Digestive and Liver Disease
Volume 40, Issue 9 , Pages 794-799, September 2008

Muscle cramps in cirrhosis:

The therapeutic value of quinine. Is it underused?

The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery, Royal Free Hospital, Pond Street, Hampstead, London, UK

Received 23 August 2007; accepted 30 January 2008. published online 25 March 2008.

Article Outline

Abstract 

Muscle cramps are a common and recurring symptom in patients with cirrhosis. Although, the pathophysiology has not been specifically studied in cirrhosis, this is thought to be the same for cramps in general, originating in the motorneurone, with high frequency firing of motor unit action potentials. However precise pathophysiological mechanisms are not known.

Risk factors in cirrhosis have been little studied. Neither aetiology, nor pre-ascitic or ascitic stage, nor electrolyte disturbances, nor use of diuretic therapy has been found to have a statistical association with cramps in patients with cirrhosis. Effective treatments, from this literature review, are albumin, which however is expensive and has little applicability as preventative therapy and oral quinine or quinidine. Quinine is little used in Italy but licensed in the UK for the therapy of muscle cramps. There is evidence for the efficacy of quinine in patients without cirrhosis and in healthy subjects. In cirrhosis quinidine (isomer of quinine) has also been shown to be effective versus placebo. Its major effect is in the prevention of cramps. More widespread use of quinine and further studies are needed, particularly in Italy and other countries, in which its use has been limited, as it is effective therapy in many patients with cirrhosis.

Keywords: Cramps, Cirrhosis, Quinine

 

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1. Introduction 

Muscle cramps are a recognised symptom in patients with cirrhosis. However as they also occur in the general population, their management has often been neglected, as it has not been acknowledged as of sufficient importance. However it is a troublesome symptom. In non-cirrhotic and normal subjects there is an increasing prevalence of cramps: 33% over the age of 60 [1] and 50% over the age of 80 [2]. One study, in a healthy population, describes a prevalence of 21% [3]. However in cirrhosis they are often recurrent, and so comparison of prevalences, underestimates the problem. They do affect quality of life (Table 1, Table 2).

Table 1. Prevalence of muscle cramps in patients with cirrhosis vs. controls
Study (reference)Prevalence in cirrhotic patients (%)Prevalence in controls (%)p-ValueNo of patients with cirrhotic
[19]8010<0.000129
[4]4913<0.001171
[11]567<0.001100
[10]317<0.0180
Table 2. Studies evaluating muscle cramps in cirrhosis
Study (reference)DrugDosePeriodEffectSide effect
[30]Quinidine400mg daily4 weeks88% symptom reduction grater than 50%3% mild diarrhoea
[4]Human albumin100ml/25% i.v. weekly4 weeks59% symptom reduction 16% symptom disappearedNone
[19]Vitamin E200mg three times a day4 weeks100% symptom reductionNone
[16]Zinc220mg three times a day12 weeks58% symptom reduction 25% symptom disappeared8% mild diarrhoea
[18]Taurine6g three times a day6 months34% symptom reduction 66% symptom disappearedNone
[10]Eperisone hydrochloride150–300mg daily8 weeks33% symptom reduction 61% symptom disappeared8% fatigue 8% dizziness 11% epigastric discomfort

True muscle cramps are defined as involuntary painful muscle contractions that affect mostly small muscles, involving mainly calf and foot muscles, but also fingers and hands. They occur frequently at night and at rest and they are improved or completely relieved with stretching [4]. Usually the pain resolves spontaneously after a few minutes. Even if they are a benign phenomenon, they can cause severe distress for patients and sometimes they are difficult to treat [5]. Muscle cramps are associated with metabolic disorders, drugs, and inherited syndromes but in many cases no factors are found particularly in the elderly.

In hepatology textbooks the occurrence of cramps is often only mentioned briefly and treatment recommendations are not clearly given [6], [7], [8], [9].

Konikoff and Theodor report an incidence of 80% in a study of 16 cirrhotic patients versus 10% in healthy controls (p<0.0001). Cramps occurred several times a week mainly at rest and lasted for few minutes [3]. Kobayashi et al. reported 31% in 176 patients. Cramps occurred at least once a week compared to controls 7% [10] (p<0.01). Angeli et al. evaluated 171 patients: the prevalence of more than three crises of cramps per month was 49% in cirrhotic patients but only 13% in controls (p<0.001). More than three crises of cramps per week were found in 29% of patients with cirrhosis and 9% in controls (p<0.001). The prevalence of cramps was higher also in pre-ascitic patients with cirrhosis compared to controls, so that diuretic therapy and electrolyte imbalance are not the sole mechanism for cramps in cirrhosis, as is often thought [4].

Baskol et al. reported prevalence of 56% in 100 non-alcoholic patients with cirrhosis but only 7% in controls (p<0.001). Cramps occurred at least once a week recurring over a period greater than 1 year, both at rest and at night, disturbing sleep [11] (Table 1). A recent survey in patients with cirrhosis shows a high prevalence of cramps [12].

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2. Pathophysiology 

The pathophysiology of cramps is still not clearly understood. Electromyographically when muscle cramps occur there is an increased frequency of motor unit action potentials, repetitively firing at high frequency [13]. These potentials spread throughout the muscle group and produce a sustained muscle contraction [14].

In cirrhosis the mechanism is presumably the same, but no specific studies have been performed. Risk or causative factors have been poorly documented but electrolyte imbalance such as hyponatremia caused by diuretics, or severe liver disease per se, and fluid shifts have been implicated. These associations are supported by day-to-day clinical observation.

Abrams et al. performed a trial in 132 patients with chronic liver disease to identify which factors were involved with the genesis of cramps. The controls were heart failure patients. They found muscle cramps to be independent of the aetiology of cirrhosis, the use of diuretic therapy and of serum electrolyte concentrations [15], and importantly despite a higher use of diuretics in heart failure patients more cramps in cirrhosis. This suggests electrolyte disturbances are not the prime pathophysiological factor in causing cramps in cirrhosis.

Angeli et al. suggested that reduced effective plasma was involved in the pathophysiology of cramps, suggesting it was a symptom of an early hypovolemic state, at least in ascitic patients with cirrhosis. Human albumin infusion had an important role in expanding circulating volume and for the therapy of cramps in this study [4].

Kugelmas have hypothesised that zinc is involved in the pathogenesis of cramps. The exact mechanism is not well understood, but zinc has a role in stabilising the cell membrane [16]. However these observations have not been confirmed by Baskol et al. who studied the zinc concentrations in 100 cirrhotic patients and did not find any significant relationship with the development of muscle cramps [11].

Taurine is an aminoacid-containing sulphur that decreases the muscle hyperexcitability stabilising the cell membrane [17], and it has also been considered a possible cofactor in the development of muscle cramps. In liver cirrhosis abnormal aminoacid metabolism occurs with an increased release of aminoacids including taurine from muscles, because of the increased catabolism [18].

Vitamin E is a fat-soluble vitamin that is decreased in cirrhosis and particularly in those patients with chronic cholestatic disease. Potentially a deficiency of vitamin E could be involved in the development of cramps [19].

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3. Treatment 

Treatment for muscle cramps in general and in cirrhosis in particular, still remains empirical. There are no guidelines to follow and is no consensus about therapy.

Magnesium sulphate is commonly used in Italy in routine clinical practice, but no trials in patients with cirrhosis have been published. In cirrhosis there is a lower serum concentration of magnesium, particularly in alcoholic cirrhosis, but no studies have been performed to show a correlation with muscle cramps. In cirrhosis there is low total body magnesium often associated with the administration of diuretics that increase magnesium excretion in urine, and also there is poor absorption in the jejunum and secondary deficiency due to malnutrition. Magnesium uptake is higher in decompensated patients with cirrhosis compared to controls following infusion with magnesium sulphate, suggesting a true deficiency (p<0.036) [20].

Frusso et al. performed a randomised study in 45 patients without cirrhosis with a history of cramps (at least six episodes in the previous month) giving them magnesium (900mg citrate) twice a day for 1 month followed by a matching placebo for 1 month or they received placebo first followed by magnesium. There was no difference between the two groups, the number of cramps was 11.1 for placebo versus 11.8 for magnesium (p=0.59) [21].

Baskol et al. found no significant correlation between magnesium concentration and the development of cramps in patients with cirrhosis (p>0.05), whether in the pre-ascitic and ascitic phase of the disease [11].

Interestingly, cramps have not been reported following the frequent hypomagnesaemia as a complication of calcineurin inhibitors used as immunosuppression in solid organ transplantation [22].

Quinine, commonly used for the treatment of malaria, is approved for the treatment of cramps only in the United Kingdom although it is available in other countries [23].

Quinine has a curar-like action on muscles and on the neuromuscular junction. It reduces the excitability of the motor end plate to nerve stimulation and increases the refractory period of skeletal muscular contraction [24]. Usually it is used as a sulphate or as hydroquinine. Trials, which have tested the efficacy of quinine versus placebo in healthy older people with cramps, also confirm that quinine is effective in reducing nocturnal leg cramps [25], [26], [27].

In 1995 a meta-analysis of six randomised, double blind, crossover, placebo controlled studies confirmed that quinine was effective in preventing nocturnal leg cramps, reducing their frequency (doses varying from 200 to 500mg/day) in a total of 107 patients who suffered regular muscle cramps (two or more cramps per week and in one study at least six cramps per week). However neither the severity the nor duration of cramps was affected. Only one patient of 107 had major side effects, i.e. nausea, myalgia, leucopenia and thrombocytopenia that resolved after the discontinuation of quinine [28].

A later meta-analysis by the same authors comprising eight studies, which also included unpublished data, allowed a better estimate of the efficacy of quinine. Over treatment periods of 4 weeks quinine was effective. In this meta-analysis the published trials reported an average of 8.83 fewer episodes of cramps in a 4-week period with quinine compared to placebo, whereas unpublished trials reported an average of 2.45 fewer episodes of cramps. Despite this variability the efficacy of quinine was statistically significant (p=0.0008). Tinnitus was the only side effect that occurred with a significantly higher frequency in patients treated with quinine than placebo (p<0.013) with no difference in fever, dizziness, pruritus, headache or blurred vision [29].

In patients with cirrhosis there have been only a few studies with quinine or related compounds. Lee et al. evaluated quinidine (optical isomer of quinine) versus placebo in 31 patients for 4 weeks at a dose of 400mg/day orally in a single-blind randomised outpatient study.

A decrease in the number of episodes of cramps was seen in the quinidine group while unchanged in placebo group: 88% of patients showed a reduction in the number of cramps greater than 50% during the period of treatment (p<0.0001). In 12.5% of the quinidine-treated patients there was a total absence of cramps for the treatment period. In the placebo group the number of cramps remained unchanged (p>0.05).

The decrease in frequency of muscle cramps significantly correlated with the increase of serum quinidine concentrations (average concentration 0.7±0.1mg/l). The drug was well tolerated and the only adverse effect detected was mild diarrhoea in 31% of patients [30]. No trials have been reported with quinine in patients with liver disease.

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4. Drug toxicity of quinine 

Quinine is usually well tolerated but rarely causes hypersensitivity reactions or adverse effects. There are a triad of dose-related toxicities with overdose or when given at full therapeutic doses, which are not used for therapy in muscle cramps: cinchonism, hypoglycaemia and hypotension. Cinchonism is reversible after drug withdrawal, symptoms can involve the central nervous system (headache, vertigo), gastrointestinal system (nausea and vomiting, abdominal pain, diarrhoea), optic system (disturbed vision) and auditory system (tinnitus). With high serum concentrations, skin rushes and pruritis can occur [31]. Hypoglycaemia requires rapid glucose infusion and hypotension is rare if the drug is given orally [24].

Hypersensitivity reactions are rare: symptoms reported are skin rashes, fever, gastrointestinal disturbances, and visual and auditory changes, seizures and thrombocytopenia [32].

Using 300mg/day of quinidine sulphate, a sufficient dose for cramps in cirrhosis, no side effects were reported in the study by Lee et al. The peak serum concentration of quinidine reached was 1.3±0.1mg/l which is far lower than the therapeutic dose for cardiac arrhythmias (2–5μg/l) [30].

More serious adverse effects of quinine but rare also include haemolysis, disseminated intravascular coagulation, and the immune thrombocytopenia with haemolytic uremic syndrome, the prognosis of which is better than all the other forms of adult HUS; its incidence is reported less than 1% [33].

Cardiac effects and arrhythmias (tachycardia and ventricular fibrillation) may result from an overdose [34] or with high serum concentrations that can cause also transient hypotension [35]. Quinine blocks the inward pump of sodium, slowing the depolarisation and widening the QRS complex. It also inhibits the potassium and calcium channels. No cardiac effects are reported in prospective studies in severe malaria with concentrations up to 20μg/ml [35].

Hepatotoxicity with fever and an increase in liver enzymes has been known about since 1942 when the first case report was published. The incidence of quinine hepatotoxicity is quoted as 2–2.2% [32]. There are few case reports of hepatotoxicity after the ingestion of quinine [32], [36] and the mechanism is not clearly understood.

Although, severe effects are rare at therapeutic doses used for the treatment of leg cramps (200–300mg/day), the possibility of an overdose needs to be considered in prescribing this drug. The fatal dose varies from 2 to 8g [23], [24].

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5. Albumin 

Human albumin has been widely used to treat cramps, and is used in Italy for this indication. Angeli et al. performed a study with 12 cirrhotic patients with a history of cramps (more than three crises per week) who received a placebo (100ml of 5% dextrose solution intravenously) once a week for 4 weeks, followed by a period of 4 weeks in which they received human albumin (100ml 25% of human albumin intravenously) once a week. No changes were observed during the “placebo period” but during the “albumin period” 75% of patients reported a reduction of cramps and 16% of patients did not suffer with cramps at all. In the washout period the frequency of cramps gradually returned to baseline values (the mean duration of the effect was 15±6 days). No side effects were described [4]. Although, effective albumin remains an expensive therapy and requires intravenous administration. It is not practical as a preventive therapy.

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6. Other therapies 

Konikoff et al. evaluated 23 patients with cirrhosis and cramps; these had significantly lower vitamin E levels than those without cramps (6.3±3.2 vs. 11.5±4.8, p=0.01). They treated 13 of them, with tocopherol acetate (200mg three times a day) with an improvement in the frequency (p=0.01), duration (p=0.04) and pain (p=0.02) related to cramp episodes. No side effects were reported but no controls were included [19].

Zinc supplementation of 220mg two times a day was evaluated in a single trial of 12 patients with cirrhosis for 12 weeks, who had a history of episodes of cramps occurring at least thrice weekly. The treatment was effective in 58% and improved symptoms in 25%. However the duration of effect after supplementation if any, was not stated. The side effects observed were only mild diarrhoea in 8%; no controls are mentioned.

Taurine was tested by Matzusaki et al.; they gave 6g of oral taurine three times a day for 6 months to 12 non-alcoholic patients with cirrhosis who had suffered frequent muscle cramps. No controls were evaluated. After 1 month of therapy, cramps resolved in 66% of patients and there was a reduction in frequency in the remainder.

The efficacy was maintained during the 6 months of treatment, but not after the withdrawal of taurine. No adverse effects were reported [18].

Antispastic agents were used in a trial of 18 patients with chronic liver disease who received 150–300mg/day of eperisone hydrochloride orally for 8 weeks; no controls were evaluated. Cramps disappeared in 61% and decreased in 33%. In 17% of the patients, treatment was interrupted. Side effects were fatigue in 8%, dizziness in 8% and epigastric discomfort in 11% [10].

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7. Conclusions 

Muscle cramps are known to be a common symptom in patients with cirrhosis. Although, the pathophysiology is not totally understood, the motorneurones are the origin of cramps.

Many factors have been evaluated and appear to be associated with cramps although conclusive evidence is lacking. These may be involved in the pathogenesis: electrolyte disturbances, diuretic therapy, presence of ascites, etc.

The reported prevalence in cirrhosis covers a wide range between 31% and 80%, because of the different definitions used.

No consensus exists about the first choice treatment to adopt in cirrhosis and no guidelines are published. The use of magnesium, although frequently used particularly in Italy, is not supported by any evidence. The use of albumin, which is supported by one Italian study, is very expensive and not applicable as preventative therapy.

Quinine has been used in the UK for many years and has a license for use in patients with muscle cramps and is also used in some other countries. There is evidence from meta-analyses that in non-cirrhotic individuals, quinine is effective.

Its therapeutic effect outlasts the period of administration [26] and its main use is as preventive therapy. There are no trials in patients with cirrhosis. Lee et al. performed a trial with quinidine, confirming therapeutic benefit, and with only mild diarrhoea in few patients as a side effect [30].

Since the prevalence and recurrence rate of cramps in cirrhosis is high, further use and evaluation of quinine are indicated to assess its therapeutic benefit. Ideally studies could be carried out in countries such as in Italy in which its use is not widespread.

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Practice points 


•Muscle cramps are a common and troublesome symptom in patients with cirrhosis.

•Patients with cirrhosis need education about muscle cramps being a complication of cirrhosis.

•Overuse of diuretic therapy is associated with muscle cramps but precise aetiology is unclear.

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Research agenda 


•There are too few studies of therapies for cramps in cirrhosis.

•Prospective evaluation of patients with cirrhosis would be worthwhile to document frequency,severity and duration of episodes of cramps and their effect on quality of life.

•Randomized controlled trials of quinine and quinine like drugs for which there is the best evidence as effective therapy in patients without cirrhosis need to be carried out in patients with cirrhosis.

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Conflict of interest 

None declared.

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PII: S1590-8658(08)00044-3

doi:10.1016/j.dld.2008.01.021

Digestive and Liver Disease
Volume 40, Issue 9 , Pages 794-799, September 2008

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