A review of nocturnal leg cramps in older people

Abstract

Nocturnal leg cramps are common and troublesome, especially in later life, and have a significant impact on quality of life, particularly sleep quality. This article reviews the current state of knowledge regarding the diagnosis, frequency, pathophysiology and management of cramps. Recent evidence suggests that diuretic and long-acting beta-agonist therapy predispose to leg cramps. There is conflicting evidence regarding the efficacy of prophylactic stretching exercises in preventing cramps. Quinine remains the only medication proven to reduce the frequency and intensity of leg cramps. However, the degree of benefit from quinine is modest and the risks include rare but serious immune-mediated reactions and, especially in older people, dose-related side effects. Quinine treatment should be restricted to those with severe symptoms, should be subject to regular review and requires discussion of the risks and benefits with patients.

older people, nocturnal leg cramps, quinine, sleep disorders, muscle cramps

Introduction

Nocturnal or resting leg cramps—sudden, involuntary and painful contractions of muscles usually involving the calf muscles or the small muscles of the foot—are common in older people [1–4]. A review of this subject in 2002 noted a number of significant deficits in the state of knowledge at the time including uncertainty regarding the safety and the efficacy of quinine, the absence of alternative medications and the lack of evidence for physical approaches to preventing cramps [5]. In this article, we review the current state of knowledge regarding the diagnosis, frequency, pathophysiology and management of nocturnal leg cramps.

Definition

Progress on this topic has been hampered by the lack of consensus on a clear definition of nocturnal leg cramps. The definition used in the latest International Classification of Sleep Disorders (2014) may be helpful in the future but has not been widely adopted to date [6]. This describes three diagnostic criteria:

• 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.

In contrast to nocturnal leg cramps, muscle cramps due to neuromuscular or systemic diseases are more likely to occur throughout the day or to involve other parts of the body. For example, while the majority of cramps in normal controls in one study were nocturnal and occurred in the calves, cramps in amyotrophic lateral sclerosis patients were frequently located in the distal small muscles of toes or feet and in those of fingers or hands, were mainly movement-induced and occurred both during daytime and at night [7]. Other muscle cramps occur in specific situations such as after vigorous, often unaccustomed, exercise or associated with dialysis.

Prevalence and impact

While leg cramps can occur at any age, they are more common and often more severe in later life. In a general practice-based study of 233 people aged 60 years or more, almost one-third had had rest cramps during the previous 2 months, including half of those aged 80 years or more, 40% had cramps more than three times per week and 21% described their symptoms as very distressing [8]. Another study of 350 elderly outpatients found that 50% had rest cramps, with 20% reporting symptoms for 10 years or more although many had not reported symptoms to their doctors [9]. Most studies note that nocturnal cramps are more common in women [2, 3, 9], especially older women [10, 11]. One study, using new quinine prescriptions and internet searches as proxy markers for cramp incidence, found a markedly increased rate in summer compared with winter months in both Australia and Canada [12].

Nocturnal leg cramps can have a major impact on quality of life. In addition to distress caused by pain, people with frequent cramps also report more disturbances of sleep, poorer quality sleep and more daytime somnolence than matched controls without cramps [3, 8].

Pathophysiology

Muscle cramps ultimately result from rapid repetitive firing of motor unit action potentials at a rate much higher than involuntary contractions. The balance of evidence suggests that this most often results from spontaneous discharges of motor nerves rather than having a central or muscular origin [13]. Factors that may contribute include abnormal excitability of anterior horn cells or of intramuscular motor nerve terminals. Afferent fibres influence the generation of motor discharges, and disturbance of sensory inputs may contribute to muscle cramps.

Age-related loss of motor neurons, which is more pronounced in the legs than the arms, is common in later life and may contribute to a propensity to leg cramps in older people [13]. This is supported by a case–control study of mainly older subjects in which those with nocturnal cramps had lower scores on measures of lower limb muscle strength than those without cramps [14]. Mechanical factors such as tendon shortening in later life and during prolonged immobility can also increase nerve terminal excitability and contribute to cramp development [15].

Associated conditions and medications

Although nocturnal cramps are idiopathic in most people, a large number of potential aetiological factors have been reported (Table 1) [15, 16–18]. It is not always easy to interpret the validity of many reported associations: cramps are poorly defined in many series and may have been confused with other conditions causing leg symptoms; given the high prevalence of cramps, associations with other common conditions may have occurred by chance.

Table 1.

Possible causes of muscle cramps

Medications	Diuretics, inhaled long-acting beta 2 agonists, statins, nifedepine, acetylcholinesterase inhibitors, steroids, morphine, cimetidine, penicillamine, antiretrovirals, neuroleptics
Metabolic disorders	Hepatic failure, chronic kidney disease, diabetes mellitus, hypothyroidism, hypoadrenalism
Fluid/electrolyte disorders	Hypokalaemia, hyperkalaemia, hypocalcaemia, hyponatraemia, hypomagnesaemia, haemodialysis, acute volume depletion
Neurological disorders	Motor neuron disease, neuropathy, radiculopathy, small-fibre sensory neuropathy, Parkinson's disease, multiple sclerosis
Others	Vitamin deficiencies, exercise, coffee, peripheral vascular disease, chronic venous disease, obstructive sleep apnoea

Medications

The medications most commonly linked to cramp development have been diuretics, statins and inhaled long-acting beta 2 agonists (LABA). The best quality evidence to date regarding these associations comes from a study using 8 years of prescribing information in British Columbia, Canada, which found that new prescriptions for quinine were substantially more common in the year following prescriptions for LABAs, thiazide diuretics and potassium sparing diuretics, and that one or other of these drugs had been prescribed to 60% of quinine recipients [19]. There was a weaker association between the use of statins and loop diuretics and subsequent cramp treatment.

The stimulatory effect of beta agonists on motor neurons and neuronal excitation due to diuretic-induced changes in electrolyte concentration around motor end plates are possible explanations for the links between cramps and these medications. In contrast, cramps are not a feature of statin-induced myopathy although one study of patients with motor neuron disease (MND) did find a link between statins and cramps [20].

Neurological disease

Although central neurological conditions such as Parkinson's disease and multiple sclerosis can be associated with cramps, perhaps as a result of spinal disinhibition or immobility, cramps are particularly associated with disorders affecting the lower motor neuron [15]. Cramps are a common early feature of MND and occur in over 60% of those with polyneuropathy [21]. A small study in which patients with cramps but without neuropathic complaints underwent skin biopsies showed a high prevalence of small-fibre neuropathy, a condition that particularly affects older people [22].

Other conditions

Muscle cramps have been reported to be associated with many metabolic and fluid and electrolyte disturbances. In particular, they occur in about two-thirds of diabetics and are especially common in those with Type 2 diabetes mellitus and in association with diabetic neuropathy [23]. Although cramps occur in about half of those with uraemia, this association is not due to neuropathy [24].

Although chronic venous disease is often noted as a cause of muscle cramps, the association is not clear-cut, given the variety of leg symptoms that can occur in such patients. Indeed, the Bonn Venous Study, a large and meticulous cross-sectional survey, recently concluded that that muscle cramps should no longer be considered a venous leg symptom [25]. Similar issues arise in interpreting the association between leg cramps and cardiovascular, especially peripheral vascular, disease noted in some [8, 18] (but not other [14]) studies.

Investigations

A careful history and the absence of clinical signs on examination remains the mainstay of diagnosis for idiopathic nocturnal cramps. The history and examination should aim to exclude other potential causes of leg symptoms such as restless leg syndrome, muscle strain and claudication and to identify signs of neurological disease such as weakness, atrophy and fasciculations. Investigations in those with frequent cramps should include urea, electrolytes, magnesium and glucose levels and liver and thyroid function tests; other tests are required only in selected patients.

Pharmacological management

Quinine

Quinine and its derivatives are alkaloids produced from the bark of the cinchona tree. They reduce the excitability of the motor end plate to nerve stimulation and have been used for decades to treat leg cramps. Quinine is also used as a flavouring in foods and beverages, notably tonic water and bitter lemon; a standard mixer bottle of tonic water contains 7–14 mg of quinine depending on the brand [1,26].

Efficacy

A 2015 Cochrane review identified 23 randomized controlled trials (RCT) using quinine (median 300 (range 200–500) mg/day) involving over 1,500 participants, mostly older subjects with idiopathic nocturnal leg cramps [1]. Compared to placebo, quinine reduced cramp numbers over a 2-week period by 28% (absolute difference of about 2.5 cramps). Those receiving quinine had approximately 1 extra day out of 14 without cramps—a 20% reduction. Cramp intensity, measured on a scale from 1 (mild) to 3 (severe), was reduced by 0.12—a 10% reduction. Although all of these differences were statistically significant, the 0.12 reduction in cramp intensity was below the 0.16 reduction that would be regarded as the minimal clinically significant difference on a 3-point quality of life scale [27]. There was insufficient evidence to judge the optimal dosage or duration of quinine treatment.

Grouped results may mask the fact that some people can derive substantial benefit from quinine [2]. N-of-1 trials, in which patients act as their own controls, allow potential benefit for individuals to be assessed. In a series of N-of-1 trials, in which 10 patients who had been taking quinine for cramps underwent three double-blind crossover trials in which they alternated between quinine and placebo for 4 weeks at a time, quinine was clearly beneficial for only three participants, six showed a non-significant benefit and one showed no benefit (although all chose to continue quinine post-study) [28].

There were no significant differences in the efficacy of quinine compared to vitamin E alone, to a quinine–vitamin E combination or to xylocaine injections into the gastrocnemius muscles [1]. A single study suggested that a quinine–theophylline combination was significantly better than quinine alone on all outcome measures [29], although significant methodological issues have been raised regarding this study [30].

Notwithstanding the generally positive results with quinine, RCTs of this and other agents suggest that there is often a marked placebo response [28, 31,32]. It is possible that this represents a regression to the mean, perhaps exacerbated by seasonal changes in cramp frequency [12]. Only one study has formally examined the effect of discontinuing long-term treatment with quinine [33]. As part of a trial of stretching exercises, 94 of 191 patients in general practice who had been prescribed quinine for night cramps were advised to discontinue this medication. Those receiving this advice were more than three times more likely (absolute difference 26%) have stopped quinine at 12 weeks, and cessation was not associated with any increase in cramp symptoms.

Risks

Quinine use is associated with serious and potentially fatal immune-mediated reactions, particularly thrombocytopenia [34, 35,36]. A 1994 US Food and Drug Administration (FDA) analysis suggested that thrombocytopenia affects between 1:1,000 and 1:3,500 quinine users 37; a more recent estimate suggests an incidence rate of 1.7/1,000 person-years [34]. Systematic reviews identify quinine as second only to its stereoisomer quinidine as a cause of drug-induced thrombocytopenia and as the commonest cause of drug-induced thrombotic macroangiopathy [38]. Such reactions are not dose-dependent and can follow consumption of quinine-containing beverages (which also means that the true frequency of quinine-induced reactions may be underestimated) [39]. Immune-mediated reactions generally occur within 3 weeks of starting quinine but can occur later especially with intermittent use [34, 38] (Table 2).

Other complications of quinine are dose-related, and serum quinine levels are strongly related to the likelihood of such side effects. Quinine overdose, sometimes inadvertent in older people, is extremely dangerous and can lead to death due to cardiac dysfunction and to chronic visual impairment and blindness [40, 41, 42]. Complications that can arise with therapeutic doses of quinine include ‘cinchonism’—a constellation of symptoms including nausea, vomiting, headache, vertigo, visual disturbances and tinnitus and hearing impairment. Such side effects are usually reversible with drug withdrawal.

A recent Danish epidemiological study of 1,35,000 heart failure patients found that quinine was used by more than 10% at some point and was associated with an increased risk of mortality, especially in those with concomitant beta-blocker use and early after treatment initiation [43]. Although the mechanism for this increase in mortality was unclear and, by definition, such studies cannot exclude all potential confounding factors, this was a large and meticulous study and the conclusion that ‘the risk of quinine being a real danger to patients with heart failure is very high’ seems reasonable.

The frequency and severity of adverse effects may be greater in older people since altered pharmacokinetics with age results in greater absorption, less efficient metabolism, a substantially longer half-life, higher blood concentrations of quinine and a greater risk of drug accumulation with chronic treatment even in healthy older subjects [37, 44,45, 46]. Even low-dose quinine in young healthy volunteers causes measureable albeit clinically silent deterioration in hearing and in vestibular function testing in many subjects [47, 48]. Older people, particularly those with pre-existing sensory defects, are likely to be more sensitive to such effects; conversely, the presence of existing visual of hearing problems might mask early signs of quinine toxicity. Finally, many of the drugs that interact with quinine are most likely to be used by older people.

In the Cochrane meta-analysis, only one subject had a severe, probably immune-mediated, reaction [1]. There was a significantly increased risk (absolute difference 3%) of minor adverse events with quinine compared with placebo: the only significant risk difference was in gastrointestinal side effects and the 10-fold increase in tinnitus and 2-fold increase in visual disturbance did not reach statistical significance. The treatment period was, however, only 2 weeks in most of the trials.

Table 2.

Complications associated with quinine

Idiosyncratic, usually immune-mediated
Haematological	Thrombocytopenia, haemolytic anaemia, neutropenia, disseminated intravascular coagulation
Dermatological	Photosensitive eczema, lichen planus, toxic epidermal necrolysis
Renal	Thrombotic microangiopathy, interstitial nephritis, acute kidney failure
Others	Chills, fever, hypotension, anaphylaxis, liver toxicity, pulmonary oedema, hypoglycaemia, rhabdomyolysis
Dose-related
Mild toxicity	Flushed skin, tinnitus, blurred vision, impaired hearing, confusion, headache, abdominal pain, vertigo, dizziness, nausea, vomiting, diarrhoea
Severe toxicity	Reduced consciousness, seizures, hypoglycaemia, deafness, peripheral visual field constriction, reduced visual acuity, blindness, cardiac arrhythmias
Drug interactions
Increased quinine toxicity with concurrent use of potent CYP3A4 inhibitors including azole antifungal drugs, HIV protease inhibitors, macrolide antibiotics and  grapefruit juice  Increased risk of ventricular arrhythmias when used in combination with other drugs that prolong the QT interval such as amiodarone and haloperidol  Increased risk of hypoglycaemia when taken concurrently with hypoglycaemic medications  Increased plasma concentration of digoxin and warfarin

Regulatory responses

The FDA have strongly advised against off-label use of quinine for leg cramps since 2006 [49,50], and this has resulted in a 99% decline in the amount of quinine prescribed in the USA [34]. A similar approach has been taken in Australia [51] and New Zealand [52]. There are possible undesirable effects, however, from discouraging the use of quinine including an increased use of medications with no evidence of benefit in cramps [53,54] and an increase in self-medication by patients using imported quinine tablets or large volumes of beverages such as tonic water [55].

In the UK and Ireland, regulatory authorities have advised against the routine use of quinine for leg cramps, although the use is still permitted in severe cases with careful monitoring and a trial withdrawal of treatment after 4 weeks [56,57]. A subsequent English study found that quinine prescribing remained common although substantial reductions were seen in areas which instigated comprehensive prescribing reviews [41].

Other pharmacological approaches

A meta-analysis of seven RCTs (361 subjects) comparing magnesium 300–900 mg/day to placebo in the treatment of nocturnal leg cramps concluded that magnesium was not an effective treatment for idiopathic cramps but may have a small positive effect in pregnant women [58] (Table 3).

Single RCTs provide some support for the efficacy of diltiazem 30 mg nocte [59], vitamin B complex [60], naftidrofuryl (a vasodilator available in some countries for treating peripheral vascular disease) [61] and orphenadrine citrate (an anticholinergic medication used as a muscle relaxant in some countries) [62] in the treatment of muscle cramps. Although all of these drugs were relatively well tolerated, the trials had substantial methodological flaws and the numbers of subjects recruited (13–59) were small [35].

In an open-label study, seven of eight cramp sufferers refractory to quinine treatment reported an improvement in cramp symptoms with verapamil 120 mg at night [63]. Other small open-label studies suggest benefit from gabapentin 600–1200 mg/day [64] (although a double-blind RCT in 204 MND patients showed no effect [65]), from the antiarrhythmic drug disopyramide [66] and from a vitamin K2 subtype [67].

Table 3.

Other pharmacological treatments used in treatment of idiopathic muscle cramps

Support from RCT

Diltiazem

Vitamin B complex

Naftidrofuryl

Orphenidrine citrate

Magnesium

Support from open-label studies

Verapamil

Gabapentin

Vitamin K2, menaquinone-7

No supporting studies

Baclofen

Carbamezapine

Phenytoin

Non-pharmacological Interventions

Cramps can be aborted by stretching the affected muscles or, using reciprocal inhibition reflexes, by contracting an antagonistic group of muscles. Thus, for example, forcible dorsiflexion of the foot with the knee extended can relieve calf cramps. It has been suggested as a result that prophylactic stretching might prevent nocturnal leg cramps. Other reported non-drug interventions include footwear changes, night ankle dorsiflexion splints, changes to sleeping position, avoidance of heavy bed covers and folklore remedies such as sleeping with a horseshoe or potatoes under the mattress [68].

In an uncontrolled study of 44 patients prophylactic stretching successfully prevented cramp [69]. Subjects were asked to stand 3 feet from a wall, leaning against it with arms outstretched and to gently tilt forward with the heels in contact with the floor until a non-painful stretch was felt in the calves; this procedure, held for 10 seconds, was repeated three times a day.

Two RCTs of this approach have now been reported. A 12-week study in 191 patients prescribed quinine for night cramps failed to show any benefit [33], although participants were only shown how to do the exercises once and the degree of compliance with the exercises was unclear [68]. In contrast, a 6-week RCT in 80 subjects, in which a home visit was used to ensure participants continued to perform the stretches correctly, found a reduction in the frequency and severity of cramps [70]. Although the degree of benefit in the latter study was comparable to that in the quinine trials, in a small survey in which cramp sufferers were asked to rate the effectiveness of therapies they had tried, 3 of 21 who tried prophylactic stretching compared with 16/18 who used quinine reported substantial benefit [2].

Recommendations

Associated conditions and medications should be sought in those with troublesome or frequent nocturnal leg cramps. Alternatives should be sought, if feasible, for those receiving diuretic or LABA medications. There is conflicting evidence regarding the efficacy of prophylactic stretching exercises, but these can be considered in suitable patients. While other medications warrant further investigation, quinine remains the only medication shown to reduce the frequency and intensity of leg cramps (even in the absence of convincing evidence, a trial of calcium channel blocker may be justified in those with cramps and another indication, such as hypertension, for such treatment). The degree of benefit from quinine is modest, the quality of evidence is relatively low and there are significant hazards. These factors suggest that there is no latitude for clinicians to go beyond the recommendation that treatment should be restricted to those with severe symptoms and should be subject to regular review (Table 4). Ultimately, only patients themselves can judge if the risks are justified by the potential benefits, and informed consent should always be sought before initiating a trial of treatment.

Table 4.

Recommendations for using quinine for nocturnal leg cramps

Quinine treatment should only be considered if:

Cramps are frequent or severe or regularly disrupt sleep Treatable causes of cramp have been ruled out Prophylactic stretching exercises have proved ineffective or would not be practical or safe for the patient The clinician and the patient agree that the potential benefits outweigh the risks for that individual

Quinine should not be prescribed if there has been any prior adverse reaction to quinine (including that found in beverages).

When initiating quinine treatment:

Patients should be warned never to exceed the recommended maximum doses of 300 mg quinine sulphate or quinine bisulphate Patients should be warned to stop treatment and consult a physician if symptoms or signs of thrombocytopenia, such as unexplained bruising or bleeding, or of cinchonism develop Particular caution should be exercised in those taking medications that might interact with quinine including warfarin, hypoglycaemic agents, potent CYP3A4 inhibitors and drugs that prolong the QT interval

Quinine treatment should be stopped after 4 weeks if there is no or uncertain benefit; cramp diaries may be a helpful adjunct to patient reports. In those who report benefit from quinine, treatment should be reassessed and a trial of discontinuation recommended every 3 months. A trial of discontinuation should be recommended in those taking long-term quinine.

Key points

• Nocturnal leg cramps are common and troublesome in older people and have a significant impact on quality of life.

• Diuretic and long-acting beta-agonist therapy predispose to leg cramps.

• There is conflicting evidence regarding the efficacy of prophylactic stretching in preventing cramps.

• Quinine remains the only medication proven to reduce the frequency and intensity of leg cramps.

• Balancing the potential risks and benefits from quinine requires careful consideration and discussion with the patient.

Conflicts of interest

The authors report no conflicts of interest

Funding

There was no funding for this study.