Clinical Topic A-Z Clinical Speciality

Leg cramps

Leg cramps
D009120Muscle Cramp
D007866Leg
Musculoskeletal
2012-09-01Last revised in September 2012

Leg cramps - Summary

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.

One third of people over 60 years of age are thought to suffer from leg cramps, with 40% having three or more attacks per week.

Idiopathic leg cramps are indicated by a history of sudden calf, thigh, or foot pain; most often in an elderly person, and at night (or when resting). The pain usually lasts for several minutes and there are no abnormal findings on physical examination.

The following points in a history and examination may help exclude secondary causes (e.g. lower motor neuron problems, metabolic problems, medications, and pregnancy) or other conditions which mimic leg cramps (e.g. inflammation, Baker’s cyst, deep vein thrombosis, dystonia, myoclonus, and parkinsonism):

Symptoms of calf pain with exercise, an urge to move the legs, or leg numbness or weakness.

Signs of muscle wasting and fasciculations, skin pallor, calf swelling, or varicose veins. Abnormal leg pulses, capillary refill, loss of sensation or power, or altered reflexes.

History (or symptoms) of an underlying condition (e.g. thyroid disease).

Medication (e.g. diuretics, salbutamol, nifedipine).

Investigations are usually not needed, unless an underlying cause is suspected (e.g. blood tests for electrolytes, calcium, thyroid function tests, fasting glucose, liver function tests, magnesium, and creatinine kinase).

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.

Advice on the use of 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.

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 self-care measures fail and leg cramps are frequent and affecting the person's quality of life:

200–300 mg (at bedtime) should be prescribed for 4–6 weeks.

The person should monitor any benefit using a sleep and cramp diary.

If beneficial, treatment can be continued for 3 months, then the aim is to stop treatment to reassess ongoing need. If further treatment is required, a review should be undertaken every 3–6 months.

If no benefit is seen after 4 weeks, stopping treatment is recommended.

Referral should be arranged to the appropriate speciality (e.g. neurology, rheumatology) when an underlying cause is suspected which cannot be managed in primary care.

A referral to general medicine should 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?

144months3060monthsBoth

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-leg syndrome, tetany, contracture, dystonia, or the management of secondary causes of leg cramps.

There are separate CKS topics on Deep vein thrombosis, 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 health care.

How up-to-date is this topic?

How up-to-date is this topic?

Changes

Last revised in September 2012

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.

Previous changes

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 [MHRA, 2010]. Issued in July 2010.

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

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. Issued in September 2008.

October 2005 — minor technical update. Issued in November 2005.

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 September 2012.

HTAs (Health Technology Assessments)

No new HTAs since 1 September 2012.

Economic appraisals

No new economic appraisals relevant to England since 1 September 2012.

Systematic reviews and meta-analyses

No new systematic reviews since 1 September 2012.

Primary evidence

No new randomized controlled trials published in the major journals since 1 September 2012.

New policies

No new national policies or guidelines since 1 September 2012.

New safety alerts

No new safety alerts since 1 September 2012.

Changes in product availability

No changes in product availability since 1 September 2012.

Goals and outcome measures

Goals

To make an accurate assessment of someone with leg cramps

To give appropriate self-care advice and treatment (if needed) to manage leg cramps

To refer to secondary care if appropriate

Background information

Definition

What are they?

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 [Miller and Layzer, 2005].

Prevalence

How common are they?

One third of people over 60 years of age are thought to suffer from leg cramps, with 40% having three or more attacks per week [Naylor and Young, 1994].

Assessment

Assessment for an underlying cause of leg cramps

Assessment for underlying cause

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

Idiopathic leg cramps are indicated by a history of sudden calf, thigh, or foot pain; most often in an elderly person, and at night (or when resting). The pain usually lasts for several minutes and there are no abnormal findings on physical examination.

The following points in a history and examination may help exclude secondary causes (see Table 1) or other conditions which mimic leg cramps:

Symptoms of calf pain with exercise, an urge to move the legs, or leg numbness or weakness.

Signs of muscle wasting and fasciculations, skin pallor, calf swelling, or varicose veins. Abnormal leg pulses, capillary refill, loss of sensation or power, or altered reflexes.

History (or symptoms) of an underlying condition (e.g. thyroid disease).

Medication (e.g. diuretics, salbutamol, nifedipine).

Investigations are usually not needed, unless an underlying cause is suspected (e.g. blood tests for electrolytes, calcium, thyroid function tests, fasting glucose, liver function tests, magnesium, and creatinine kinase).

Additional information

Additional information

Other conditions that may mimic leg cramps [Miller and Layzer, 2005]:

Focal muscle pain:

With swelling — trauma, ruptured tendon, Baker's cyst, deep vein thrombosis, thrombophlebitis, infection, inflammation (myositis).

Without swelling — exertional myalgia, peripheral arterial disease, restless legs syndrome.

Generalized muscle pain:

With muscle weakness — inflammation (polymyositis), infection (toxoplasmosis), metabolic (alcohol, statins), Guillain–Barré syndrome.

Without muscle weakness — polymyalgia rheumatica, collagen-vascular disease, Parkinsonism, fibromyalgia.

Dystonia — involuntary muscle contractions that lead to abnormal movements. Can be generalized or focal (e.g. writer's, pianist's, or typist's cramp).

Myoclonus — sudden, involuntary jerking of a muscle or group of muscles without pain. For example, while drifting off to sleep.

Secondary causes of leg cramps are shown in Table 1.

Table 1 . Secondary causes of leg cramps.
Cause Conditions Symptoms and signs
Exercise Cramp often occurs during rest after exercise.
Lower motor neurone problems Motor neurone disease Radiculopathy (e.g. peripheral nerve injury) Neuropathy (e.g. peripheral neuropathy) Wasting muscles, power loss, and absent reflexes.
Metabolic problems Renal disease (50% of people with uraemia complain of leg cramps) Liver disease Hyperthyroidism Hypothyroidism (20–50% of people) Hyperthyroidism may lead to myopathy and associated leg cramps. Hypothyroidism is associated with weakness, enlarged muscles, and painful muscle spasms.
Acute volume depletion (possible low sodium levels) Heat cramps (miners, firemen, athletes) Diarrhoea, vomiting Diuretics
Medication Diuretics, salbutamol, raloxifene, nifedipine, phenothiazines, penicillamine, nicotinic acid, statins
Pregnancy 30% in the third trimester. Cramps stop after delivery.
Data from: [McGee, 1990; Riley and Antony, 1995; Kanaan and Sawaya, 2001; Salih, 2001; Miller and Layzer, 2005]

Basis for recommendation

Basis for recommendation

CKS did not identify any national guidelines on the assessment of leg cramps in primary care. These recommendations are based on expert opinion from review articles [Miller and Layzer, 2005; Shaker et al, 2005].

An assessment will allow the healthcare professional to initiate appropriate management (self care or investigations) by distinguishing leg cramps from other conditions, and excluding an underlying cause [McGee, 1990; Riley and Antony, 1995; Kanaan and Sawaya, 2001].

Management

Management

Scenario: Management : covers when to refer people with leg cramps, and the management of people with idiopathic leg cramps.

Scenario: Management

Scenario: Management for leg cramps of unknown cause

144months3060monthsBoth

Advice for management of leg cramps

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.

Advise all people about self-care measures:

To alleviate an attack, advise stretching and massaging the affected muscle(s). For example, upon calf cramps straighten the leg and dorsiflex the ankle, or walk around on the heels for a few minutes.

To help reduce the frequency of attacks:

Do stretching exercises of the affected muscle(s) three times a day. If beneficial, continue indefinitely at an acceptable frequency.

When sleeping, try to stop toes from pointing downwards. For example, if lying supine prop the feet up (using a pillow), or if prone hang the feet over the end of the bed. Keep blankets loose.

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.

Additional information

Additional information

Calf exercises: stand 1 metre from a wall. Lean forward with the arms outstretched to touch the wall and keep the soles of the feet flat on the floor. Hold for 5 seconds; repeat the exercise for 5 minutes, three times a day, especially before going to bed.

Basis for recommendation

Basis for recommendation

CKS did not identify any national guidelines for the management of leg cramps in primary care. These recommendations are based on expert opinion from review articles [Miller and Layzer, 2005; Shaker et al, 2005; Blyton et al, 2012].

Idiopathic nocturnal leg cramps have a relatively benign natural history, with no serious complications. Most cases will resolve spontaneously [Salih, 2001].

There are no controlled trials evaluating massage or stretching for acute cramps; nor evaluating sleeping positions for the prevention of cramps. However, some experts [Weiner and Weiner, 1980] believe such strategies are useful. Trials looking at massage and sleeping positions may be impractical.

The evidence for stretching exercises to prevent leg cramps is limited to an observational study [Daniell, 1979] and one randomized controlled trial (RCT). The RCT showed no benefit for stretching exercises compared with non-stretching exercises at 12 weeks [Coppin et al, 2005], however the participants were already on quinine, limiting the generalizability of the findings. Exercises are safe and are considered by experts to be helpful to people with leg cramps [Postgraduate Medicine, 2002].

Use of quinine for leg cramps

Should I use quinine for treating 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 self-care measures fail and leg cramps are frequent and affecting the person's quality of life:

Prescribe 200–300 mg (at bedtime) for 4–6 weeks.

Ask the person to monitor any benefit using a sleep and cramp diary.

If beneficial, continue for 3 months, then aim to stop treatment to reassess ongoing need. If further treatment is required, review every 3–6 months.

If no benefit is seen after 4 weeks, stop treatment.

For more information on the adverse effects, contraindications, and drug interactions of quinine see the British National Formulary (www.bnf.org).

Basis for recommendation

Basis for recommendation

CKS did not identify any national guidelines on the indications for using quinine in the management of leg cramps in primary care. These recommendations are based on expert opinion from review articles [Miller and Layzer, 2005; Shaker et al, 2005].

Evidence from a systematic review [Man-Son-Hing et al, 1998] and two randomized controlled trials [Diener et al, 2002; Woodfield et al, 2005] suggests a reduced frequency in leg cramps with quinine, compared with placebo over a 4-week period.

There are no trials which have evaluated the long-term efficacy or safety of quinine use for leg cramps. Observational studies and case reports have raised concerns about the risk:benefit ratio with quinine, mainly at the higher doses used for treating malaria [Mackie and Davidson, 1995; DTB, 1996; Reddy et al, 2004]. Therefore, experts recommend a treatment trial with careful monitoring of efficacy and adverse effects [Butler et al, 2002].

The Medicines and Healthcare products Regulatory Agency (MHRA) has recently reminded prescribers that quinine is not a routine treatment of nocturnal leg cramps and should only be considered when cramps cause regular disruption of sleep. The MHRA advise that quinine should be stopped if no benefit is seen after 4 weeks of treatment [MHRA, 2010].

Referral for leg cramps

When should I refer someone with leg cramps?

Refer to the appropriate speciality (e.g. neurology, rheumatology) when an underlying cause is suspected which cannot be managed in primary care.

Consider a referral to general medicine if:

The diagnosis is in doubt.

Treatment in primary care fails and symptoms are affecting the person's quality of life.

Basis for recommendation

Basis for recommendation

CKS could not identify any national guidelines on referral advice for leg cramps in primary care. These recommendations are based on expert opinion from review articles [Miller and Layzer, 2005; Shaker et al, 2005] and pragmatism.

A referral will allow further investigations (e.g. electromyography studies, muscle biopsy) to confirm or exclude an underlying cause for leg cramps. Specialists may then offer treatments (e.g. naftidrofuryl, diltiazem, vitamin B, vitamin E, magnesium, or verapamil) in addition to primary care measures.

The evidence for treatments that might be offered by a specialist is limited to small uncontrolled trials, and is currently of uncertain benefit [Young, 2009].

Evidence

Evidence

Supporting evidence

Stretching exercises

Evidence on stretching exercises

The evidence for stretching exercises in the prevention of leg cramps is based mainly on expert opinion, an observational study, and one randomized controlled trial (RCT). The trial evidence suggests no benefit over non-stretch exercises. However, experts argue for stretching exercises based on a plausible mechanism of action and safety. Moreover, the placebo effect in leg cramp trials appears to be considerable, and exercises will encourage health promotion.

Based on the observation that cramps appear to occur more frequently in contracted muscles, stretching a cramping muscle and activating the antagonist muscles is thought to help terminate a cramp and possibly reduce further cramps [Miller and Layzer, 2005].

In an observational study (n = 44), people with frequent cramps were instructed to carry out simple stretching exercises three times a day until their cramps disappeared. The characteristics of the people who were investigated were not reported, including whether they were taking quinine. All reported cure within a week (21 people reported cure within 72 hours) and most remained cramp-free for follow-up periods as long as 1 year [Daniell, 1979].

An RCT (n = 191) investigated stretching exercise in people (over 60 years of age) taking quinine. People were randomized to one of four groups defined by two 'advice' factors: undertake stretching exercises (versus non-stretch exercise) and stop quinine (versus placebo) [Coppin et al, 2005]:

At 12 weeks, there was no difference seen in the number or severity of leg cramps and symptom burden in the exercise group compared with the non-stretch exercise group. An important consideration is that non-stretch exercises may have had a beneficial affect, making stretching exercises appear ineffective.

Interestingly, one in four people who were advised to stop quinine had continued not to take quinine without any undue symptom burden, suggesting it may be possible in practice to stop quinine (in people on long-term treatment) without any recurrence of symptoms.

Quinine

Evidence on quinine

Quinine reduces the frequency of leg cramps compared with placebo, based on one systematic review and two randomized controlled trials (RCTs). The effect of quinine on leg cramp intensity is less certain, but quinine does not appear to alter the duration of leg cramps once started. Currently, there is no evidence on the long-term efficacy or safety of quinine for leg cramps, as most trials have been of a short duration (4 weeks).

Quinine is believed to increase the muscle refractory period and decrease the excitability of the motor end plate [Diener et al, 2002]. Based on these observations, quinine is given to people with leg cramps, where the pathophysiology is believed to be due to abnormal excitability of motor nerves.

It is conventionally believed that quinine is the most effective drug for treating leg cramps, since a series of studies reported benefits in the 1940s. However, these studies involved small numbers of people and were neither randomized nor controlled. Since then, numerous trials have looked at the role of quinine in leg cramps, but have still only involved a small number of people for a short duration [Miller and Layzer, 2005].

A systematic review (search date: 1997) including eight RCTs (n = 659) reported that quinine [Man-Son-Hing et al, 1998]:

Significantly reduced the frequency of leg cramps compared with placebo over a 4-week period (absolute risk reduction [ARR] 3.6 cramps per month, 95% CI 2.15 to 5.15, relative risk [RR] 0.21, 95% CI 0.12 to 0.30).

Reduced the number of nights during which people had cramps by 27%.

Significantly reduced individual cramp intensity, but did not change the duration of cramps once started.

Should be used for a minimum of 4 weeks for benefits to be seen (shorter studies did not reach statistical significance).

Significantly increased the risk of tinnitus (ARR for tinnitus: 3% for quinine versus 1.1% for placebo, RR 2.86, 95% CI 1.22 to 6.71) and one person experienced serious adverse affects (thrombocytopenia). Treatment periods were too short to exclude long-term complications.

A double-blind, placebo-controlled, parallel-group trial (n = 98, 18–70 years of age) reported [Diener et al, 2002]:

A significant reduction in leg cramps with quinine sulphate 200 mg twice a day for 2 weeks compared with placebo: a reduction in leg cramps of 50% or more was reported by 80% of the quinine group, compared with 53% of the placebo group.

Global efficacy (frequency, intensity, pain) was in favour of quinine (reported as statistically significant by the physician, but not by the participants).

This study used a higher quinine dose than is used in the UK, making it difficult to generalize the results to UK practice.

A concern with the use of quinine in leg cramps is the risk:benefit ratio. Quinine has known serious adverse effects, which appear to be dose-related and mainly seen in people taking quinine at high doses for malaria treatment:

The dose of quinine needed to treat leg cramps is less than that needed for malaria. However, adverse effects have been observed (e.g. tinnitus, gastrointestinal symptoms) [Diener et al, 2002].

The prolonged use of quinine (at a leg cramp dose) may lead, in some people, to cinchonism (a complex of nausea, vomiting, vertigo, visual disturbance, and hearing impairment).

To date, the long-term safety and efficacy of quinine has not been evaluated in clinical trials, but a systematic review is underway to answer this question [El-Tawil et al, 2010].

Treatments not recommended in primary care

Evidence on treatments not recommended in primary care

Magnesium, diltiazem, vitamin B complex, vitamin E, naftidrofuryl, orphenadrine, and verapamil are not currently recommended in primary care, as most studies involving them included only a small number of participants and have shown limited evidence of effectiveness.

Magnesium appears no more effective than placebo for leg cramps:

One randomized controlled trial (RCT) (n = 46) reported no significant improvement in the frequency, severity, or duration of leg cramps with magnesium 300 mg compared with placebo over 4 weeks. Both groups experienced a significant reduction in leg cramps from baseline (p = 0.008) [Roffe et al, 2002].

Another RCT (n = 42) found no evidence of effectiveness of magnesium 900 mg compared with placebo over 1 month (p = 0.59). In both treatment and control groups there were significant improvements in leg cramps (p = 0.027) [Frusso et al, 1999].

Both studies used crossover designs, making it difficult to interpret results owing to the potential effects of carry-over between treatment groups.

Diltiazem (30 mg) reduced the frequency, but not the intensity, of leg cramps in 12 people, compared with placebo [Voon and Sheu, 2001].

Vitamin E (800 IU) did not improve leg cramps or reduce sleep disturbance in 27 men, compared with quinine or placebo [Connolly et al, 1992].

Naftidrofuryl significantly reduced the frequency of leg cramps in 14 people, compared with placebo [Young and Connolly, 1993].

Orphenadrine: a trial in 59 people suggested that orphenadrine reduced the frequency of nocturnal leg cramps [Latta, 1989]. The frequency of leg cramps in the treated group was 39% less than that experienced in the placebo group. However, the results are difficult to interpret, as almost half the people were either lost to follow up or discontinued the orphenadrine.

Verapamil resolved leg cramps within 8 weeks in an open-labelled study of eight elderly people whose cramps were unresponsive to quinine [Baltodano et al, 1988].

Vitamin B complex significantly reduced the frequency, intensity, and duration of leg cramps in 28 elderly people with hypertension [Chan, 1998]:

Of the people taking vitamin B complex, 28% had almost complete remission of leg cramps, and 57% showed significant reduction in leg cramps. Improvement was seen after 4 weeks and persisted for 12 weeks.

The exact ingredients in the vitamin B complex were stated in the study, which was undertaken in Taipei. It is unknown which of these ingredients may have been beneficial, making it difficult to generalize these findings to the UK market.

Search strategy

Scope of search

A literature search was conducted for guidelines and systematic reviews on the primary care management of leg cramps.

Search dates

June 2008 - September 2012

Key search terms

Various combinations for searches were carried out. The terms listed below are the core search terms that were used for Medline and these were adapted for other databases. Further details are available on request.

exp Muscle Cramp/, exp Leg/, muscle cramp.tw., leg.tw. or cramp$.tw., nocturnal cramp$.tw.

Table 1 . Key to search terms.
Search commands Explanation
/ indicates a MeSh subject heading with all subheadings selected
.tw indicates a search for a term in the title or abstract
exp indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree
$ indicates that the search term was truncated (e.g. wart$ searches for wart and warts)
Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

Royal College of Physicians

Royal College of General Practitioners

Royal College of Nursing

NICE Evidence

Health Protection Agency

World Health Organization

National Guidelines Clearinghouse

Guidelines International Network

TRIP database

GAIN

NHS Scotland National Patient Pathways

New Zealand Guidelines Group

Agency for Healthcare Research and Quality

Institute for Clinical Systems Improvement

National Health and Medical Research Council (Australia)

Royal Australian College of General Practitioners

British Columbia Medical Association

Canadian Medical Association

Alberta Medical Association

University of Michigan Medical School

Michigan Quality Improvement Consortium

Singapore Ministry of Health

National Resource for Infection Control

Patient UK Guideline links

UK Ambulance Service Clinical Practice Guidelines

RefHELP NHS Lothian Referral Guidelines

Medline (with guideline filter)

Driver and Vehicle Licensing Agency

NHS Health at Work (occupational health practice)

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

NIHR Health Technology Assessment programme

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

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

Bandolier

Drug & Therapeutics Bulletin

TRIP database

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

Patient experiences

Healthtalkonline

BMJ - Patient Journeys

Patient.co.uk - Patient Support Groups

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.

British National Formulary (BNF)

electronic Medicines Compendium (eMC)

European Medicines Agency (EMEA)

LactMed

Medicines and Healthcare products Regulatory Agency (MHRA)

REPROTOX

Scottish Medicines Consortium

Stockley's Drug Interactions

TERIS

TOXBASE

Micromedex

UK Medicines Information

References

Baltodano, N., Gallo, B.V. and Weidler, D.J. (1988) Verapamil vs quinine in recumbent nocturnal leg cramps in the elderly. Archives of Internal Medicine 148(9), 1969-1970. [Abstract]

Blyton, F., Chuter, V., Walter, K.E.L. and Burns, J. (2012) Non-drug therapies for lower limb muscle cramps (Cochrane Review). The Cochrane Library. Issue 1. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Butler, J.V., Mulkerrin, E.C. and O'Keeffe, S.T. (2002) Nocturnal leg cramps in older people. Postgraduate Medical Journal 78(924), 596-598. [Abstract] [Free Full-text]

Chan, P. (1998) Randomized, double-blind, placebo-controlled study of the safety and efficacy of vitamin B complex in the treatment of nocturnal leg cramps in elderly patients with hypertension. Journal of Clinical Pharmacology 38(12), 1151-1154. [Abstract]

Connolly, P.S., Shirley, E.A., Wasson, J.H. and Nierenberg, D.W. (1992) Treatment of nocturnal leg cramps. A crossover trial of quinine vs. vitamin E. Archives of Internal Medicine 152(9), 1877-1880. [Abstract]

Coppin, R.J., Wicke, D.M. and Little, P.S. (2005) Managing nocturnal leg cramps - calf-stretching exercises and cessation of quinine treatment: a factorial randomised controlled trial. British Journal of General Practice 55(512), 186-191. [Abstract] [Free Full-text]

Daniell, H.W. (1979) Simple cure for nocturnal leg cramps. New England Journal of Medicine 301(4), 216.

Diener, H.C., Dethlefsen, U., Dethlefsen-Gruber, S. and Verbeek, P. (2002) Effectiveness of quinine in treating muscle cramps: a double-blind, placebo-controlled, parallel-group, multicentre trial. International Journal of Clinical Practice 56(4), 243-246. [Abstract]

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El-Tawil, S., Al Musa, T., Valli, H. et al. (2010) Quinine for muscle cramps (Cochrane Review). The Cochrane Library. Issue 12. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

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Latta, D. (1989) An alternative to quinine in nocturnal leg cramps. Current Therapeutic Research, Clinical & Experimental 45(5), 833-837.

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Reddy, J.C.M., Shuman, M.A.M. and Aster, R.H.M. (2004a) Quinine/quinidine-induced thrombocytopenia: a great imitator. Archives of Internal Medicine 164(2), 218-220.

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Salih, A. (2001) Treating leg cramps and restless syndrome. Prescriber 12(3), 93-97.

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