Age and Ageing 2016; 45: 776–782 © The Author 2016.

2016. Published by Oxford University Press on behalf of the British Geriatrics Society.
doi: 10.1093/ageing/afw139 All rights reserved. For Permissions, please email: journals.permissions@oup.com

REVIEW

A review of nocturnal leg cramps in older people

LOUISE RABBITT1, EAMON C. MULKERRIN1, SHAUN T. O’KEEFFE2
1
Geriatric Medicine, Galway University Hospitals, Galway, Ireland
2
Unit 4, Geriatric Medicine, Merlin Park Regional Hospital, Merlin Park Hospital, Galway, Ireland

Downloaded from https://academic.oup.com/ageing/article-abstract/45/6/776/2499229 by guest on 15 October 2019

Address correspondence to: S. T. O’Keeffe. Tel: (353) 91 775561; Fax: (353) 91 7705. Email: sokanc@iolfree.ie

Abstract

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

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

Introduction • The painful muscle contractions occur during the time in

Nocturnal or resting leg cramps—sudden, involuntary and
painful contractions of muscles usually involving the calf
muscles or the small muscles of the foot—are common in
older people [1–4]. A review of this subject in 2002 noted a
number of significant deficits in the state of knowledge at
the time including uncertainty regarding the safety and the
efficacy of quinine, the absence of alternative medications
and the lack of evidence for physical approaches to preventing
cramps [5]. In this article, we review the current state of
knowledge regarding the diagnosis, frequency, pathophysiology
and management of nocturnal leg cramps.
Definition
Progress on this topic has been hampered by the lack of
consensus on a clear definition of nocturnal leg cramps.
The definition used in the latest International Classification
of Sleep Disorders (2014) may be helpful in the future but
has not been widely adopted to date [6]. This describes
three diagnostic criteria:
• A painful sensation in the leg or foot associated with sudden,
involuntary muscle hardness or tightness, indicating a strong
muscle contraction.
bed, although they may arise from either wakefulness or
sleep.
• The pain is relieved by forceful stretching of the affected
muscles, thus releasing the contraction.
In contrast to nocturnal leg cramps, muscle cramps due
to neuromuscular or systemic diseases are more likely to
occur throughout the day or to involve other parts of the
body. For example, while the majority of cramps in normal
controls in one study were nocturnal and occurred in the
calves, cramps in amyotrophic lateral sclerosis patients were
frequently located in the distal small muscles of toes or feet
and in those of fingers or hands, were mainly movement-
induced and occurred both during daytime and at night [7].
Other muscle cramps occur in specific situations such as after
vigorous, often unaccustomed, exercise or associated with
dialysis.
Prevalence and impact
While leg cramps can occur at any age, they are more common
and often more severe in later life. In a general practice-based
study of 233 people aged 60 years or more, almost one-third
had had rest cramps during the previous 2 months, including
half of those aged 80 years or more, 40% had cramps more

776

than three times per week and 21% described their symptoms as
very distressing [8]. Another study of 350 elderly outpatients
found that 50% had rest cramps, with 20% reporting symptoms
for 10 years or more although many had not reported symptoms
to their doctors [9]. Most studies note that nocturnal cramps
are more common in women [2, 3, 9], especially older
women [10, 11]. One study, using new quinine prescriptions
and internet searches as proxy markers for cramp incidence,
found a markedly increased rate in summer compared with
winter months in both Australia and Canada [12].
Nocturnal leg cramps can have a major impact on quality
of life. In addition to distress caused by pain, people with
frequent cramps also report more disturbances of sleep,
poorer quality sleep and more daytime somnolence than
matched controls without cramps [3, 8].
Pathophysiology
Muscle cramps ultimately result from rapid repetitive firing
of motor unit action potentials at a rate much higher than
involuntary contractions. The balance of evidence suggests
that this most often results from spontaneous discharges
of motor nerves rather than having a central or muscular
origin [13]. Factors that may contribute include abnormal
excitability of anterior horn cells or of intramuscular motor
nerve terminals. Afferent fibres influence the generation of
motor discharges, and disturbance of sensory inputs may
contribute to muscle cramps.
Age-related loss of motor neurons, which is more
pronounced in the legs than the arms, is common in later
life and may contribute to a propensity to leg cramps in
older people [13]. This is supported by a case–control study
of mainly older subjects in which those with nocturnal
cramps had lower scores on measures of lower limb muscle
strength than those without cramps [14]. Mechanical factors
such as tendon shortening in later life and during prolonged
immobility can also increase nerve terminal excitability and
contribute to cramp development [15].
Associated conditions and medications
Although nocturnal cramps are idiopathic in most people, a
large number of potential aetiological factors have been
reported (Table 1) [15, 16–18]. It is not always easy to inter-
pret the validity of many reported associations: cramps are
poorly defined in many series and may have been confused
Table 1. Possible causes of muscle cramps
Medications Diuretics, inhaled long-acting beta 2 agonists, statins, nifedepine, acetylcholinesterase inhibitors, steroids, morphine, cimetidine,
penicillamine, antiretrovirals, neuroleptics
Metabolic disorders Hepatic failure, chronic kidney disease, diabetes mellitus, hypothyroidism, hypoadrenalism
Fluid/electrolyte Hypokalaemia, hyperkalaemia, hypocalcaemia, hyponatraemia, hypomagnesaemia, haemodialysis, acute volume depletion
disorders
Neurological disorders Motor neuron disease, neuropathy, radiculopathy, small-fibre sensory neuropathy, Parkinson’s disease, multiple sclerosis
Others Vitamin deficiencies, exercise, coffee, peripheral vascular disease, chronic venous disease, obstructive sleep apnoea
Review of nocturnal leg cramps
with other conditions causing leg symptoms; given the high
prevalence of cramps, associations with other common
conditions may have occurred by chance.
Medications
The medications most commonly linked to cramp develop-
ment have been diuretics, statins and inhaled long-acting
beta 2 agonists (LABA). The best quality evidence to date
regarding these associations comes from a study using 8 years
of prescribing information in British Columbia, Canada, which
found that new prescriptions for quinine were substantially
Downloaded from https://academic.oup.com/ageing/article-abstract/45/6/776/2499229 by guest on 15 October 2019
more common in the year following prescriptions for
LABAs, thiazide diuretics and potassium sparing diuretics,
and that one or other of these drugs had been prescribed to
60% of quinine recipients [19]. There was a weaker association
between the use of statins and loop diuretics and subsequent
cramp treatment.
The stimulatory effect of beta agonists on motor neurons
and neuronal excitation due to diuretic-induced changes in
electrolyte concentration around motor end plates are possible
explanations for the links between cramps and these medica-
tions. In contrast, cramps are not a feature of statin-induced
myopathy although one study of patients with motor neuron
disease (MND) did find a link between statins and cramps
[20].
Neurological disease
Although central neurological conditions such as Parkinson’s
disease and multiple sclerosis can be associated with
cramps, perhaps as a result of spinal disinhibition or immo-
bility, cramps are particularly associated with disorders
affecting the lower motor neuron [15]. Cramps are a com-
mon early feature of MND and occur in over 60% of those
with polyneuropathy [21]. A small study in which patients
with cramps but without neuropathic complaints underwent skin
biopsies showed a high prevalence of small-fibre neuropathy,
a condition that particularly affects older people [22].
Other conditions
Muscle cramps have been reported to be associated with
many metabolic and fluid and electrolyte disturbances. In
particular, they occur in about two-thirds of diabetics and
are especially common in those with Type 2 diabetes mellitus
and in association with diabetic neuropathy [23]. Although
777
L. Rabbit et al.
cramps occur in about half of those with uraemia, this asso-
ciation is not due to neuropathy [24].
Although chronic venous disease is often noted as a cause
of muscle cramps, the association is not clear-cut, given the
variety of leg symptoms that can occur in such patients. Indeed,
the Bonn Venous Study, a large and meticulous cross-sectional
survey, recently concluded that that muscle cramps should no
longer be considered a venous leg symptom [25]. Similar
issues arise in interpreting the association between leg
cramps and cardiovascular, especially peripheral vascular,
disease noted in some [8, 18] (but not other [14]) studies.
Investigations
A careful history and the absence of clinical signs on exam-
ination remains the mainstay of diagnosis for idiopathic
nocturnal cramps. The history and examination should aim
to exclude other potential causes of leg symptoms such as
restless leg syndrome, muscle strain and claudication and to
identify signs of neurological disease such as weakness,
atrophy and fasciculations. Investigations in those with fre-
quent cramps should include urea, electrolytes, magnesium
and glucose levels and liver and thyroid function tests; other
tests are required only in selected patients.
Pharmacological management
Quinine
Quinine and its derivatives are alkaloids produced from the
bark of the cinchona tree. They reduce the excitability of the
motor end plate to nerve stimulation and have been used for
decades to treat leg cramps. Quinine is also used as a flavouring
in foods and beverages, notably tonic water and bitter lemon;
a standard mixer bottle of tonic water contains 7–14 mg of
quinine depending on the brand [1, 26].
Efficacy
A 2015 Cochrane review identified 23 randomized controlled
trials (RCT) using quinine (median 300 (range 200–500) mg/day)
involving over 1,500 participants, mostly older subjects with
idiopathic nocturnal leg cramps [1]. Compared to placebo,
quinine reduced cramp numbers over a 2-week period by
28% (absolute difference of about 2.5 cramps). Those
receiving quinine had approximately 1 extra day out of 14
without cramps—a 20% reduction. Cramp intensity, measured
on a scale from 1 (mild) to 3 (severe), was reduced by 0.12—a
10% reduction. Although all of these differences were statistically
significant, the 0.12 reduction in cramp intensity was below the
0.16 reduction that would be regarded as the minimal clinically
significant difference on a 3-point quality of life scale [27]. There
was insufficient evidence to judge the optimal dosage or duration
of quinine treatment.
Grouped results may mask the fact that some people
can derive substantial benefit from quinine [2]. N-of-1
trials, in which patients act as their own controls, allow
778
potential benefit for individuals to be assessed. In a series
of N-of-1 trials, in which 10 patients who had been taking
quinine for cramps underwent three double-blind crossover
trials in which they alternated between quinine and placebo
for 4 weeks at a time, quinine was clearly beneficial for only
three participants, six showed a non-significant benefit and
one showed no benefit (although all chose to continue quinine
post-study) [28].
There were no significant differences in the efficacy of
quinine compared to vitamin E alone, to a quinine–vitamin
E combination or to xylocaine injections into the gastrocnemius
muscles [1]. A single study suggested that a quinine–theophylline
Downloaded from https://academic.oup.com/ageing/article-abstract/45/6/776/2499229 by guest on 15 October 2019
combination was significantly better than quinine alone on all
outcome measures [29], although significant methodological
issues have been raised regarding this study [30].
Notwithstanding the generally positive results with quinine,
RCTs of this and other agents suggest that there is often a
marked placebo response [28, 31, 32]. It is possible that this
represents a regression to the mean, perhaps exacerbated by
seasonal changes in cramp frequency [12]. Only one study
has formally examined the effect of discontinuing long-term
treatment with quinine [33]. As part of a trial of stretching
exercises, 94 of 191 patients in general practice who had been
prescribed quinine for night cramps were advised to discon-
tinue this medication. Those receiving this advice were more
than three times more likely (absolute difference 26%) have
stopped quinine at 12 weeks, and cessation was not associated
with any increase in cramp symptoms.
Risks
Quinine use is associated with serious and potentially fatal
immune-mediated reactions, particularly thrombocytopenia
[34, 35, 36]. A 1994 US Food and Drug Administration
(FDA) analysis suggested that thrombocytopenia affects
between 1:1,000 and 1:3,500 quinine users 37; a more recent
estimate suggests an incidence rate of 1.7/1,000 person-years
[34]. Systematic reviews identify quinine as second only to its
stereoisomer quinidine as a cause of drug-induced thrombo-
cytopenia and as the commonest cause of drug-induced throm-
botic macroangiopathy [38]. Such reactions are not dose-
dependent and can follow consumption of quinine-containing
beverages (which also means that the true frequency of quinine-
induced reactions may be underestimated) [39]. Immune-
mediated reactions generally occur within 3 weeks of starting
quinine but can occur later especially with intermittent use [34,
38] (Table 2).
Other complications of quinine are dose-related, and
serum quinine levels are strongly related to the likelihood of
such side effects. Quinine overdose, sometimes inadvertent in
older people, is extremely dangerous and can lead to death due
to cardiac dysfunction and to chronic visual impairment and
blindness [40, 41, 42]. Complications that can arise with thera-
peutic doses of quinine include ‘cinchonism’—a constellation
of symptoms including nausea, vomiting, headache, vertigo, vis-
ual disturbances and tinnitus and hearing impairment. Such
side effects are usually reversible with drug withdrawal.
 Review of nocturnal leg cramps

Table 2. Complications associated with quinine

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

Downloaded from https://academic.oup.com/ageing/article-abstract/45/6/776/2499229 by guest on 15 October 2019

Increased risk of ventricular arrhythmias when used in combination with other drugs that prolong the QT interval such as amiodarone and haloperidol
Increased risk of hypoglycaemia when taken concurrently with hypoglycaemic medications
Increased plasma concentration of digoxin and warfarin

A recent Danish epidemiological study of 1,35,000 heart
failure patients found that quinine was used by more than
10% at some point and was associated with an increased risk
of mortality, especially in those with concomitant beta-blocker
use and early after treatment initiation [43]. Although the
mechanism for this increase in mortality was unclear and, by
definition, such studies cannot exclude all potential con-
founding factors, this was a large and meticulous study and
the conclusion that ‘the risk of quinine being a real danger to
patients with heart failure is very high’ seems reasonable.
The frequency and severity of adverse effects may be
greater in older people since altered pharmacokinetics with
age results in greater absorption, less efficient metabolism,
a substantially longer half-life, higher blood concentrations of
quinine and a greater risk of drug accumulation with chronic
treatment even in healthy older subjects [37, 44, 45, 46]. Even
low-dose quinine in young healthy volunteers causes measure-
able albeit clinically silent deterioration in hearing and in ves-
tibular function testing in many subjects [47, 48]. Older people,
particularly those with pre-existing sensory defects, are likely to
be more sensitive to such effects; conversely, the presence of
existing visual of hearing problems might mask early signs of
quinine toxicity. Finally, many of the drugs that interact with
quinine are most likely to be used by older people.
In the Cochrane meta-analysis, only one subject had a
severe, probably immune-mediated, reaction [1]. There was
a significantly increased risk (absolute difference 3%) of
minor adverse events with quinine compared with placebo:
the only significant risk difference was in gastrointestinal
side effects and the 10-fold increase in tinnitus and 2-fold
increase in visual disturbance did not reach statistical signifi-
cance. The treatment period was, however, only 2 weeks in
most of the trials.
Regulatory responses
The FDA have strongly advised against off-label use of
quinine for leg cramps since 2006 [49, 50], and this has
resulted in a 99% decline in the amount of quinine prescribed
Table 3. Other pharmacological treatments used in treat-
ment of idiopathic muscle cramps
Support from RCT
Diltiazem
Vitamin B complex
Naftidrofuryl
Orphenidrine citrate
Magnesium
Support from open-label studies
Verapamil
Gabapentin
Vitamin K2, menaquinone-7
No supporting studies
Baclofen
Carbamezapine
Phenytoin
in the USA [34]. A similar approach has been taken in Australia
[51] and New Zealand [52]. There are possible undesirable
effects, however, from discouraging the use of quinine including
an increased use of medications with no evidence of benefit in
cramps [53, 54] and an increase in self-medication by patients
using imported quinine tablets or large volumes of beverages
such as tonic water [55].
In the UK and Ireland, regulatory authorities have advised
against the routine use of quinine for leg cramps, although the
use is still permitted in severe cases with careful monitoring and
a trial withdrawal of treatment after 4 weeks [56, 57]. A subse-
quent English study found that quinine prescribing remained
common although substantial reductions were seen in areas
which instigated comprehensive prescribing reviews [41].
Other pharmacological approaches
A meta-analysis of seven RCTs (361 subjects) comparing
magnesium 300–900 mg/day to placebo in the treatment of
nocturnal leg cramps concluded that magnesium was not
an effective treatment for idiopathic cramps but may have a
small positive effect in pregnant women [58] (Table 3).

779
L. Rabbit et al.

Table 4. Recommendations for using quinine for nocturnal leg cramps

Quinine treatment should only be considered if:
• Cramps are frequent or severe or regularly disrupt sleep
• Treatable causes of cramp have been ruled out
• Prophylactic stretching exercises have proved ineffective or would not be practical or safe for the patient
• The clinician and the patient agree that the potential benefits outweigh the risks for that individual
Quinine should not be prescribed if there has been any prior adverse reaction to quinine (including that found in beverages).
When initiating quinine treatment:
• Patients should be warned never to exceed the recommended maximum doses of 300 mg quinine sulphate or quinine bisulphate
• Patients should be warned to stop treatment and consult a physician if symptoms or signs of thrombocytopenia, such as unexplained bruising or bleeding, or of
cinchonism develop
• Particular caution should be exercised in those taking medications that might interact with quinine including warfarin, hypoglycaemic agents, potent CYP3A4
inhibitors and drugs that prolong the QT interval

Downloaded from https://academic.oup.com/ageing/article-abstract/45/6/776/2499229 by guest on 15 October 2019

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

Single RCTs provide some support for the efficacy of
diltiazem 30 mg nocte [59], vitamin B complex [60], naftidro-
furyl (a vasodilator available in some countries for treating
peripheral vascular disease) [61] and orphenadrine citrate (an
anticholinergic medication used as a muscle relaxant in some
countries) [62] in the treatment of muscle cramps. Although
all of these drugs were relatively well tolerated, the trials had
substantial methodological flaws and the numbers of subjects
recruited (13–59) were small [35].
In an open-label study, seven of eight cramp sufferers
refractory to quinine treatment reported an improvement in
cramp symptoms with verapamil 120 mg at night [63]. Other
small open-label studies suggest benefit from gabapentin 600–
1200 mg/day [64] (although a double-blind RCT in 204 MND
patients showed no effect [65]), from the antiarrhythmic drug
disopyramide [66] and from a vitamin K2 subtype [67].
Non-pharmacological Interventions
Cramps can be aborted by stretching the affected muscles
or, using reciprocal inhibition reflexes, by contracting an
antagonistic group of muscles. Thus, for example, forcible
dorsiflexion of the foot with the knee extended can relieve
calf cramps. It has been suggested as a result that prophylactic
stretching might prevent nocturnal leg cramps. Other reported
non-drug interventions include footwear changes, night ankle
dorsiflexion splints, changes to sleeping position, avoidance of
heavy bed covers and folklore remedies such as sleeping with a
horseshoe or potatoes under the mattress [68].
In an uncontrolled study of 44 patients prophylactic
stretching successfully prevented cramp [69]. Subjects were
asked to stand 3 feet from a wall, leaning against it with
arms outstretched and to gently tilt forward with the heels
in contact with the floor until a non-painful stretch was felt
in the calves; this procedure, held for 10 seconds, was
repeated three times a day.
Two RCTs of this approach have now been reported. A
12-week study in 191 patients prescribed quinine for night
cramps failed to show any benefit [33], although participants
were only shown how to do the exercises once and the degree
of compliance with the exercises was unclear [68]. In contrast, a
6-week RCT in 80 subjects, in which a home visit was used to
ensure participants continued to perform the stretches correctly,
found a reduction in the frequency and severity of cramps [70].
Although the degree of benefit in the latter study was comparable
to that in the quinine trials, in a small survey in which cramp suf-
ferers were asked to rate the effectiveness of therapies they had
tried, 3 of 21 who tried prophylactic stretching compared with
16/18 who used quinine reported substantial benefit [2].
Recommendations
Associated conditions and medications should be sought in
those with troublesome or frequent nocturnal leg cramps.
Alternatives should be sought, if feasible, for those receiving
diuretic or LABA medications. There is conflicting evidence
regarding the efficacy of prophylactic stretching exercises, but
these can be considered in suitable patients. While other med-
ications warrant further investigation, quinine remains the
only medication shown to reduce the frequency and intensity
of leg cramps (even in the absence of convincing evidence, a
trial of calcium channel blocker may be justified in those with
cramps and another indication, such as hypertension, for
such treatment). The degree of benefit from quinine is
modest, the quality of evidence is relatively low and there are
significant hazards. These factors suggest that there is no lati-
tude for clinicians to go beyond the recommendation that
treatment should be restricted to those with severe symptoms
and should be subject to regular review (Table 4). Ultimately,
only patients themselves can judge if the risks are justified by
the potential benefits, and informed consent should always be
sought before initiating a trial of treatment.
Key points
• Nocturnal leg cramps are common and troublesome in
older people and have a significant impact on quality of
life.

780

• Diuretic and long-acting beta-agonist therapy predispose
to leg cramps.
• There is conflicting evidence regarding the efficacy of
prophylactic stretching in preventing cramps.
• Quinine remains the only medication proven to reduce
the frequency and intensity of leg cramps.
• Balancing the potential risks and benefits from quinine
requires careful consideration and discussion with the
patient.
Supplementary data
Supplementary data are available in Age and Ageing online.
Conflicts of interest
The authors report no conflicts of interest
Funding
There was no funding for this study.
References
The very long list of references supporting this review has meant
that only the most important are listed here and are represented
by bold type throughout the text. The full list of references is
available in Supplementary data available in Age and Ageing
online
1. El-tawil S, Musa TAl, Valli H, Lunn MPT, El-tawil T, Weber
M. Quinine for muscle cramps (Review). Cochrane Database
Syst Rev 2015; 5: CD005044. DOI: 10.1002/14651858.
CD005044.pub3 (23 July 2016, date last accessed).
2. Blyton F, Chuter V, Burns J. Unknotting night-time muscle
cramp: a survey of patient experience, help-seeking behaviour
and perceived treatment effectiveness. J Foot Ankle Res
2012; 5: 7.
3. Hawke F, Chuter V, Burns J. Impact of nocturnal calf
cramping on quality of sleep and health-related quality of life.
Qual Life Res 2013; 22: 1281–6.
4. Brown TM. Sleep-related leg cramps. Sleep Med Clin 2015;
10: 385–92.
5. Butler JV, Mulkerrin EC, O’Keeffe ST. Nocturnal leg cramps
in older people. Postgrad Med J 2002; 78: 596–8.
8. Naylor R, Young J. A general population survey of leg
cramps. Age Ageing 1994; 23: 418–20.
9. Abdulla A, Jones P, Pearce V. Leg cramps in the elderly:
prevalence, drug and disease associations. Int J Clin Pract
1999; 53: 494–6.
13. Miller TM, Layzer RB. Muscle cramps. Muscle Nerve 2005;
32: 431–42.
15. Katzberg HD. Neurogenic muscle cramps. J Neurol 2015;
262: 1814–21.
19. Garrison SR, Dormuth CR, Morrow RL, Carney G, Khan
KM. Nocturnal leg cramps and prescription use that precedes
Review of nocturnal leg cramps
them: a sequence symmetry analysis. Arch Intern Med 2012;
172: 120–6.
23. Katzberg H, Kokokyi S, Halpern E et al. Prevalence of mus-
cle cramps in patients with diabetes. Diabetes Care 2014; 37:
e17–8.
25. Wrona M, Jöckel KH, Pannier F, Bock E, Hoffmann B,
Rabe E. Association of venous disorders with leg symptoms:
results from the Bonn vein study 1. Eur J Vasc Endovasc
Surg 2015; 50: 360–7.
28. Woodfield R, Goodyear-Smith F, Arroll B. N-of-1 trials of
quinine efficacy in skeletal muscle cramps of the leg. Br J
Gen Pract 2005; 55: 181–5.
31. Jansen PH, Veenhuizen KC, Wesseling AI, de Boo T,
Downloaded from https://academic.oup.com/ageing/article-abstract/45/6/776/2499229 by guest on 15 October 2019
Verbeek AL. Randomised controlled trial of hydroquinine in
muscle cramps. Lancet 1997; 349: 528–32.
33. Coppin RJ, Wicke DM, Little PS. Managing nocturnal leg
cramps—calf-stretching exercises and cessation of quinine
treatment: a factorial randomised controlled trial. Br J Gen
Pract 2005; 55: 186–91.
34. Houstoun M, Reichman ME, Graham DJ et al. Use of an
active surveillance system by the FA to observe patterns of
quinine sulfate use and adverse hematologic outcomes in
CMS Medicare data. Pharmacoepidemiol Drug Saf 2014; 23:
911–7.
35. Katzberg HD, Khan AH, So YT. Assessment: symptomatic
treatment for muscle cramps (an evidence-based review):
Report of the Therapeutics and Technology Assessment
Subcommittee of the American Academy of Neurology.
Neurology 2010; 74: 691–6.
40. Langford NJ, Good AM, Laing WJ, Bateman DN. Quinine
intoxications reported to the Scottish Poisons Information
Bureau 1997–2002: a continuing problem. Br J Clin
Pharmacol 2003; 56: 576–8.
41. Acheampong P, Cooper G, Khazaeli B et al. Effects of
MHRA drug safety advice on time trends in prescribing vol-
ume and indices of clinical toxicity for quinine. Br J Clin
Pharmacol 2013; 76: 973–9.
43. Gjesing A, Gislason GH, Christensen SB et al. Use of quinine
and mortality-risk in patients with heart failure—a Danish
nationwide observational study. Pharmacoepidemiol Drug
Saf 2015; 24: 310–318.
44. Wanwimolruk S, Chalcroft S, Coville P, Campbell A.
Pharmacokinetics of quinine in young and elderly subjects.
Trans R Soc Trop Med Hyg 1991; 85: 714–7.
49. U.S. Food and Drug Administration. Drug safety communi-
cation: new risk management plan and patient medication
guide for qualaquin (quinine sulfate) 2010 http://www.fda.
gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationfor
PatientsandProviders/ucm218202.htm.
53. Fat MJ, Kokokyi S, Katzberg HD. Neurologist practice pat-
terns in treatment of muscle cramps in Canada. J Foot Ankle
Res 2013; 6: 1–2.
56. Medicines and Healthcare Products Regulatory Agency.
Quinine: not to be used routinely for nocturnal leg cramps.
Drug Saf Update 2010; 3: 3–4.
58. Sebo P, Cerutti B, Haller DM. Effect of magnesium therapy
on nocturnal leg cramps: a systematic review of randomized
controlled trials with meta-analysis using simulations. Fam
Pract 2014; 31: 7–19.
59. Voon W, Sheu S. Diltiazem for nocturnal leg cramps. Age
Ageing 2001; 30: 91–2.
781
L. Rabbit et al.

63. Baltodano N, Gallo B, Weidler D. Verapamil vs quinine in
recumbent nocturnal leg cramps in the elderly. Intern Med
1988; 148: 1969–70.
68. Blyton F, Chuter V, Walter KEL, Burns J. Non-drug therapies
for lower limb muscle cramps (Review). Cochrane Database
Syst Rev 2012; 1: CD008496. DOI: 10.1002/14651858.
CD008496.CD008496.pub2 (23 July 2016, date last accessed).
69. Daniel H. Simple cure for nocturnal leg cramps. N Engl J
Med 1979; 301: 216.
70. Hallegraeff JM, van der Schans CP, de Ruiter R, de Greef
MHG. Stretching before sleep reduces the frequency and
severity of nocturnal leg cramps in older adults: a randomised
trial. J Physiother 2012; 58: 17–22.
Received 24 March 2016; accepted in revised form 27 June
2016

Downloaded from https://academic.oup.com/ageing/article-abstract/45/6/776/2499229 by guest on 15 October 2019

782