Table E-1. Data Analysis Table for Clinical Trials in the Treatment of Muscle Cramps

Table e-1. Data analysis table for clinical trials in the treatment of muscle cramps

Treatment,
Dosage / Class (reference) / Cohort
Size,
Completion
Rate
(n; %) / Inclusion,
exclusion
criteria / Study Design / Length / Primary outcome / Efficacy,
effect size / Secondary
Outcomes / Comments
Daily stretching
exercises and
quinine sulfate / II (10) / 191; 95% / Inclusion:
Patients on quinine
for muscle cramps
over the previous 3
months, age >60
Exclusion:
patients with
conditions
preventing
stretching, ie pain,
dementia,
osteoarthritis,
history of
peripheral vascular
disease / Double blind
(using sham
exercise and
pills), head to
head, factorial
randomized
study into 4
groups
involving
combinations
of treatment
with quinine
and stretching
for 6 weeks.
An open label
period
followed also
lasting 6
weeks. / Symptom burden
score, frequency of
cramps, quinine
usage / No effect on
frequency of
cramps, more
patients who
stretched
reduced quinine
usage (odds
ratio 3.32, 95%
CI 1.37-8.06) / Severity of
cramps and
“overall
symptom
burden” from
cramps / This study
was
downgraded to
Class II due to
difficulties in
the blinding
procedures.
Hydroquinine 200
mg at dinner and
100 mg qhs / I (11) / 112; 90% / Inclusion:
At least 3
cramps / week
Exclusion:
History of drug
and alcohol
abuse, allergy,
conflicting
medication / Three
weeks of
run-in, 3
weeks of
treatment,
followed by
3 weeks of
Washout / Cramps, cramp days / 36% decrease
in number of
cramps in
treatment vs
placebo
during study
period.
Decrease in
median
number of
cramps (5 cramps,
95% CI 2-8)
and cramp
days (1 cramp-day, 95%
CI 0-3) in the
treatment
group during
the study
period. / Side effects / 3
400 mg quinine /
Day / I (12) / 109; 90% / Inclusion:
Age 18-70, at
least 6 cramps in
2 weeks
Exclusion :
history of drug
or alcohol
abuse, allergy or
objection to
quinine, patient
is on other
medication
interfering with
analysis / Two
weeks of
run-in, 2
weeks of
treatment, 2
weeks
washout / Reduction in
frequency of
cramps / Reduction in
median
number of
cramps during
study period
in treatment
group (8, 95%
CI 7-10) vs
placebo (6,
95% CI 3-7).
Median
number of
cramps
reduced 25%. / Intensity,
frequency,
pain at
night.
Hydroxyquinine
hydrobromide
300 mg qhs / II (13) / 20; 95% / Inclusion : More
than 3 cramps /
week, otherwise
healthy. / Three 2 week
periods :
run in,
treatment,
wash-out / Mean, number of cramps / There was a
58% decrease
in the mean
number of
cramps in the
treatment
group vs
placebo (mean reduction of 16.1 cramps in treatment group vs mean reduction of 5 cramps in placebo
(p=0.004) / Frequency ,
duration,
severity,
location of
cramps and
side effects. / Trial
downgraded to
Class II
because of
unequal
baseline
characteristics
(number of
cramps
different in
placebo and
treatment
groups)
Quinine sulfate
200 mg at supper
and 300 mg qhs
(500 mg total).
Vitamin E 800
IU. / II (14) / 30; 90 % / Inclusion:
general
medicine walkins
or referrals
with at least 6
cramps / month.
Exclusion: Preexisting
conditions,
medication / Three groups assessed :
quinine,
vitamin E or
placebo after
4 week run-in
phase.
assessments
Three 4
week
treatment
periods
during which
patients
crossed over
in between
treatments
and
separated by
4 week
washout
periods. / Number of
cramps, cramp
severity, sleep
disturbance / Reduction
in the mean
number of
cramps
from 44 in
the run-in
phase to
19.2 ±5.3 in
the
treatment
group and
only 36.6
±6.6 in the
placebo
group
(p=0.0046).
Impact on
sleep
disturbance
and severity
of cramps
also. / None / Study downgraded because baseline characteristics not mentioned in the article
Quinine bisulfate
300 mg qhs / II (15) / 43; 52 % / Inclusion: At
least 2 cramps
per week
Exclusion:
quinine hypersensitivity,
unstable medical
condition, fluids
or electrolyte
imbalance,
exercise induced
cramps / Two
week run in
followed by2
sequential 3
week periods
of treatment
or placebo
(crossed
over) / Cramp frequency and cramp index / Non-significant for all / Quinine blood levels, side effects / Study
downgraded to
Class II
because
baseline
characteristics
not mentioned
and because of
poor
completeness
of follow-up
(52%).
Quinine sulfate 200 mg phs / II (16) / 23; 70% / Typical outpatients with more than 2 cramps per week / Two
weeks of
run-in, 2
weeks of
treatment, 2
weeks of
washout, 2
weeks of
cross-over / Frequency duration and intensity of cramps / Non-significant in all ratings / Side effects / Study
downgraded to
Class II
because
baseline
characteristics
are not
mentioned and
completeness
of follow-up
was poor
Quinine sulfate 200 mg qhs / III (17) / 8; 88 % / Inclusion :
cramps for at
least 1 year, at
least 2 cramps /
week
Exclusion :
Abnormal
bloodwork,
elderly subjects
(age ?) / Four weeks of treatment,
one week
washout, 4
weeks of
cross-over / Number, duration, and severity of cramps / Summary
statistics not
specified in
manuscript,
only
individual
patient raw
data and
p<0.01. / None / Study
downgraded to
Class III due
to lack of
documentation
of baseline
characteristics
and lack of
summary
statistics.
300 mg quinine sulfate / III (18) / 25; N/A / Inclusion:
Inpatients with
at least 2
cramps / week
Exclusion: No
pregnancy, optic
neuritis, tinnitus
or hypocalcemia / Two
weeks of
treatment for
the duration of a hospital stay, however, details of the study design were not given / Severity of
cramps, number of
nights with
cramps, total
number of cramps / Non-significant for all parameters / Side effects / Study
downgraded to
Class III
because
primary
outcome not
clearly
defined, dropouts
were not
accounted for,
baseline characteristics were not mentioned, completeness of follow-up was not documented and blinding and randomization was not detailed.
Quinine sulfate 300 mg qhs / III (19) / 9; N/A / Inclusion:
Patients from
general
practice
population,
cramps with at
least 2
cramps / week
Exclusion: No
cardiac,
hepatic, renal
or mental
disease and
no conflicting
medication / Four
phases
included : 2
weeks run in,
2 weeks
treatment, 2
weeks
washout, 2
weeks
crossover within subjects. / Number of cramps, sleep disturbance, -ramp severity, cramp duration / Number of
cramps
during at
night was
unchanged.
4/9 vs 0/9
patients
were cramp
free on
quinine vs
placebo. / Not mentioned / Study was
downgraded to
Class III
because the
outcomes,
baseline
characteristics,
dropouts,
blinding and
randomization
procedures
were not
detailed. The
patients were
used as their
own controls,
which further
also
automatically
downgrades
the study to
Class III.
Quinine sulfate 300 mg qhs / III (20) / 28; 89% / Patients from 2
practices who
were already on
quinine
regularly.
No other
inclusion /
exclusion
mentioned / Three
day run-in
and 30 day
treatment,
followed by
repeat 3 day
washout and
cross-over of
treatment for
30 days / Number of nights with cramps / Reduction in
nights with
cramps by
50% vs 21%
in placebo
(p<0.01) / None / Study was downgraded to Class III because the inclusion, exclusion criteria, dropouts, baseline characteristics, and blinding procedures not clearly mentioned
Quinine 200 mg
or 300 mg
(different for
different patients) / III (21) / 13; 80% / Inclusion : More
than 4 cramps >
in 2 weeks
during run in
period, ability
to complete
diary
Exclusion:
Hepatic, renal,
electrolyte
abnormality or
medication
interfering with
quinine / 12 weeks of
treatment
(3 treatment
blocks of 4
weeks. Each
4 week
block was
split into 2
weeks of
placebo and
2 weeks of
quinine
treatment) / Daily symptom
diaries, quinine
sulfate/placebo
capsule returns
and plasma
quinine levels / 3 patients
showed
statistically
significant
benefit in
reduction in
number of
cramps
(p,0.05), 6
patients
showed a
trend toward
benefit and 1
patient
showed no
change. / Post-trial interview about continuation of quinine / Study
downgraded to
Class III
because
patients used
as their own
controls.
Gabapentin 3600 mg/day / I (24) / 204; 63% / Inclusion:
Patients aged 18-
51 with ALS < 3
years and FVC
>60%
Exclusion:
1) bulbar patients
2) patients not
taking Riluzole / Nine months
of active
treatment
evaluating
ALS outcome
Measures / Visual analog scale of cramp severity from 0-10 / “not significant” / N/A / These were Class I studies for ALS outcome measures, not cramps outcome measures
Vitamin B complex
(50 mg ursultiamine, 250
ug
hydroxycobalamin,
30 mg pyridoxal
phosphate,
5 mg riboflavin) / II (25) / 28; N/A / Inclusion :
Patients aged > 65,
from hypertension clinic
Exclusion :
secondary
conditions, other
medications,
unstable blood
pressure / Six week
treatment
phase / Severity (as a
composite of
frequency, duration and intensity) of
cramps / 86% of patients
on treatment
underwent remission versus
no change in
outcomes in
placebo group. / Side effects / Study was
downgraded to
Class II due to inadequate description of baseline characteristics and completeness of follow-up.
Naftidrofuryl 300
mg bid equivalent / II (26) / 14; N/A / Inclusion : 2
cramps per week
Exclusion :
secondary causes
of cramps, already
on treatment / Two week
run in perieod,
4 week treatment,
2 week
washout, 4
week crossover / Median number of cramps, cramp free days / Reduced median
number of
cramps (17 vs 5,
p<0.004) and
cramp free days
(22 vs 14,
p<0.004) / Side effects / Downgraded
to Class II due
to inadequate
description of
baseline
characteristics
and lack of comments on follow-up.
Magnesium
300 mg /
day / II (27) / 46; 64% / Non-pregnant volunteers / Six
weeks of
active
treatment / Number and duration of cramps / Trend only
towards less
number of
cramps in the
magnesium
treatment
group. / Perception of whether
medications
help with
symptoms / Study
downgraded to
Class II due to
poor
completion
rate.
Magnesium citrate 900 mg /
day / II (28) / 45; 93% / Inclusion: 6 cramps per week / Four
treatment
phases :
30 days
washout, 30
days
treatment, 30
days repeat
washout, 30
days crossover / Number of cramps / Nonsignificant
for
primary
outcome
measure. / Duration of cramps, severity of cramps, sleep disturbance / Study
downgraded to
Class II
because
baseline
characteristics
not
mentioned.
Diltiazam
hydrochloride 30
mg / II (29) / 13, 93 / Inclusion :
Patients with
cramps more
than 2 times per
week
Exclusion :
Electrolyte
disturbances,2nd
or 3rd degree
atrioventricular
block, sick sinus
syndrome and
congestive heart
failure / Four
phases : 2
weeks of
run-in, 2
weeks of
treatement, 2
weeks of
wash-out
and 2 weeks
of cross-over / Frequency and intensity of muscle cramps / Statistically
significant
decrease in
frequency of
muscle
cramps in
patients on
diltiezam vs
placebo
during
treatment
phases (95%
CI -5.8 to -
0.17).
No effect on
intensity of
cramps. / Side effects / Downgraded due to poor description of baseline characteristics.
Gabapentin
600mg tid,
titrated up to
1200mg tid
depending on
effectiveness of
treatment / IV (30) / 30; 93% / Inclusion :
1) 5 or more
cramps per week
for 1 year
2) no use of
other drugs that
relieve cramps
3) no known
intolerance of
gabapentin. Exclusion:
1)decreased
creatinine
clearance 2)
serious hepatic,
respiratory,
hematologic,
cardiovascular
disease
3) use of drugs
that cause
cramps cramps
4) pregnancy or
lactation
5) electrolyte
imbalances
6) inability to
complete a diary / Three
month
baseline
assessment
followed by
6 months of
Treatment / Frequency of cramps per week / At 2 weeks, 1,
3 and 6
months of
therapy,
patients
taking
gabapentin
had a
significant
decrease in
cramps per week when compared to their pre-treatment frequency / Pain rating scale and sleep rating scale / Classified as
Class IV study
due to the open
label design of
the study.
Verapamil 120 mg qhs / IV (31) / 8, 100 / Inclusion: Elderly
patients with
recumbent
nocturnal cramps,
previously taking
quinine without
success
Exclusion criteria:
muscular
dystrophies, ALS,
spinal nerve
damage, heart
block, recent MI or
dysrhythmia / Eight weeks of
active
treatment / Resolution of cramps / 7 of 8 patients
taking verapamil
had complete
resolution of
cramps / Not mentioned / Classified as Class IV due to open label trial design
Lidocaine
injections vs quinine
sulfate 300 mg qhs / IV (32) / 24; N/A / Patients with
nocturnal calf
cramps and
myofacial trigger
points in the calves / Four
weeks of
treatment and 4
weeks of
follow-up post
treatment / Quantitative
measures of cramps
severity (frequency,
duration, pain
intensity, pain
intensity, cramp
index,pain threshold
of gastrocnemius
muscle) / Statistically
significant
improvements in
all measures of
cramp severity
during treatment
period and
during followup
period
(except pain
threshold for the
latter period) / None / Classified as Class IV due to open label design
Levetiracetam in
escalating doses up
to 3000 mg per day / IV (33) / 20; N/A / Inclusion: Patients
with motor neuron
disease (ALS, PLS
or PMA) and
muscle cramps (at
least 50/100 on a
severity score or
spasticity. Stable
renal function,
stable riluzole dose
Exclusion:
Pregnancy, mental
illness, dementia,
drug abuse, noncompliance / Baseline
parameters evaluated for
3 months,
followed by 9
months of
active
treatment / Cramp-painseverity
score,
cramp-frequency
score.
Modified
Ashworth
Spasticity Score,
Penn Spasm
Score, / Significant
reduction in
cramp severity
and frequency
scores lasting
for the duration
of the trial.
Reduction in
phasic but not
tonic spasticity
observed. / Adverse events,
tolerability,
FVC,
ALSFRS and
MMT scores. / Classified as Class IV due to open label design

Legend : N/A = not available, qhs = every night, ALS = amyotrophic lateral sclerosis, MI = myocardial infarction, tid = three times a day, bid = twice a day, FVC = forced vital

capacity, mg = milligrams, g = grams, ug = micrograms, IU = international units, PLS = primary lateral sclerosis, PMA = progressive muscular atrophy, ALSFRS-R = ALS

functional rating scale, FVC = forced vital capacity, MMT = manual muscle testing