Assessment: Symptomatic treatment for muscle cramps (an evidence-based review)

SPECIAL ARTICLE
Assessment: Symptomatic treatment for
muscle cramps (an evidence-based review)
Report of the Therapeutics and Technology Assessment
Subcommittee of the American Academy of Neurology
Hans D. Katzberg, MD
Ahmir H. Khan, MD
Yuen T. So, MD, PhD
Address correspondence and
reprint requests to American
Academy of Neurology, 1080
Montreal Ave., St. Paul, MN
55116
[email protected]
ABSTRACT
Background: A Food and Drug Administration advisory in 2006 warned against the off-label use
of quinine sulfate and its derivatives in the treatment of muscle cramps. Physicians are faced with
a difficult scenario in choosing a treatment regimen for patients with muscle cramps. This American Academy of Neurology assessment systematically reviews the available evidence on the
symptomatic treatment of muscle cramps.
Methods: A total of 563 potential articles were reviewed, of which 24 met the inclusion criteria of
prospective trials evaluating the efficacy of a particular treatment on muscle cramps as a primary
or secondary outcome.
Results: There are Class I studies showing the efficacy of quinine derivatives for treatment of
muscle cramps. However, the benefit is modest and there are adverse effects from published
prospective trials as well as case reports. There is one Class II study each to support the use of
Naftidrofuryl, vitamin B complex, lidocaine, and diltiazem in the treatment of muscle cramps.
Recommendations: Although likely effective (Level A), quinine derivatives should be avoided for
routine use in the management of muscle cramps because of the potential of toxicity, but in select
patients they can be considered for an individual therapeutic trial once potential side effects are
taken into account. Vitamin B complex, Naftidrofuryl, and calcium channel blockers such as diltiazem are possibly effective and may be considered in the management of muscle cramps (Level
C). Further studies are needed to identify agents that are effective and safe for the treatment of
muscle cramps. Neurology® 2010;74:691–696
GLOSSARY
ALS ⫽ amyotrophic lateral sclerosis; CI ⫽ confidence interval; FDA ⫽ Food and Drug Administration.
Muscle cramps are involuntary, generally painful contractions of a muscle or muscle group. Some patients are
bothered by very frequent and severe muscle cramps
that may be disabling. A cross-sectional prevalence
study of 365 outpatients aged 65 or older in the United
Kingdom reports that 50% of outpatients report frequent cramps.1 Another review of 515 elderly veterans
reports a similar prevalence of 56%, with half having
cramps occurring at least once per week.2 When the
motor system is stressed, either by a neuromuscular disease or by a physiologic stress such as dehydration or
excessive exercise, cramps become more frequent. Muscle cramps are caused by ectopic discharges from nerves
or nerve terminals3; therefore, a variety of neuropathic
conditions such as amyotrophic lateral sclerosis (ALS),
peripheral neuropathies, and cramp-fasciculation syndrome are commonly associated with cramps.4 In addition to neurologic conditions, multiple medical
conditions such as hypomagnesemia, hypocalcemia, hypothyroidism, and renal or liver dysfunction may be the
cause of cramps. Cramps are also frequent during the
last trimester of pregnancy and in athletes such as marathon runners.5,6 When no underlying cause of recurrent
muscle cramps can be identified, they are referred to as
idiopathic muscle cramps, which can be variable in presentation from patient to patient but are usually most
prominent in the lower leg and foot muscles and more
evident at night.
Since early reports in the 1930s and 1940s,7 quinine and its derivatives have been the mainstay of
Supplemental data at
www.neurology.org
From the Stanford University School of Medicine, Palo Alto, CA.
Appendices e-1 through e-4 and table e-1 are available on the Neurology® Web site at www.neurology.org.
Approved by the Therapeutics and Technology Assessment Subcommittee on April 28, 2009; by the Practice Committee on July 1, 2009; and by the
AAN Board of Directors on November 9, 2009.
Disclosure: Author disclosures are provided at the end of the article.
Copyright © 2010 by AAN Enterprises, Inc.
691
therapy for idiopathic muscle cramps. However, a
United States Food and Drug Administration (FDA)
Federal Register statement released on December 15,
2006, ordered unapproved quinine drugs to be removed from the market and cautioned consumers
about their “off-label” use, citing “665 reports of adverse events with serious outcomes associated with
quinine use, including 93 deaths” since 1969.8 Quinine sulfate, in particular Qualaquin®, is the only
FDA-approved drug for the treatment of plasmodium falciparum malaria. Use of the drug for any
other indication, including muscle cramps, is unapproved. In addition to quinine, a number of other
agents have been studied in the treatment of muscle
cramps, including antiepileptics, calcium channel
blockers, and various vitamins, supplements, and
minerals. This assessment addresses the available evidence on the efficacy as well as possible adverse effects of symptomatic treatment of idiopathic muscle
cramps.
DESCRIPTION OF THE ANALYTIC PROCESS
The main search strategy was a comprehensive search
of MEDLINE and EMBASE from 1950 to May 31,
2008, using the search term “muscle cramp” limited
to keywords “therapy,” “drug therapy,” and “prevention and control,” which yielded 558 results in 4 languages (including French, German, Spanish, and
English). Additional articles were identified by crossreferencing bibliographies from meta-analyses, review articles, and case reports identified in the initial
search, which yielded 5 additional articles. “Muscle
cramp” was defined as a sustained, generally painful,
involuntary contraction of a muscle or muscle group.
“Cramps” alone was not used as a search term due to
excessive articles on gynecologic and gastrointestinal
cramps.
The abstracts and titles from the 563 articles identified were reviewed, and a study was included if it
was a prospective clinical trial with effect on muscle
cramps as a primary or secondary outcome. Exclusion criteria were 1) review articles, 2) meta-analyses,
3) case reports or case series that did not involve a
treatment, 4) phenomena not consistent with muscle
cramps, such as muscle spasms, dystonia, or muscle
pains, 5) pregnancy-induced cramps, 6) medical conditions such as hemodialysis and cirrhosis, and 7)
cramps due to extreme physiologic stress such as excessive exercise, heat, or dehydration. Cramps secondary to medical conditions were excluded from
this analysis because the mechanisms underlying the
formation of cramps and often the treatment directed to correct them are distinct from the routine
treatment of muscle cramps, and most treatment tri692
Neurology 74
February 23, 2010
als assessing idiopathic cramps also excluded these
conditions. Muscle cramps due to myopathies were
also excluded due to the distinct underlying mechanisms. Articles excluded after initial review of the
563 titles and abstracts included 13 articles on hemodialysis, 6 articles on cirrhosis, 4 articles on physiologically induced cramps, 11 articles on pregnancy,
39 review articles, and 10 case reports without treatments (total 63 articles). Upon further review, 450
articles were excluded as they were letters or types of
publications other than clinical trials or did not deal
with muscle cramps or therapy. A total of 50 potential studies were identified for full review. Full review
of the articles led to further exclusion of 26 articles
that were review articles, letters, or repeat publications of the same clinical trials. The remaining 24
articles were chosen for inclusion in the final review,
including one article dealing with nonpharmacologic
therapy, 5 open-label pharmacologic trials, and 18
randomized pharmacologic trials.
The final 24 articles involving symptomatic treatment of cramps were distributed to all 3 panel members for critical analysis and classification. Each
member of the panel made an independent determination of class of evidence and a final meeting was called
to discuss the articles and resolve differences. Data regarding cohort size, completion rate, inclusion and exclusion criteria, treatment and dosage, design of the
study, length of study, primary and secondary outcomes, efficacy, and effect size were extracted from each
article and tabulated (table e-1 on the Neurology® Web
site at www.neurology.org). Each article was classified
according to the American Academy of Neurology therapeutic classification of evidence scheme (appendix e-3)
and recommendations were based on the level of evidence (appendix e-4).
ANALYSIS OF EVIDENCE Question 1: Are there
effective nonpharmacologic treatments for muscle
cramps? Many nonpharmacologic therapies are em-
ployed by patients prior to prescription treatment,
but there is little evidence to support the use of any of
them. Hydration, particularly for exercise-associated
cramping, is frequently used by patients; however,
there are no formal studies supporting its use. An
open-label (Class IV) study from 1979 suggested that
stretching affected muscles 3 times a day could reduce cramping.9 A randomized Class II study of 191
patients compared patients who stretched their calves
3 times a day to patients instructed in a sham exercise
that involved moving the legs without stretching and
found no benefit of stretching on the frequency of
cramps or number of cramp-free nights.10 This trial
was limited because it had acknowledged difficulties
maintaining good patient blinding, and the control
patients were given sham exercises that could theoretically provide some benefit.
Conclusion. Data are insufficient to draw any conclusion on the efficacy of calf stretching in reducing
the frequency of muscle cramps.
Recommendation. None (Level U).
Question 2: Is quinine effective in the treatment of
muscle cramps? Thirteen studies were found involv-
ing quinine or quinine derivatives: 2 Class I studies
showing efficacy,11,12 4 Class II studies (2 showing
efficacy and 2 showing lack of efficacy),13-16 5 Class
III studies (2 showing efficacy and 3 showing lack of
efficacy),17-21 and 1 Class IV study showing efficacy.22
Only the Class I and II studies are discussed below.
Class I studies. A randomized trial in 1997 assessed
the efficacy of hydroquinine hydrobromide dihydrate 300 mg at night in 112 patients.11 The trial
showed a greater reduction in median number of
cramps in treated patients compared to placebo (5
fewer cramps, 95% confidence interval [CI] 2– 8
cramps) and a reduction of cramp days in treated
patients compared to placebo (1 fewer cramp day,
95% CI 0 –3 cramp days) during the 3-week study
period. The mean number of cramps was reduced by
37%. Another Class I study (n ⫽ 109) using 400 mg
of quinine showed a modest though significant reduction in the median number of cramps between
the run-in and treatment phases (8 cramps, 95% CI
7–10 cramps vs 6 cramps, 95% CI 3–7 cramps).12
The median number of cramps was reduced by 25%.
One criticism of this trial was the restrictive inclusion
criteria, which excluded patients above age 70 (who
are often the patients with difficult-to-treat muscle
cramps).
Class II studies. All 4 Class II studies involved small
cohorts (20 – 43 patients) and none addressed sample
size and power calculation.13-16 Two showed efficacy
but were limited by inadequate description of baseline characteristics of the treatment and placebo
groups,13,14 which does not allow for a fair comparison between the groups and does not control for the
potential of inadequate randomization. A trial published in 1994 showed a significant decrease in the
mean number of cramps in the group treated with
hydroquinine hydrobromide 300 mg in the treatment phase compared to the run-in phase (16.1
cramps, SD 14.7 cramps), whereas the placebo group
did not (5 cramps, SD 16.3 cramps).13 A second
Class II study found a significant reduction in the
mean number of cramps from 44 in the run-in phase
to 19.2 ⫾ 5.3 in the treatment group (500 mg quinine sulfate at night) and from 44 to 36.6 ⫾ 6.6 in
the placebo group ( p ⫽ 0.0046). There were also
beneficial effects on the number of nights with
cramps and sleep disturbance.14
Two other Class II studies were limited by poor
patient compliance and low completion rates of 52%
and 70%.15,16 Neither showed a significant effect of
quinine sulfate (200 –300 mg qhs quinine sulfate) on
frequency or intensity of muscle cramps.
Adverse effects of quinine and its derivatives. Common
and serious side effects reported in the literature as
case reports or series as well as all side effects identified in the 13 studies are listed in the table. A total of
10 minor and 11 serious side effects were identified; the
most consistently reported minor side effects were cinchonism (headache and tinnitus) and bitter taste. The
most common serious side effects reported were hematologic abnormalities such as hemolytic uremic
syndrome–thrombotic thrombocytopenia purpura, disseminated intravascular coagulation, and bleeding diathesis. There were no reports of cinchonism leading to
deafness. The frequency of any serious side effect from
the studies published in this review was 2% to 4%. We
did not find any reports of fatalities from quinine sulfate
in any of the studies reviewed in this article. A recent
FDA statement reports 93 fatalities and 663 serious adverse events related to quinine; however, no details regarding these events are available for general review.8
Although inclusion of all references for case reports is
outside the scope of this article, an article that overviews
the majority of common and serious side effects of quinine is referenced here.23
Conclusion. On the basis of data from 2 Class I studies, quinine derivatives are effective in reducing the frequency of muscle cramps, although the magnitude of
benefit is small. Moreover, these agents are associated
with serious though uncommon side effects.
Recommendation. Although likely effective (Level
A), the use of quinine derivatives for treatment of
muscle cramps should be avoided for routine treatment of cramps. These agents should only be considered when cramps are very disabling, no other agents
relieve symptoms, and there is careful monitoring of
side effects. They should only be used after informing the patient of the potentially serious side effects.
Question 3: Are there any other pharmacologic treatments effective for the treatment of muscle cramps?
Class I studies. A double-blind randomized con-
trolled trial of 3,600 mg per day of gabapentin in 204
patients with ALS evaluated muscle cramps (among
other symptoms such as fasciculations, stiffness,
sleeping, and emotionality) using a severity score from
0 to 10 and found no difference between treatment
and placebo with respect to any symptom score.24
Class II studies. A Class II study of 28 patients in
1998 showed that vitamin B complex (including 30
mg per day of vitamin B6) induced remission of
muscle cramps in 86% of treated patients who were
not known to be vitamin deficient compared to plaNeurology 74
February 23, 2010
693
Table
Reported side effects in case reports and prospective trials using
quinine sulfate or derivatives
Risk
Exposure
Class
(reference)
SER
Typical dosage (300 mg PO qhs)
IV
1/49 (2%)
300 mg hydroquinine/day
I (11)
1/23 (4%)
200 mg quinine sulfate qhs
II (16)
Hypoglycemia
SER
Typical dosage (300 mg PO qhs)
IV
Vision loss (retinal
toxicity)
SER
Typical dosage (300 mg PO qhs)
IV
Hepatotoxicity
SER
Typical dosage (300 mg PO qhs)
IV
Cardiac arrhythmias
SER
Typical dosage (300 mg PO qhs)
IV
1/49 (2%)
300 mg hydroquinine/day
I (11)
Acute pulmonary edema
SER
Typical dosage (300 mg PO qhs)
IV
Acute hypersensitivity
reaction
SER
Typical dosage (300 mg PO qhs)
IV
1/30 (3%)
500 mg/day, mention rest of
rxns not doc
II (14)
Psychosis
SER
Typical dosage (300 mg PO qhs)
IV
Abortion
SER
Typical dosage (300 mg PO qhs)
IV
Esophagitis
SER
Typical dosage (300 mg PO qhs)
IV
SER
Typical dosage (300 mg PO qhs)
IV
Side effects
Serious
HUS-TTP with DIC,
HUS-TTP with acral
necrosis, pancytopenia,
thrombocytopenia, bleeding
diathesis
Minor
Photosensitivity reactions,
blurry vision
Cinchonism
1/8 (12.5%)
200 mg quinine sulfate qhs
II (17)
SER
Typical dosage (300 mg PO qhs)
IV
1/8 (12.5%)
200 mg quinine sulfate qhs
II (17)
1/49 (2%)
300 mg hydroquinine/day
I (11)
1/47 (2%)
400 mg quinine sulfate/day
I (12)
Hyperpigmentation, lichen
planus
SER
Typical dosage (300 mg PO qhs)
IV
Bitter taste, dry mouth
10/49 (20%)
300 mg hydroquinine/day
I (11)
3/20 (15%)
Hydroxyquinine hydrobromide
300 mg qhs
II (13)
10/49 (20%)
300 mg hydroquinine/day
I (11)
1/20 (5%)
Hydroxyquinine hydrobromide
300 mg qhs
II (13)
Headache
5/49 (10%)
300 mg hydroquinine/day
I (11)
Dizziness
3/49 (6%)
300 mg hydroquinine/day
I (11)
1/23 (4%)
200 mg quinine sulfate qhs
II (16)
Tremor
2/49 (4%)
300 mg hydroquinine/day
I (11)
Itching
2/49 (4%)
300 mg hydroquinine/day
I (11)
Tingling
1/20 (5%)
Hydroxyquinine hydrobromide
300 mg qhs
II (13)
Gastrointestinal related,
nausea and vomiting
Abbreviations: DIC ⫽ disseminated intravascular coagulation; HUS-TTP ⫽ hemolytic uremic syndrome–thrombotic thrombocytopenia purpura; SER ⫽ single event reported, no statistics available.
cebo, but the completion rate and compliance were
not detailed in the study.25 The use of severity as an
outcome measure is also questionable, as almost all
other trials use the frequency of cramps as the major
694
Neurology 74
February 23, 2010
outcome measure. A small Class II study using Naftidrofuryl 300 mg BID in 14 patients showed efficacy
in the reduction of cramps, but dropouts were not
adequately accounted for.26 Naftidrofuryl oxalate is a
drug that may enhance utilization of oxygen and glucose in peripheral vascular disease and protection of
brain parenchyma during anoxia; it is not available
for use in the United States. A trial (n ⫽ 27) evaluated the efficacy of vitamin E 800 U qhs vs placebo
and found no effect on the mean number of cramps,
number of nights with cramps, or sleep disturbance.14 A Class II study using magnesium citrate
(900 mg) with a sample size of 58 calculated to detect
25% reduction in cramp frequency at a power of
80% could not conclude that there was a significant
improvement in the number of cramps in patients on
treatment ( p ⫽ 0.07),27 and further had a high dropout rate (64%). Another Class II study evaluating the
efficacy of magnesium sulfate (dose 300 mg of Mg)
with a sample size of 42 calculated to detect 25%
reduction in cramp frequency at a power of 90%
found that treatment was not superior to placebo for
number of cramps, severity, duration, or sleep disturbance.28 A Class II, double-blind, crossover study of
13 patients studied the effects of 30 mg of diltiazem
hydrochloride on the number and intensity of
cramps in patients experiencing 2 or more cramps
per week. The trial showed a reduction (⫺5.84 to
⫺0.16 cramps per 2-week treatment phase, p ⫽
0.04) in the number of cramps over time in patients
treated with diltiazem compared to placebo, with no
effect on the intensity of cramps.29
Open-label studies. Thirty patients treated with
gabapentin for 9 months showed a decrease in frequency of cramps in an open-label, unblinded
study.30 Eight elderly patients refractory to quinine
for treatment of cramps showed response to verapamil in a small open-label study.31 A small study
(n ⫽ 24) of lidocaine injected directly into the calf
was shown to be as effective as quinine in reducing
cramps, but there are practical limitations of this
mode of administration.32 A recent open-label study
on the use of levetiracetam in 20 patients with motor
neuron disease showed a reduction in the frequency
and severity of muscle cramps over placebo in the 9
months of treatment compared to the 3-month
run-in period.33
It is worthwhile to note that although agents such
as baclofen, carbamazepine, and oxcarbazepine are
frequently used in clinical practice for the management and treatment of muscle cramps, there are no
clinical trials in the literature evaluating their efficacy
for this indication. A few case reports and reviews
commenting on the efficacy of some of these agents
in the treatment of particular neuropathic conditions
(such as cramp-fasciculation syndrome) have been
published.34,35
Also of note, variable amounts of quinine derivatives are present in consumer products such as tonic
water. Although there are a few case reports reporting
their efficacy in treatment of muscle cramps, there
are insufficient data to allow a specific comment on
their use.36
Adverse events. No serious side effects occurred in
trials evaluating gabapentin, vitamin B complex, diltiazem, and magnesium for treatment of muscle
cramps. Minor side effects such as lightheadedness,
nausea, and abdominal discomfort occurred infrequently and with equal frequency in controls and
treatment groups in trials of vitamin B25 and magnesium.27,28 Diarrhea was equally common (10%) in
magnesium- and placebo-treated patients in one
trial27 and slightly more frequent in magnesiumtreated patients (30% vs 17%, p ⫽ 0.1) in another
trial.28 Minor side effects that occurred more frequently
with gabapentin treatment included lightheadedness,
drowsiness, falls, and limb swelling24 and with Naftidrofuryl treatment included mild gastrointestinal discomfort.26 A small trial of diltiazem did not report any
side effects in treated or placebo patients.29
Conclusion. On the basis of single Class II studies,
Naftidrofuryl, vitamin B complex, and diltiazem are
possibly effective in the treatment of muscle cramps.
Naftidrofuryl is currently not available in the United
States. Data regarding the use of magnesium preparations (2 Class II studies) and gabapentin (1 study
in ALS) show that these agents are probably not effective in the treatment of muscle cramps.
Recommendation. Naftidrofuryl, diltiazem, and vitamin B complex may be considered for the treatment of muscle cramps (Level C).
RECOMMENDATIONS FOR FUTURE RESEARCH Given the lack of evidence for any con-
vincing treatments for muscle cramps, further
research is indicated. Further investigations into the
efficacy and adverse effects of medications such as
baclofen, carbamazepine, oxcarbazepine, levetiracetam, lidocaine, vitamin B complex, Naftidrofuryl,
gabapentin, magnesium, and calcium channel blockers are warranted. Future studies should also include
an assessment of the impact of cramps on the quality
of life and nonpharmacologic interventions in the
treatment of muscle cramps.
DISCLOSURE
Dr. Katzberg has received funding for travel from the Muscular Dystrophy
Association. Dr. Khan reports no disclosures. Dr. So receives royalties from
the publication of Occupational & Environmental Medicine (Appleton &
Lange, 2007) and articles published in UpToDate (2007); receives research
support from Pfizer Inc, NeurogesX, Inc., and the NIH (NIEHS R01 [Co-I],
NIEHS R01 [Co-I], and NINDS R01 [Site PI]); estimates 10% of his clinical
effort is spent on EMG; and holds equity in Satoris, Inc.
DISCLAIMER
This statement is provided as an educational service of the American
Academy of Neurology. It is based on an assessment of current scientific
and clinical information. It is not intended to include all possible proper
methods of care for a particular neurologic problem or all legitimate criteria for choosing to use a specific procedure. Neither is it intended to
exclude any reasonable alternative methodologies. The AAN recognizes
that specific patient care decisions are the prerogative of the patient and
the physician caring for the patient, based on all of the circumstances
involved.
CONFLICT OF INTEREST
The American Academy of Neurology is committed to producing independent, critical and truthful clinical practice guidelines (CPGs). Significant efforts are made to minimize the potential for conflicts of interest to
influence the recommendations of this CPG. To the extent possible, the
AAN keeps separate those who have a financial stake in the success or
failure of the products appraised in the CPGs and the developers of the
guidelines. Conflict of interest forms were obtained from all authors and
reviewed by an oversight committee prior to project initiation. AAN limits the participation of authors with substantial conflicts of interest. The
AAN forbids commercial participation in, or funding of, guideline
projects. Drafts of the guideline have been reviewed by at least three AAN
committees, a network of neurologists, Neurology® peer reviewers and
representatives from related fields. The AAN Guideline Author Conflict
of Interest Policy can be viewed at www.aan.com.
Received July 23, 2009. Accepted in final form November 9, 2009.
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hyperexcitable peripheral nerve disorder. Neurology 1991;
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Endorsed by the American Association of Neuromuscular & Electrodiagnostic Medicine.
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Neurology 74
February 23, 2010
AAN Summary of Evidence-based Guideline for PATIENTS and their FAMILIES
DRUG TREATMENTS FOR SYMPTOMS
OF MUSCLE CRAMPS
This fact sheet may help you understand which drugs are the best choices for treating symptoms of muscle cramps.
Neurologists from the American Academy of Neurology are doctors who identify and treat diseases of the brain and nervous
system. The following evidence-based information* is provided by experts who carefully reviewed all available scientific studies
on drugs for treating muscle cramps.
There are several drugs available to treat symptoms of muscle cramps. However, more research is needed on their safety and
effectiveness. If you have muscle cramps, it is important to see your doctor to find out the cause.
Muscle cramps due to menstruation (monthly periods) or to kidney or muscle diseases are not discussed here.
What is a muscle cramp?
A muscle cramp is a contraction (tightening) of the muscle.
This contraction often is painful and can be caused by
movement. The contraction also is involuntary. This means
the muscle tightens without the person’s control. The
cramping causes the muscle to feel hard. The muscle often
seems to be bulging. The cramps can affect one muscle
or a group of muscles. Muscle cramps differ from muscle
twitches. Twitches are slight movements in a small area
of a muscle.
Many people experience muscle cramps. For some, the
cramps happen often and are very severe. For these people,
muscle cramps can be disabling.
Muscle cramps have many causes. The main causes are
dehydration (not enough fluid in the body), heavy exercise,
or muscle fatigue or tiredness. Other causes include
alcoholism, drug use, pregnancy, or poor nutrition.
However, the cause is not always known.
In some cases, muscle cramps are a sign of a more serious
problem. Talk with your doctor to find out more about
possible causes.
What drugs help treat muscle cramps?
There are several drugs available to treat symptoms of muscle
cramps. There is weak evidence that naftidrofuryl, diltiazem,
and vitamin B complex may help treat these symptoms.
However, as of February 2010, naftidrofuryl is not available
in the United States.
There are no serious side effects of these drugs. Studies
reported some mild side effects, such as lightheadedness,
nausea (upset stomach), and diarrhea. Mild indigestion from
naftidrofuryl use also has been reported. Research shows
magnesium supplements and gabapentin likely are not
helpful treatments.
Strong evidence shows that the quinine drug family helps to
treat symptoms of muscle cramps. However, quinine poses a
risk of serious side effects. These include blood and kidney
problems. These risks are serious but uncommon. Milder
risks include headache, sweating, blurred vision, and ringing
of the ears.
In December 2006, the US Food and Drug Administration
(FDA) issued a news release on risks of quinine use. The
release warns against using quinine for leg cramps. The
release also reports that 93 deaths since 1969 occurred from
quinine use. To learn more, go to www.fda.gov/NewsEvents/
Newsroom/PressAnnouncements/2006/ucm108799.htm.
Due to these risks, quinine generally should be avoided.
Doctors should prescribe this drug only in special cases.
Quinine should be considered only when cramp symptoms
are very disabling and other drugs have not helped. Also,
people considering quinine should be informed of possible
risks. Anyone taking quinine should be monitored for serious
side effects.
More research is needed on the safety and effectiveness of
all these drug treatments. Such studies also should focus on
how muscle cramps affect a person’s quality of life.
Are there therapies that help with
muscle cramps?
Some health experts recommend stretching muscles to
relieve cramping. However, there is not enough evidence
to show if therapies such as stretching are helpful. Future
studies of muscle cramps should look at how useful such
therapies are.
This statement is provided as an educational service of the American Academy of Neurology. It is based on an assessment of current scientific and clinical information. It is
not intended to include all possible proper methods of care for a particular neurologic problem or all legitimate criteria for choosing to use a specific procedure. Neither is it
intended to exclude any reasonable alternative methodologies. The AAN recognizes that specific patient care decisions are the prerogative of the patient and the physician
caring for the patient, based on all of the circumstances involved.
*After the experts review all of the published research studies, they describe the strength of the evidence supporting each recommendation:
Strong evidence = more than one high-quality scientific study
Good evidence = at least one high-quality scientific study or two or more studies of a lesser quality
Weak evidence = the studies, while supportive, are weak in design or strength of the findings
Not enough evidence = either different studies have come to conflicting results or there are no studies of reasonable quality
©2010 American Academy of Neurology
Copies of this summary and additional companion
tools are available at www.aan.com or through
AAN Member Services at (800) 879-1960.
1080 Montreal Avenue • St. Paul, MN 55116
www.aan.com • (651) 695-1940
AAN Summary of Evidence-based Guideline for CLINICIANS
Symptomatic Treatment for
Muscle Cramps
This is a summary of the American Academy of Neurology (AAN) guideline (Neurology ® 2010; 74:691–696) regarding symptomatic treatment for
muscle cramps.
Please refer to the full guideline at www.aan.com for more information.
NONPHARMACOLOGIC TREATMENTS
Are there effective nonpharmacologic treatments for muscle cramps?
Insufficient evidence Data are insufficient to support or refute the efficacy of calf stretching in reducing the frequency of muscle cramps (Level U†).
PHARMACOLOGIC TREATMENTS
Is quinine effective in the treatment of muscle cramps?
Strong evidence
Although likely effective (Level A), the use of quinine derivatives for treatment of cramps should be avoided for routine
treatment of cramps. These agents should only be considered when cramps are very disabling, no other agents relieve
symptoms, and there is careful monitoring of side effects. They should only be used after informing the patient of the
potentially serious side effects.
Are there any other pharmacologic treatments effective for the treatment of muscle cramps?
Weak evidence
Naftidrofuryl, diltiazem, and vitamin B complex may be considered for the treatment of muscle cramps (Level C).
Classification of Recommendations: A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified
population. (Level A rating requires at least two consistent Class I studies.)* B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given
condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.) C = Possibly effective, ineffective or harmful (or possibly useful/
predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.) U = Data inadequate
or conflicting; given current knowledge, treatment (test, predictor) is unproven.
†
*In exceptional cases, one convincing Class I study may suffice for an “A” recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit
of the confidence interval is >2).
Classification of Evidence for Studies of Therapeutic Intervention: Class I = A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome
assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment
for differences. The following are also required: a. concealed allocation, b. primary outcome(s) clearly defined, c. exclusion/inclusion criteria clearly defined, d. adequate accounting for
dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias, e. for noninferiority or equivalence trials
claiming to prove efficacy for one or both drugs, the following are also required**: 1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for
equivalence or noninferiority. 2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug,
the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective). 3. The inclusion and exclusion criteria for patient selection and the outcomes
of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment. 4. The interpretation of the results of the study is based upon a
per protocol analysis that takes into account dropouts or crossovers. Class II = A randomized controlled clinical trial of the intervention of interest in a representative population with masked or
objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets
b–e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. Class III = All other
controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently
derived by objective outcome measurement.*** Class IV = Studies not meeting Class I, II or III criteria including consensus or expert opinion.
**Note that numbers 1–3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.
***Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative
outcome data).
This is an educational service of the American Academy of Neurology. It is designed to provide members with evidence-based guideline recommendations to assist the decision making in
patient care. It is based on an assessment of current scientific and clinical information and is not intended to exclude any reasonable alternative methodologies. The AAN recognizes that specific
patient care decisions are the prerogative of the patient and the physician caring for the patient, and are based on the circumstances involved. Physicians are encouraged to carefully review the
full AAN guidelines so they understand all recommendations associated with care of these patients.
©2010 American Academy of Neurology
Copies of this summary and additional companion
tools are available at www.aan.com or through
AAN Member Services at (800) 879-1960.
1080 Montreal Avenue • St. Paul, MN 55116
www.aan.com • (651) 695-1940
Hans Dieter Katzberg Discusses New Guideline on Symptomatic
Treatment for Muscle Cramps
The AAN has published a new guideline on symptomatic treatment for
muscle cramps. The guideline recommends that the drug quinine, although
effective, be avoided for treatment of routine muscle cramps due to
uncommon but serious side effects. Lead guideline author Hans D.
Katzberg, MD, spoke with Neil A. Busis, MD, FAAN, AAN.com Practice
& Technology Website Associate Editor.
AAN.com: Please tell us about the 2006 Food and Drug Administration advisory that warned
against the off-label use of quinine sulfate and its derivatives in the treatment of muscle
cramps.
Katzberg: In December 2006, the FDA issued a statement ordering unapproved quinine
drugs to be pulled off the market and warning consumers against the use of these drugs for
the treatment of muscle cramps. The reason for the statement was 663 reports of serious
adverse events (the main ones being hematologic events such as idiopathic thrombocytopenic
purpura (ITP), or thrombotic thrombocytopenic purpura (TTP)), as well as 93 deaths
attributed to quinine drugs reported since 1969. The FDA stated that these harms outweighed
any potential benefit from the medication for use in treatment of muscle cramps. This
statement has now made it onto a boxed warning for quinine sulfate, which is still
manufactured in limited amounts and indicated only for the treatment of plasmodium
falciparum malaria in the United States.
AAN.com: What is the purpose of this AAN clinical practice guideline?
Katzberg: To educate physicians and the public on the role of quinine for treatment of
muscle cramp symptoms and to increase knowledge of alternative symptomatic treatments
for muscle cramps. By highlighting the lack of available evidence, we also hope to encourage
research on alternative treatments for muscle cramps.
AAN.com: Who is the target audience?
Katzberg: Health care providers who treat patients with muscle cramps as well as patients
with muscle cramps and their families and caregivers.
AAN.com: What are the main conclusions of these new guidelines?
Katzberg: First, there are several drugs available to treat muscle cramp symptoms, but more
research is needed on their safety and effectiveness. Also, we found evidence that quinine
drugs effectively treat muscle cramp symptoms, but should be generally avoided due to
uncommon but serious side effects.
1080 Montreal Avenue • St. Paul, Minnesota 55116 • tel: 651.695.1940 • fax: 651.695.2791 • www.aan.com
AAN.com: How should these guidelines be used in clinical practice?
Katzberg: Physicians should be aware that disabling muscle cramps may be due to a number
of medical or neurologic conditions, which should be ruled out before diagnosing someone
with idiopathic cramps. When symptomatic treatment is required, a number of drugs included
in our review may be used, including calcium channel blockers and vitamin B complex.
Quinine drugs should be considered only in special cases: when cramp symptoms are very
disabling, when other drugs don't help, and when side effects are carefully watched.
AAN.com: Class I studies showed the efficacy of quinine derivatives for treatment of muscle
cramps. However, their benefit was modest. Please explain.
Katzberg: In the two Class I studies identified, there was a reduction of approximately 25 to
40 percent in number of muscle cramps, which translated into a reduction of two to five
cramps per three-week treatment phase: this is significant, but it does not eliminate or even
nearly eliminate muscle cramps.
AAN.com: There were significant adverse effects from quinine derivatives in published
prospective trials as well as case reports. What were they?
Katzberg: The significant major side effects from quinine drugs were hematological
abnormalities such as hemolytic uremic syndrome-thrombotic thrombocytopenia purpura
(HUS-TTP), disseminated intravascular coagulation (DIC), and bleeding diathesis. Less
common side effects included hypoglycemia, retinal toxicity, hepatotoxicity, cardiac
arrhythmias, pulmonary edema, and hypersensitivity reactions.
AAN.com: The guidelines recommended against routine use of quinine derivatives for the
management of cramps, but in select patients it can be considered for an individual
therapeutic trial. How do you recommend clinicians work through this decision process?
Katzberg: We recommend that clinicians use any of the alternate medications listed in the
practice parameter that have some evidence for efficacy in the management of muscle
cramps. If a patient is experiencing significant disability from cramps and is still refractory to
these treatments, a trial of quinine drugs may be warranted if the patient is aware of all the
potential side effects, including death, associated with their use.
AAN.com: What are the roles of vitamin B complex, naftidrofuryl, and calcium channel
blockers such as diltiazem in the management of cramps?
Katzberg: Diltiazem and vitamin B complex each have Level C evidence and are acceptable
medications as first and second line treatment of symptomatic muscle cramps. Naftidrofuryl
also has Level C evidence for treatment of muscle cramps; however, it is not available for
use in the United States.
1080 Montreal Avenue • St. Paul, Minnesota 55116 • tel: 651.695.1940 • fax: 651.695.2791 • www.aan.com
Author Disclosure
Within the past 24 months, Dr. Busis received personal compensation for his work as
AAN.com Practice and Technology Editor, as well as for speaking at AAN and AANEM
courses. In the same period, he served as Editorial Advisor for Neurology Coding Alert. He
has also given expert testimony on coding issues.
1080 Montreal Avenue • St. Paul, Minnesota 55116 • tel: 651.695.1940 • fax: 651.695.2791 • www.aan.com
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