofen 5 to 10 mg orally at bedtime is another option for patients who do not respond to the above therapies. It should be used cautiously in older adults and in those with impaired kidney function. In the study cited above, baclofen and gabapentin had similar efficacy in treating leg cramps in patients with spinal stenosis [43].

Limited role for quinine — In patients resistant to initial pharmacotherapies (see 'Initial drug therapies' above) who have severe nocturnal muscle cramps, we suggest tonic water (which contains quinine) over alternative therapies. (See 'Limited role for other interventions' below.)

Because quinine is not available by prescription in the United States, the author suggests use of 6 ounces (180 mL) of tonic water before bedtime, which contains approximately 15 mg of quinine. Patients should limit their use of tonic water to once nightly; after the nocturnal muscle cramps improve, patients should try reducing their use of tonic water to the minimum frequency required to control their symptoms. A trial of a month is generally adequate to determine if there is a reduction in the severity of attacks.

In many countries, quinine sulfate (or bisulfate) is available in 200 or 300 mg tablets. However, in the United States, this approach is no longer sanctioned by the US Food and Drug Administration (FDA) due to the potential for serious side effects. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Quinine'.)

●Rationale – Quinine has been the best-studied drug for nocturnal muscle cramps and has been found effective in reducing the frequency and severity of cramps in some well-designed randomized trials [45,46]. The most common dose in the trials was 300 mg daily (range 200 to 500 mg daily).

In clinical trials, only minor adverse effects, mainly gastrointestinal symptoms, were more common with quinine compared with placebo [46]. However, such studies were generally short term.

Quinine is no longer recommended for the treatment of nocturnal muscle cramps due to the potential for serious and/or life-threatening side effects (eg, cardiac arrhythmias, thrombocytopenia, hemolytic uremic syndrome [HUS]-thrombotic thrombocytopenic purpura [TTP], and severe hypersensitivity reactions), which occur in 2 to 4 percent of patients [47]. An FDA warning issued in December 2006 and reaffirmed in 2010 stated that, due to these potential serious events, the risks associated with quinine use do not justify its use in the unapproved/unlabeled prevention and treatment of leg cramps [48,49].

Limited role for other interventions — We do not routinely use the approaches listed below, due to limited evidence of efficacy and/or potential for harm:

●Naftidrofuryl (which was effective in a small randomized trial [50])

●Quinidine (which was effective in a small randomized trial in patients with muscle cramping associated with hepatic cirrhosis [51])

●Shakuyaku-kanzo-to granule (which was effective in a series of hemodialysis patients [52])

●Botulinum toxin injection (which was effective in patients with nocturnal muscle cramps due to lumbar spinal stenosis [53])

●Muscle relaxants (eg, carisoprodol and orphenadrine [54])

●Chloroquine phosphate [55,56]

●Hydroxychloroquine sulfate [57]

When to refer — Patients in whom pharmacotherapy is ineffective, and who experience distress associated with nocturnal muscle cramps, should be referred to a sleep specialist to determine if the patient has an underlying sleep disorder (eg, restless legs syndrome [RLS], periodic limb movements of sleep [PLMS], or obstructive sleep apnea) associated with nocturnal muscle cramps [16]. Specifically, "leg jerks," which may reflect PLMS, were highly associated with nocturnal leg cramps in a large epidemiologic survey [3]. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults" and "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults", section on 'Periodic limb movements of sleep' and "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)

PROGNOSIS — 

Longitudinal studies assessing those with and without nocturnal muscle cramps as well as controlling for important covariates, which might provide information on the long-term prognosis of this problem, do not exist. However, we know that those with such leg cramps have poorer sleep and health-related quality of life, even controlling for common comorbidities. On the other hand, in patients with an underlying medical or neurologic condition, the prognosis depends upon the associated underlying disorder.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment of muscle cramps".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Nocturnal (nighttime) leg cramps (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Risk factors – Risk factors for nocturnal muscle cramping include anatomic disorders and/or activities that place repetitive stress on the leg and foot muscles. While multiple medications have been linked to nocturnal muscle cramps; the association is strongest with inhaled long-acting beta agonists , thiazide diuretics, and potassium-sparing diuretics. Sleep disorders and other chronic conditions have also been associated with nocturnal muscle cramps. (See 'Pathophysiology' above.)

●Clinical features – Patients with nocturnal muscle cramps complain of sudden, painful tightness in the calf, foot, or thigh that lasts for seconds to minutes and may resolve with persistent muscle soreness. Symptoms typically occur at night.

●Evaluation – Nocturnal muscle cramps are common, and many patients will have an adequate response to the initial preventive therapies described above or will have a self-limited course. Therefore, a detailed evaluation is unnecessary for most patients.

However, when nocturnal muscle cramps are persistent or recurrent and resistant to initial preventive therapies, we evaluate the patient for potentially treatable risk factors and disease mimics prior to starting drug therapy.

The role of the physical examination is to identify findings that may suggest an underlying cause (eg, peripheral vascular disease, hypermobility) or suggest an alternative diagnosis (eg, neurologic findings). Laboratory tests are not necessary to confirm a diagnosis of nocturnal muscle cramps but may suggest an underlying cause (eg, hypokalemia, iron deficiency, hypomagnesemia, hypocalcemia). (See 'Evaluation' above.)

●Diagnosis – To be diagnosed with nocturnal muscle cramps, patients should meet all of the following criteria (see 'Diagnosis' above):

•A painful sensation in the leg or foot associated with sudden, involuntary muscle hardness or tightness, indicating a strong muscle contraction

•The painful muscle contractions occur during the time in bed, although they may arise from either wakefulness or sleep

•The pain is relieved by forceful stretching of the affected muscles, thus releasing the contraction

●Differential diagnosis – Many types of leg pain are described as muscle cramps. A careful history and physical examination can identify alternate diagnoses, including restless leg syndrome , periodic limb movements of sleep, myoclonic jerks, peripheral vascular disease, peripheral neuropathy, and dystonias. (See 'Differential diagnosis' above.)

●Treatment of acute nocturnal muscle cramps – Patients with an acute leg cramp should forcefully stretch the affected muscle (eg, active dorsiflexion of the foot with the knee extended, for patients with calf cramps). This typically provides rapid relief of the acute cramp. (See 'Treatment of acute leg cramps' above.)

●Prevention of nocturnal muscle cramps

•Initial prevention strategy – For prevention of recurrent attacks, we suggest initial treatment with daily stretching exercises (picture 1) rather than pharmacotherapy (Grade 2C). Trials of other nonpharmacologic interventions can be added to daily stretching if desired. (See 'Initial preventive therapies' above.)

•Drug therapy for inadequate response to initial prevention strategies – In patients with an inadequate response to initial preventive therapies, we suggest one or more two- to four-week trials of selected medical therapies (Grade 2C) (eg, vitamin B complex, vitamin E, or, in older adults, vitamin K₂; diltiazem or verapamil; gabapentin or pregabalin; baclofen) (algorithm 1).

Although there is only modest evidence of benefit for each of these alternative agents, they have much better safety profiles than quinine. (See 'Initial drug therapies' above.)

•Limited role for quinine – In patients with debilitating nocturnal muscle cramps resistant to the medical therapies listed above, we suggest tonic water (which contains quinine) over alternate agents (Grade 2C). Six ounces (180 mL) of tonic water may be taken nightly, before bedtime. After symptoms improve, patients should reduce their frequency of tonic water use to the minimum required to control their symptoms.

We recommend against the use of quinine in other forms due to the potential for serious side effects, including arrythmias and thrombocytopenia. (See 'Limited role for quinine' above.).