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Musculoskeletal

Leg cramps

Last revised in December 2022

A cramp is a transient, involuntary episode of pain, usually sustained for several minutes (up to 10 minutes), in which muscle(s) go into spasm.

Leg cramps: Summary

  • A leg cramp is a sudden, involuntary, painful muscle contraction, usually in the posterior calf, but sometimes involving the foot or thigh.
  • Nocturnal leg cramps are common, with prevalence increasing in older people.
  • Most cases of nocturnal leg cramps are thought to be idiopathic, but cramps may be associated with a number of underlying conditions.
  • Idiopathic leg cramps are indicated by a history of sudden intense calf or foot (rarely thigh) pain; visible or palpable knotting or tightening of the muscle or abnormal posture; pain usually lasting seconds to less than 10 minutes; single muscle (or part of muscle) involvement; no abnormal findings on physical examination; good response to passive and active stretching; residual tenderness in the affected muscle; and causing sleep disruption.
  • A history and examination may help exclude secondary causes (for example lower motor neuron problems, metabolic problems, medications, and pregnancy) or other conditions that mimic leg cramps (including claudication, restless legs syndrome, myalgia and myositis, Baker’s cyst, deep vein thrombosis, dystonia, and myoclonus).
  • Investigations are usually not needed unless the cramp has atypical features or an underlying cause is suspected.
  • Management of idiopathic leg cramps includes:
    • Reassurance that idiopathic leg cramps are common, have no underlying cause, and can resolve spontaneously.
    • Advice about self-care measures such as stretching and massaging the affected muscle(s) to alleviate or reduce the frequency of attacks.
    • Offering written self-care advice.
    • Advice on the use of analgesia if the muscle is tender after a cramp. It is impractical to use analgesia during a cramp, as most attacks are short-lived.
  • Quinine is generally not recommended for treating idiopathic leg cramps due to the poor benefit-to-risk ratio. However, a trial of quinine may be considered in certain circumstances if self-care measures fail, leg cramps are frequent, and the person's quality of life is affected.
  • The person should be admitted to hospital if the cramps are severe and they have other concerning symptoms (for example, anuria, altered consciousness, or hyper- or hypopyrexia).
  • Referral should be arranged to the appropriate specialty (for example, neurology or rheumatology) when an underlying cause is suspected that cannot be managed in primary care.
  • Specialist referral should also be considered if:
    • The diagnosis is in doubt.
    • Treatment in primary care fails and symptoms are affecting the person's quality of life.

Have I got the right topic?

From age 18 years onwards.

This CKS topic covers the management of idiopathic leg cramps occurring in the calf, thigh, or foot.

This CKS topic does not cover leg cramps in pregnancy, exercise-induced cramp, restless legs syndrome, tetany, contracture, dystonia, or the management of secondary causes of leg cramps.

There are separate CKS topics on Deep vein thrombosis, Peripheral arterial disease, Restless legs syndrome, Sprains and strains, and Thrombophlebitis - superficial.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary healthcare.

How up-to-date is this topic?

Changes

December 2022 — reviewed. A literature search was conducted in November 2022 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of the topic. No major changes to clinical recommendations have been made.

Previous changes

February 2018 — reviewed. A literature search was conducted in December 2017 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of the topic. The age range of this topic has been updated to 18 years onwards. There have been minor structural changes and sections have been added on causes, complications, differential diagnosis, and prescribing information for quinine. No major changes to clinical recommendations have been made.

September 2012 — reviewed. A literature search was conducted in September 2012 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of the topic. No changes to clinical recommendations have been made.

July 2010 — minor update. Advice from the Medicines and Healthcare products Regulatory Agency (MHRA) that quinine should not routinely be used, and should be stopped if no benefit is seen after 4 weeks of treatment has been added. 

February 2009 — minor update. Minor correction to the text regarding self-care advice and calf stretches. 

July to November 2008 — converted from CKS guidance to CKS topic structure. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence. There are no major changes to the recommendations.

September 2008 — minor correction to the Changes section. 

November 2005 — minor technical update. 

March 2005 — reviewed. Validated in June 2005 and issued in July 2005.

December 2001 — reviewed. Validated in March 2002 and issued in April 2002.

January 1999 — written. Validated in March 1999 and issued in May 1999.

Update

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 November 2022.

HTAs (Health Technology Assessments)

No new HTAs since 1 November 2022.

Economic appraisals

No new economic appraisals relevant to England since 1 November 2022.

Systematic reviews and meta-analyses

No new systematic reviews since 1 November 2022.

Primary evidence

No new primary evidence which reaches the CKS threshold for inclusion published since 1 November 2022.

New policies

No new national policies or guidelines since 1 November 2022.

New safety alerts

No new safety alerts since 1 November 2022.

Changes in product availability

No changes in product availability since 1 November 2022.

Goals and outcome measures

Goals

  • To support primary healthcare professionals to:
    • Make an accurate assessment of someone with leg cramps.
    • Give appropriate self-care advice and treatment (if needed) to manage leg cramps.
    • Refer to secondary care if appropriate.

Outcome measures

No outcome measures were found during the review of this topic.

Audit criteria

No audit criteria were found during the review of this topic.

QOF indicators

No QOF indicators were found during the review of this topic.

QIPP - Options for local implementation

No QIPP indicators were found during the review of this topic.

NICE quality standards

No NICE quality standards were found during the review of this topic.

Background information

What are leg cramps?

  • A leg cramp is a sudden, involuntary, painful muscle contraction, usually in the posterior calf, but sometimes involving the foot or thigh [Katzberg, 2010; Berger, 2014; Hallegraeff, 2017].
    • Cramps usually last between a few seconds to several minutes, and cease spontaneously; although, pain and tenderness may persist for several hours afterwards [Monderer, 2010].  
    • Most leg cramps occur when at rest during the night [Maisonneuve, 2016], but some people experience daytime cramps, especially if there is a neuromuscular or systemic cause [Rabbitt, 2016].  

How common are leg cramps?

  • Nocturnal leg cramps are common, with the prevalence increasing in older people [Rabbitt, 2016].  
    • A UK general practice-based study found that around one third of 233 people over 60 years of age experienced rest cramps, with 83% having leg muscle involvement, and 40% reporting three or more attacks per week [Naylor, 1994]. 
    • A cross-sectional French study of 516 people aged 60 years and older concluded that cramps are common in primary care. The adjusted prevalence of cramps was found to be 46%, with 31% of people reporting being woken by cramps [Maisonneuve, 2016]. 
    • A US large-scale, cross-sectional study found around a third of adults reported nocturnal leg cramps at least five times a month, with 6% having at least 15 episodes per month [Grandner, 2017].  

What are the causes of leg cramps?

  • Most cases of nocturnal leg cramps are thought to be idiopathic [Monderer, 2010; El-Tawil, 2015; Rabbitt, 2016; BMJ Best Practice, 2021].
  • However, cramps may be associated with [Monderer, 2010; Allen, 2012; Berger, 2014; Rabbitt, 2016; Katzberg, 2019; Maughan, 2019; BMJ Best Practice, 2021]:
    • Peripheral arterial disease or venous insufficiency.
    • Neurological disease — for example, lumbar canal stenosis, peripheral neuropathy, Parkinson's disease, motor neurone disease, multiple sclerosis, and stroke.
    • Metabolic and endocrine disease — for example, cirrhosis and liver failure, end-stage renal disease and haemodialysis, hyperthyroidism, hypothyroidism, diabetes mellitus, and Addison's disease.
    • Electrolyte imbalance — for example, hypokalaemia, hyperkalaemia, hypocalcaemia, hyponatraemia, and hypomagnesaemia.
    • Vitamin B or D deficiency.
    • Pregnancy.
    • Strenuous exercise.
    • Medications — for example, inhaled long-acting beta-2 agonists, imatinib, nifedipine, potassium-sparing and thiazide diuretics, statins, conjugated oestrogens, naproxen, penicillamine, raloxifene, and teriparatide.

What are the complications of leg cramps?

Diagnosis of cause of leg cramps

How should I assess someone with leg cramps to identify a cause?

  • Leg cramps can usually be diagnosed from the history and examination, with investigations not always necessary.
  • Idiopathic nocturnal leg cramps are indicated by:
    • Sudden intense calf, or foot (rarely thigh) pain; most often at night (or when resting).
    • Visible or palpable knotting or tightening of the muscle or abnormal posture.
    • Duration of pain usually seconds to less than 10 minutes.
    • Single muscle (or part of muscle) involvement.
    • Unilateral symptoms.
    • No abnormal findings on physical examination.
    • Good response to passive and active stretching.
    • Residual tenderness in the affected muscle.
    • Sleep disruption.
  • Perform a history and examination to help identify underlying causes or other conditions which mimic leg cramps:
    • Duration of symptoms more than 10 minutes — suggestive of an organic cause.
    • Widespread muscle cramps — increases suspicion of motor neurone disease.
    • Symptoms of calf pain with exercise, an urge to move the legs, or leg numbness or weakness.
    • Signs of muscle wasting and fasciculations, dystonia, loss of sensation or power, or altered reflexes — an abnormal neurological or musculoskeletal examination suggests an organic cause.
    • Calf swelling, varicose veins, or abnormal leg pulses — suggestive of a circulatory condition.
    • History (or symptoms) of an underlying condition (for example, cirrhosis, severe renal disease and haemodialysis, or thyroid disease).
    • Medication (for example, diuretics, imatinib, statins, or long-acting beta-2 agonists).
  • Investigations are usually not needed if the leg cramps have the typical features described above. If the cramp has atypical features or an underlying cause is suspected from history or examination, then relevant investigations may be indicated (for example blood tests for urea, electrolytes, calcium, thyroid function tests, fasting glucose, liver function tests, and creatinine kinase; vascular studies for claudication; imaging of the lumbar spine for nerve root entrapment).

Basis for recommendation

CKS did not identify any UK guidelines on the assessment of leg cramps in primary care. 

Use of history and examination

  • Expert opinion in review articles infers that using information gathered from the history and examination will allow the healthcare professional to initiate appropriate investigation and management by distinguishing leg cramps from other conditions, and excluding an underlying cause [Monderer, 2010; Allen, 2012; Berger, 2014; BMJ Best Practice, 2021]. However, evidence is lacking on the effect of treating underlying conditions on the occurrence of leg cramps [Allen, 2012]. 

Features of idiopathic leg cramps

Features suggesting secondary causes or differential diagnoses

Investigations

  • The advice that investigations are usually not needed unless the cramp is atypical or an underlying cause is suspected and examples of tests which may be considered in these situations are based on expert opinion in review articles [Monderer, 2010; Rana, 2014; Rabbitt, 2016; Katzberg, 2019; BMJ Best Practice, 2021].
  • Routine blood tests are not considered to be helpful in making a diagnosis of leg cramps because there is no definite association of idiopathic cramps with electrolyte disturbance, anaemia, glucose levels, or renal disease [Allen, 2012]. 

What are the differential diagnoses of leg cramps?

  • Conditions that may present in a similar way to muscle cramps in the leg include:
    • Dystonia — involuntary muscle contractions that lead to abnormal movements. They are not usually relieved by stretching. 
    • Myoclonus — sudden, involuntary jerking of a muscle or group of muscles without pain (for example, while drifting off to sleep). 
    • Tetany and tetanus — muscular rigidity and/or spasms.
    • Peripheral neuropathy — numbness, tingling, and neuropathic pain, sometimes with cramps. There are usually sensory or motor findings on examination. 
    • Claudication — aching and cramping when exercising and relieved by rest (in contrast to nocturnal cramps). Peripheral pulses may be reduced. For more information, see the CKS topic on Peripheral arterial disease.
    • Myalgia and myositis — deep aching muscle pain without contraction in association with weakness and limited exercise tolerance. Often affects the legs, but can occur in different muscle groups. Myalgia may be associated with statin use.
    • Restless legs syndrome — episodes of irritating, burning, or crawling sensations (but no pain or muscle tightening) with an urge to move the legs, which relieves symptoms. Symptoms usually occur in the evening and at night when the person is inactive. For more information, see the CKS topic on Restless legs syndrome.
    • Periodic limb movement disorder — repetitive, rhythmic, slow dorsiflexion of the hips during sleep (non-painful) lasting seconds. Unlike cramp, there is no hardening of muscles or need for stretching.
    • Deep vein thrombosis — pain, swelling, redness, and warmth of the affected leg. For more information, see the CKS topic on Deep vein thrombosis.
    • Baker's cyst — may be asymptomatic, but can present with pain and swelling in the leg. For more information, see the CKS topic on Baker's cyst. 
  • Most leg cramps are idiopathic. Other conditions which may cause leg cramps are set out in the section on causes of leg cramps.

Basis for recommendation

The information on the differential diagnoses of leg cramps and their distinguishing clinical features is based on expert opinion in review articles [Monderer, 2010; Allen, 2012; Hamlet, 2012; Berger, 2014; Brown, 2015; Rabbitt, 2016; Katzberg, 2019; BMJ Best Practice, 2021] and a systematic review on the criteria in diagnosing nocturnal leg cramps [Hallegraeff, 2017].  

Management

Scenario: Management for leg cramps of unknown cause

From age 18 years onwards.

What self-care advice should I give someone about managing idiopathic leg cramps?

  • Reassure the person that idiopathic leg cramps are common; they have no underlying cause and can resolve spontaneously. Despite being common, there is little that is both safe and proven to be effective that can be suggested. A full assessment and reassurance that there is no serious cause and that usually idiopathic cramps do not have serious consequences may be the most helpful intervention in many cases. If there are no concerns about an underlying cause, and the cramps are not interfering with the person's quality of life, then no further investigation or management advice is needed. Advise the person to return if the frequency, severity, or nature of the cramps changes, or if they impact quality of life.
  • Advise all people about self-care measures that they may wish to try:
    • To alleviate an attack, advise stretching and massaging the affected muscle(s). For example, if calf cramps occur, straighten the leg and dorsiflex the ankle. Idiopathic cramps will, however, settle on their own within a few minutes.
    • Traditional advice to help reduce the frequency of attacks includes the following, but there is no definite evidence that these measures are effective: 
      • Do stretching exercises of the affected muscle(s) three times a day. If beneficial, continue indefinitely at an acceptable frequency. Combined daily calf and hamstring stretching may reduce the severity of nocturnal leg cramps, and may be more effective than calf stretching alone, but there is no standard protocol available for this.
      • When sleeping, try to stop the toes from pointing downwards. For example, prop the feet up (using a pillow) if lying supine, or hang the feet over the end of the bed if prone. Keep blankets loose and avoid heavy bed covers.
    • Offer written self-care advice, such as the patient information on Leg cramps from the NHS, which includes instructions on calf stretching exercises if the person wishes to try this.
    • Consider using analgesia if the muscle(s) is tender after a cramp. It is impractical to use analgesia during a cramp, as most attacks are short-lived. For more information, see the CKS topic on Analgesia - mild-to-moderate pain.

Basis for recommendation

Reassurance
  • CKS has extrapolated the recommendation to reassure the person about idiopathic leg cramps from prevalence data and diagnostic and prognostic information in review articles [Monderer, 2010; Allen, 2012; Rana, 2014; Rabbitt, 2016; Katzberg, 2019; BMJ Best Practice, 2021]. Additional advice that there is no particular treatment that is both safe and known to be effective is also extrapolated from these review articles, as well as Cochrane reviews [El-Tawil, 2015; Hawke, 2021], and the Medicines and Healthcare Regulatory Agency (MHRA) warnings about quinine [MHRA, 2010; MHRA, 2017].  Safety netting advice to advise the person to return if the severity or nature of the cramps changes is pragmatic and based on what CKS considers to be good practice.
Stretching exercises
  • The recommendation to use stretching and massage to alleviate an acute attack is based on anecdotal evidence, reflecting expert opinion in review articles [Monderer, 2010; Allen, 2012; Berger, 2014; Brown, 2015; Rabbitt, 2016; BMJ Best Practice, 2021].
  • Based on the available evidence, the efficacy of stretching exercises to prevent or reduce the frequency of idiopathic leg cramps is uncertain [Rana, 2014; Young, 2015; Rabbitt, 2016], but a number of experts advocate their use [Monderer, 2010; Allen, 2012; Berger, 2014; Brown, 2015; Katzberg, 2019].  A 2021 Cochrane review, however, found little evidence from studies to help guide advice given for non-drug treatment for leg or foot cramps, and noted there are not enough studies on which to base decisions, and no studies at all in people under the age of 50 [Hawke, 2021]. There was weak and low-quality evidence that combining daily hamstring and calf stretching may reduce the severity of night cramps in people aged 55 or more. CKS was unable to find any accepted regimes for this indication, and the evidence was from one small study. 
  • The self-care advice for sleeping is aimed at limiting dorsiflexion of the foot, and is based on expert opinion in review articles [Monderer, 2010; Berger, 2014; Rabbitt, 2016]. The 2021 Cochrane review above found no studies relating to this advice.
Written self-care advice and analgesia
  • A BMJ Clinical Evidence review found no RCT evidence to influence the use of analgesia for idiopathic leg cramps [Young, 2015]. These recommendations are therefore pragmatic and based on what CKS considers to be good clinical practice.

Should I use quinine for treating idiopathic leg cramps?

  • Quinine is generally not recommended for treating idiopathic leg cramps due to the poor benefit-to-risk ratio. However, a trial of quinine may be considered if:
    • Treatable causes of cramp have been excluded.
    • Leg cramps are very painful and frequent. 
    • Cramps affect the person's quality of life (for example regularly disrupt sleep).
    • Self-care measures (for example, stretching exercises) fail. 
    • The person has no medical conditions or drug interactions that increase the risk of quinine use, and adverse effects are discussed before prescribing and are carefully monitored. For more information, see Prescribing information. 
  • If quinine treatment is thought to be appropriate:
    • Prescribe 200–300 mg (at bedtime) for 4 weeks. 
    • Ask the person to monitor any benefit using a sleep and cramp diary.
    • If no benefit is seen after 4 weeks, stop treatment.
    • If beneficial, continue for 3 months, then aim to stop treatment to reassess ongoing need. If further treatment is required, review every 3 months and consider a trial discontinuation.
    • Advise the person not to exceed the recommended dose as serious adverse effects may occur. If signs of thrombocytopenia occur during treatment (for example, unexplained petechiae, bruising, or bleeding), they should seek medical advice. 

Basis for recommendation

CKS did not identify any UK guidelines on the indications for using quinine in the management of leg cramps in primary care.

Considering quinine treatment
  • These recommendations are based on advice from the Medicines and Healthcare products Regulatory Agency (MHRA) [MHRA, 2010], and are supported by a report from the American Academy of Neurology that recommends the avoidance of routine use of quinine for leg cramps because of the risk of toxicity, but notes that for certain people a trial of treatment may be an option if the possible adverse effects are considered [Katzberg, 2010]. 
  • A Cochrane systematic review on quinine for muscle cramps (search date November 2014) compared quinine with placebo, most commonly at a dosage of 300 mg daily [El-Tawil, 2015].  
    • Quinine reduced the number of cramps over 2 weeks by 28% (n = 952; low-quality evidence with significant heterogeneity between the studies), cramp days by 20% (low-quality evidence), and the intensity of cramps by 10% (n = 666; moderate-quality evidence), but the duration of cramps was unchanged. 
    • Minor adverse effects, such as gastrointestinal symptoms, were experienced by more people using quinine (127 per 1000) than with placebo (94 per 1000; risk difference 3%, 95% CI 0–6%). No significant difference was found in major adverse events, but the Cochrane authors noted that fatal events due to overdose have been reported elsewhere. 
Prescribing quinine treatment
  • These recommendations are largely based on the MHRA publication Quinine: not to be used routinely for nocturnal leg cramps [MHRA, 2010]. 
    • Dosing information is consistent with the British National Formulary [BNF, 2022], and the suggestion to monitor benefit using a sleep and cramp diary is based on expert opinion in a review article [Rabbitt, 2016].  
    • The recommendation to review the need for treatment every 3 months and consider discontinuation is pragmatic and based on the advice of the MHRA [MHRA, 2010]. A large UK study of 44,699 people with long-term quinine exposure of at least 1 year, at a dose of more than 100 mg per day, found an increased mortality risk in the quinine group compared with 130,496 people not exposed to quinine (4.2 vs 3.2 per 100 person-years; adjusted hazard ratio 1.24, 95% CI 1.21 to 1.27). However, the authors noted that confounding factors were not measured and it was not possible to determine whether quinine-containing drinks (for example, tonic water) were also consumed [Fardet, 2017]
Other pharmacological treatment
  • No recommendations are made for other pharmacological treatments as there is not strong evidence to support their use, and recent expert reviews do not generally recommend use of other treatments. A 2020 Cochrane review concluded there was no benefit to magnesium supplementation [Garrison, 2020]. Other drugs which have been used include verapamil, diltiazem, vitamin B complex, naftidrofuryl, and gabapentin [Rabbitt, 2016; Katzberg, 2019; BMJ Best Practice, 2021; Hawke, 2021]. However these drugs are not licensed for this indication [BNF, 2022], and as there is insufficient evidence to support their use [Young, 2015] they are not included in the management advice for this topic.

When should I refer someone with leg cramps?

  • Admit to hospital if the cramps are severe and the person has altered consciousness, anuria, or hyper- or hypopyrexia.
  • Refer to the appropriate specialty (for example, neurology or rheumatology) when an underlying cause is suspected which cannot be managed in primary care.
  • Consider specialist referral if:
    • The diagnosis is in doubt.
    • Treatment in primary care fails and symptoms are affecting the person's quality of life.

Basis for recommendation

CKS did not identify any national guidelines on referral advice for leg cramps in primary care.

Admission
  • This recommendation is based on expert opinion in a review article, on the basis that the features stated may indicate a systemic disorder such as volume depletion, severe electrolyte imbalance, acute kidney injury, or an intracranial disorder [BMJ Best Practice, 2021].  
Referral
  • These recommendations are extrapolated from expert opinion from review articles and are pragmatic, based on what CKS considers to be good clinical practice.
    • A referral will allow further investigations to confirm or exclude an underlying cause for leg cramps (for example serum CK-MM and aldolase if primary muscle disease is suspected; electromyography studies or nerve conduction studies if lower motor neurone disease (MND) is suspected; muscle biopsy if primary muscle disease or lower MND is suspected; and genetic studies if a familial cause is suspected) [BMJ Best Practice, 2021].  
    • Specialists may then offer other treatments (for which there is low-quality or anecdotal evidence) in addition to primary care measures [Young, 2015]. A report from the American Academy of Neurology discussed the possible effectiveness of naftidrofuryl, vitamin B complex, and diltiazem based on evidence from single studies, but noted the need for further investigation of these and other treatments [Katzberg, 2010]. Other options discussed in subsequent review articles include vitamin E, gabapentin, magnesium, or verapamil [Allen, 2012; Brown, 2015] although there is no strong evidence supporting their effectiveness [Brown, 2015; Young, 2015; Katzberg, 2019; Garrison, 2020].   

Prescribing information

Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (emc), or the British National Formulary (BNF).

Quinine

What are the contraindications and cautions when prescribing quinine?

  • Do not prescribe quinine for people who have had an adverse reaction to quinine previously (including to tonic water).
  • Quinine is also contraindicated for people with:
    • Haemolysis or haemoglobinuria.
    • Optic neuritis.
    • Tinnitus.
    • Myasthenia gravis (quinine can cause severe respiratory distress and dysphagia in this group).
  • Pregnant women should not be prescribed quinine to treat leg cramps. Breastfeeding women should not receive quinine unless the benefits outweigh the risk as quinine is excreted in breast milk.
  • Prescribe quinine with caution in older people and anyone with:
    • Cardiac disease; risk factors for QT prolongation (including medicines); atrial fibrillation, conduction defects, heart block — quinine can exacerbate conduction defects.
    • Electrolyte disturbance.
    • Glucose-6-phosphate dehydrogenase deficiency — the risk of haemolytic anaemia may be increased when taking quinine.
  • Quinine is generally not recommended for treating idiopathic leg cramps due to the poor benefit-to-risk ratio, but may be considered where symptoms are severe, other measures have failed, and there are no conditions or drug interactions which would increase the risk. See the section on management for further information.

[MHRA, 2010; MHRA, 2017; ABPI, 2019; BNF, 2022]

What are the adverse effects of quinine?

  • Quinine is extremely toxic in the event of an overdose and can cause irreversible loss of vision and life-threatening adverse effects (such as arrhythmias, convulsions, respiratory depression, and renal failure).
  • Cinchonism can occur in overdose, but has also been reported after normal doses of quinine — symptoms include nausea, vomiting, convulsions, headache, tinnitus, deafness, vasodilation, and visual disturbance.
  • In high doses, quinine can be teratogenic and may cause miscarriage.
  • Other reported adverse effects include:
    • Haematological: thrombocytopenia, intravascular coagulation, and pancytopenia.
    • Neurological: coma, vertigo, agitation, and confusion.
    • Dermatological: flushing, angio-oedema, rashes, pruritus, and hypersensitivity.
    • Musculoskeletal: weakness and aggravation of myasthenia gravis.
    • Gastrointestinal: diarrhoea, nausea, vomiting, and abdominal pain.
    • Respiratory: bronchospasm and breathlessness.
    • Cardiac: prolonged QT interval, atrioventricular conduction changes, and drop in blood pressure.

[MHRA, 2010; ABPI, 2019; BNF, 2022]

What drug interactions are associated with quinine?

  • The potential for quinine toxicity is increased by drugs that inhibit CYP3A4, including azole antifungals and HIV protease inhibitors.
  • Serum levels of quinine may be reduced by CYP3A4 inducers such as rifampicin, carbamazepine, and phenytoin.
  • Quinine can increase the plasma concentration of the following drugs:
    • Flecainide.
    • Digoxin and cardiac glycosides.
    • Mefloquine.
    • Amantadine.
  • Concurrent use of quinine and:
    • Drugs that increase the QT interval (for example, amiodarone, clarithromycin, citalopram, erythromycin, escitalopram, flecainide, hydroxyzine, lithium, moxifloxacin, ondansetron, pimozide, ranolazine, sotalol, and thioridazine) — increases the risk of ventricular arrhythmias.
    • Anticoagulants — may cause hypoprothrombinaemia and enhance anticoagulant effects.
    • Hypoglycaemics — increases the risk of hypoglycaemia.

For the full list of drugs that may interact with quinine, refer to the British National Formulary (BNF) or electronic medicines compendium (emc).

[MHRA, 2017; ABPI, 2019; BNF, 2022]

Supporting evidence

This CKS topic is largely based on expert opinion in review articles. The rationale for the assessment, referral, and primary care management of people with leg cramps is outlined in the relevant basis for recommendation sections of the topic.

How this topic was developed

This section briefly describes the processes used in developing and updating this topic. Further details on the full process can be found in the About Us section and on the Clarity Informatics website.

Search strategy

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of leg cramps.

Search dates

December 2017 - November 2022

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

  • exp Muscle Cramp/, exp Leg/, cramp*.tw., (leg or legs or calf or calves or thigh or thighs or foot or feet or limb or muscle or muscular or nocturnal or night*).tw.

Sources of guidelines

Sources of systematic reviews and meta-analyses

  • The Cochrane Library:
    • Systematic reviews
    • Protocols
    • Database of Abstracts of Reviews of Effects
  • Medline (with systematic review filter)
  • EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

Sources of randomized controlled trials

  • The Cochrane Library:
    • Central Register of Controlled Trials
  • Medline (with randomized controlled trial filter)
  • EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Sources of national policy

Patient experiences

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

Stakeholder engagement

Our policy

The external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:

  • Clinical accuracy.
  • Consistency with other providers of clinical knowledge for primary care.
  • Accuracy of implementation of national guidance (in particular NICE guidelines).
  • Usability.

Principles of the consultation process

  • The process is inclusive and any individual may participate.
  • To participate, an individual must declare whether they have any competing interests or not. If they do not declare whether or not they have competing interests, their comments will not be considered.
  • Comments received after the deadline will be considered, but they may not be acted upon before the clinical topic is issued onto the website.
  • Comments are accepted in any format that is convenient to the reviewer, although an electronic format is encouraged.
  • External reviewers are not paid for commenting on the draft topics.
  • Discussion with an individual or an organization about the CKS response to their comments is only undertaken in exceptional circumstances (at the discretion of the Clinical Editor or Editorial Steering Group).
  • All reviewers are thanked and offered a letter acknowledging their contribution for the purposes of appraisal/revalidation.
  • All reviewers are invited to be acknowledged on the website. All reviewers are given the opportunity to feedback about the external review process, enabling improvements to be made where appropriate.

Stakeholders

  • Key stakeholders identified by the CKS team are invited to comment on draft CKS topics. Individuals and organizations can also register an interest to feedback on a specific topic, or topics in a particular clinical area, through the Getting involved section of the Clarity Informatics website.
  • Stakeholders identified from the following groups are invited to review draft topics:
    • Experts in the topic area.
    • Professional organizations and societies (for example, Royal Colleges).
    • Patient organizations, Clarity has established close links with groups such as Age UK and the Alzheimer’s Society specifically for their input into new topic development, review of current topic content and advice on relevant areas of expert knowledge.
    • Guideline development groups where the topic is an implementation of a guideline.
    • The British National Formulary team.
    • The editorial team that develop MeReC Publications.
  • Reviewers are provided with clear instructions about what to review, what comments are particularly helpful, how to submit comments, and declaring interests.

Patient engagement

Clarity Informatics has enlisted the support and involvement of patients and lay persons at all stages in the process of creating the content which include:

  • Topic selection
  • Scoping of topic
  • Selection of clinical scenarios
  • First draft internal review
  • Second draft internal review
  • External review
  • Final draft and pre-publication

Our lay and patient involvement includes membership on the editorial steering group, contacting expert patient groups, organizations and individuals.

Evidence exclusion criteria

Our policy

Scoping a literature search, and reviewing the evidence for CKS is a methodical and systematic process that is carried out by the lead clinical author for each topic. Relevant evidence is gathered in order that the clinical author can make fully informed decisions and recommendations. It is important to note that some evidence may be excluded for a variety of reasons. These reasons may be applied across all CKS topics or may be specific to a given topic.

Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.

Standard exclusions for scoping literature:

  • Animal studies
  • Original research is not written in English

Possible exclusions for reviewed literature:

  • Sample size too small or study underpowered
  • Bias evident or promotional literature
  • Population not relevant
  • Intervention/treatment not relevant
  • Outcomes not relevant
  • Outcomes have no clear evidence of clinical effectiveness
  • Setting not relevant
  • Not relevant to UK
  • Incorrect study type
  • Review article
  • Duplicate reference

Organizational, behavioural and financial barriers

Our policy

The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.

  • Feasibility
    • Studies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.
  • Organizational and Financial Impact Analysis
  • Studies are selected and evaluated on whether the intervention under investigations may have an impact on local clinical service provision or national impact on cost for the NHS. The principles of clinical budget impact analysis are adhered to, evaluated and recorded by the author. The following factors are considered when making this assessment and analysis.
    • Eligible population
    • Current interventions
    • Likely uptake of new intervention or recommendation
    • Cost of the current or new intervention mix
    • Impact on other costs
    • Condition-related costs
    • In-direct costs and service impacts
    • Time dependencies
  • Cost-effectiveness or cost-benefit analysis studies are identified where available. 

We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation.

Declarations of interest

Our policy

Clarity Informatics requests that all those involved in the writing and reviewing of topics, and those involved in the external review process to declare any competing interests. Signed copies are securely held by Clarity Informatics and are available on request with the permission of the individual. A copy of the declaration of interest form which participants are asked to complete annually is also available on request. A brief outline of the declarations of interest policy is described here and full details of the policy is available on the Clarity Informatics website. Declarations of interests of the authors are not routinely published, however competing interests of all those involved in the topic update or development are listed below. Competing interests include:

  • Personal financial interests
  • Personal family interest
  • Personal non-financial interest
  • Non-personal financial gain or benefit

Although particular attention is given to interests that could result in financial gains or losses for the individual, competing interests may also arise from academic competition or for political, personal, religious, and reputational reasons. An individual is not obliged to seek out knowledge of work done for, or on behalf of, the healthcare industry within the departments for which they are responsible if they would not normally expect to be informed.

Who should declare competing interests?

Any individual (or organization) involved in developing, reviewing, or commenting on clinical content, particularly the recommendations should declare competing interests. This includes the authoring team members, expert advisers, external reviewers of draft topics, individuals providing feedback on published topics, and Editorial Steering Group members. Declarations of interest are completed annually for authoring team and editorial steering group members, and are completed at the start of the topic update and development process for external stakeholders.

Competing interests declared for this topic:

None.

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