Schreiber JU, Lysakowski C, Fuchs-Buder T, Tramer MR. Prevention of succinylcholine-induced fasciculation and myalgia: a metaanalysis of randomized trials

Article (PDF Available)inAnesthesiology 103(4):877-84 · October 2005with448 Reads
DOI: 10.1097/00000542-200510000-00027 · Source: PubMed
Abstract
Fifty-two randomized trials (5,318 patients) were included in this meta-analysis. In controls, the incidence of fasciculation was 95%, and the incidence of myalgia at 24 h was 50%. Nondepolarizing muscle relaxants, lidocaine, or magnesium prevented fasciculation (number needed to treat, 1.2-2.5). Best prevention of myalgia was with nonsteroidal antiinflammatory drugs (number needed to treat, 2.5) and with rocuronium or lidocaine (number needed to treat, 3). There was a dose-dependent risk of blurred vision, diplopia, voice disorders, and difficulty in breathing and swallowing (number needed to harm, < 3.5) with muscle relaxants. There was evidence of less myalgia with 1.5 mg/kg succinylcholine (compared with 1 mg/kg). Opioids had no impact. Succinylcholine-induced fasciculation may best be prevented with muscle relaxants, lidocaine, or magnesium. Myalgia may best be prevented with muscle relaxants, lidocaine, or nonsteroidal antiinflammatory drugs. The risk of potentially serious adverse events with muscle relaxants is not negligible. Data that allow for a risk-benefit assessment are lacking for other drugs.

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Anesthesiology 2005; 103:877-84 © 2005 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.
Prevention of Succinylcholine-induced Fasciculation and
Myalgia
A Meta-analysis of Randomized Trials
Jan-Uwe Schreiber, M.D.,* Christopher Lysakowski, M.D., Thomas Fuchs-Buder, M.D., Martin R. Trame` r, M.D., D.Phil.
This article has been selected for the Anesthesiology
CME Program. After reading the article, go to http://www.
asahq.org/journal-cme to take the test and apply for Cate-
gory 1 credit. Complete instructions may be found in the
CME section at the back of this issue.
Fifty-two randomized trials (5,318 patients) were included in
this meta-analysis. In controls, the incidence of fasciculation
was 95%, and the incidence of myalgia at 24 h was 50%. Non-
depolarizing muscle relaxants, lidocaine, or magnesium pre-
vented fasciculation (number needed to treat, 1.2–2.5). Best
prevention of myalgia was with nonsteroidal antiinflammatory
drugs (number needed to treat, 2.5) and with rocuronium or
lidocaine (number needed to treat, 3). There was a dose-depen-
dent risk of blurred vision, diplopia, voice disorders, and diffi-
culty in breathing and swallowing (number needed to harm,
< 3.5) with muscle relaxants. There was evidence of less myal-
gia with 1.5 mg/kg succinylcholine (compared with 1 mg/kg).
Opioids had no impact. Succinylcholine-induced fasciculation
may best be prevented with muscle relaxants, lidocaine, or
magnesium. Myalgia may best be prevented with muscle relax-
ants, lidocaine, or nonsteroidal antiinflammatory drugs. The
risk of potentially serious adverse events with muscle relaxants
is not negligible. Data that allow for a risk– benefit assessment
are lacking for other drugs.
SUCCINYLCHOLINE is still the accepted standard for
rapid sequence intubation.
1,2
It also seems to be a pop
-
ular muscle relaxant for ambulatory anesthesia and short
surgical procedures.
3,4
Perhaps no other drug used in
anesthesia, however, is associated with a similarly high
risk of complications.
5
Some complications are minor,
but others are potentially life threatening. Fasciculation
and myalgia are minor but frequent adverse effects of
succinylcholine. Myalgia, which can be accompanied by
muscle stiffness, can last for several days and can, at least
in some patients, induce significant discomfort.
6,7
In
1990, a meta-analysis that included data from 45 random-
ized and nonrandomized trials concluded that atra-
curium, d-tubocurarine, gallamine, pancuronium, diaze-
pam, and lidocaine all significantly decreased the
frequency of myalgia by approximately 30%.
8
During the
past 15 yr, many more trials that tested the efficacy of a
large variety of pretreatments have been published. The
aim of this quantitative systematic review was threefold:
first, to update the previously published meta-analysis on
the prevention of succinylcholine-related myalgia
8
; sec
-
ond, to include an analysis on the efficacy of pretreat-
ments on succinylcholine-induced fasciculation; and fi-
nally, to quantify pretreatment-related adverse effects.
This systematic review was performed following the
Quality of Reporting of Meta-analyses (QUOROM) rec-
ommendations.
9
Materials and Methods
Search Strategy
A systematic search of the literature was performed
without language restriction. We searched in MEDLINE,
EMBASE, IndMED, and the Cochrane Controlled Trials
Register using combinations of the free text terms suc-
cinylcholine, suxamethonium, postoperative AND
pain, randomized, and myalgia. We did not use the
term fasciculation because the primary aim was to study
myalgia which is clinically more important. Electronic
searches were conducted until February 2004 and were
complemented by screening bibliographies of retrieved
articles and reviews.
7,8
Study Selection
We considered published full reports of randomized
controlled trials that tested the efficacy of pharmaco-
logic regimens compared with placebo or no treatment
for the prevention of succinylcholine-induced fascicula-
tion or myalgia. Relevant trials had to report on dichot-
omous data on presence or absence of fasciculation or
myalgia. We did not consider data from abstracts, letters,
reviews, or animal research.
Assessment of Validity
Retrieved reports were screened for inclusion by two
authors independently (J.-U. S., M. R. T.), who excluded
irrelevant reports at that stage. Each author then inde-
pendently scored all eligible reports for methodologic
validity using the five-point Oxford scale, which takes
* Registrar, Department of Anesthesiology and Critical Care Medicine, Univer-
sity Hospital of the Saarland, Homburg, Germany. Staff Anesthesiologist,
Division of Anesthesiology, Geneva University Hospitals, Geneva, Switzerland.
Staff Anesthesiologist, De´partement d’Anesthe´sie et de Re´animation, Centre
Hospitalier Universitaire Nancy/Brabois, Nancy, France.
Received from the Department of Anesthesiology and Critical Care Medicine,
University Hospital of the Saarland, Homburg, Germany; the De´partment
d’Anesthe´sie et de Re´animation, Centre Hospitalier Universitaire Nancy/Brabois,
Nancy, France; and the Division of Anesthesiology, Geneva University Hospitals,
Geneva, Switzerland. Submitted for publication November 24, 2004. Accepted
for publication June 17, 2005. Supported by grant No. 3233-051939.97 from the
Swiss National Science Foundation, Bern, Switzerland (to Dr. Trame`r). Presented in
part as an abstract at the 13th Annual Meeting of the European Society of Anaesthe-
siology, Euroanaesthesia 2005, Vienna, Austria, May 28–31, 2005.
Address reprint requests to Dr. Schreiber: Klinik fu¨r Ana¨sthesiologie und
Intensivmedizin, Universita¨tsklinikum des Saarlandes, D-66421 Homburg,
Germany. Address electronic mail to: jan.schreiber@uniklinik-saarland.de.
Anesthesiology, V 103, No 4, Oct 2005 877
into account randomization, blinding, and description of
withdrawals.
10
The minimum score of an included ran
-
domized study was 1, and the maximum score was 5.
Detailed information from each trial was entered into
standard collection sheets. This was done by one inves-
tigator (J.-U. S.) and independently checked by the oth-
ers. Consensus on quality scores and extracted data were
reached by discussion. We converted all variable doses
to fixed doses using average body weights of the study
populations as reported in the original trials.
Data Synthesis
Because undue weight would have been given to pre-
treatments that were tested in one or two trials only, we
restricted quantitative analyses to those pretreatments
that were tested in at least three trials. We used a fixed
effect model because the data seemed to be clinically
homogenous. We calculated relative benefits as relative
risks with 95% confidence intervals for efficacy data.
Adverse effects were expressed as Peto odds ratios with
95% confidence intervals because many trials had zero
cells (i.e., they did not report on any event in one of the
study groups). We calculated the number needed to treat
(NNT) or to harm as an estimate of the clinical relevance
of a treatment effect. The number needed to treat or to
harm is the number of patients that must be treated with
an experimental intervention to achieve a particular result
(beneficial or harmful) in one of them which would not
have been the case had they all received the control inter-
vention (in this case, a placebo).
11
Statistical analyses were
performed using RevMan 4.2 (Cochrane Library, Updated
Software, Oxford, United Kingdom) and Microsoft
®
Excel
98 for Mac
®
(Microsoft Corp., Redmond, WA).
Results
Search Results
We identified 161 potentially relevant trials but subse-
quently excluded 109 (fig. 1). We eventually analyzed
data from 52 randomized trials that were published
between 1971 and 2003 and that included 5,318 pa-
tients.§
3,12–62
From the previously published meta-anal
-
ysis,
8
we accepted 17 studies but rejected 28, primarily
because they were not randomized. There was one du-
plicate cluster
63
of which we considered the older re
-
port as the original
57
and excluded the duplicate.
64
One
pediatric study was excluded,
65
because all other trials
were in adults.
The median number of patients per study was 71
(range, 20–587). The median quality score was 2; 13
trials scored 1; 24 scored 2; 11 scored 3; and 4 scored 4.
Only 6 trials (12%) reported an appropriate method of
randomization, and only 8 (15%) reported an adequate
method of blinding.
Forty-six trials (88%) studied fasciculation, 49 (94%)
studied myalgia, and 43 (83%) studied both. Most trials
scored the degree of fasciculation and myalgia on a
four-point scale, ranging from, for example, none to
mild, moderate, and severe. We extracted only data on
complete absence of fasciculation and on complete ab-
sence of myalgia to avoid interpretation bias. The inci-
dence of myalgia was most frequently reported at 24 h
after surgery. Some studies reported on myalgia at 48 h,
and a few reported on myalgia at 72 h.
Underlying Risk
We studied the relation between fasciculation and my-
algia and tested the potential impact of the induction
agent (propofol vs. thiopentone), dose of succinylcho-
line, and effects of opioids at induction on the incidence
of fasciculation and myalgia. For that purpose, we se-
lected the 35 trials that reported on both fasciculation
and myalgia at 24 h.
3,13–16,21–23,25–27,29,30,32–36,38,39,41,
4446,48,50–54,56 –59,61
In those, the average incidence of
§ Details of the trials are available at: http://www.hcuge.ch/anesthesie/data.
Accessed May 13, 2005.
Fig. 2. Incidence of fasciculation and of myalgia in control
patients who received a placebo or no treatment (i.e., control
event rate). Each symbol represents one trial. Data are shown
for 35 trials that reported on both fasciculation and myalgia,
and where the dose of succinylcholine was 1 mg/kg (gray
squares) or 1.5 mg/kg (clear circles). Number of symbols does
not add up because some symbols are overlapping.
Fig. 1. Flowchart of retrieved, excluded, and analyzed trials.
878 SCHREIBER ET AL.
Anesthesiology, V 103, No 4, Oct 2005
fasciculation in controls (i.e., the control event rate) was
94% (range, 73–100%) and of myalgia at 24 h was 51%
(range, 10 83%). Graphical display did not suggest any
relation between the incidence of these two endpoints
(fig. 2). The original data did not allow statistical testing
for an association between severity of fasciculation and
incidence of myalgia because severity of fasciculation
was only inconsistently reported.
In four trials, induction of anesthesia was with propo-
fol;
26,33,41,61
in one, it was with propofol or thiopen-
tone;
30
and in the other 47, it was with thiopentone. The
average incidence of fasciculation was 95.2% with
propofol and 95.0% with thiopentone. The difference
was not statistically significant. The average incidence of
myalgia at 24 h was 65.4% with propofol and 49.2% with
thiopentone. This difference was statistically significant;
for prevention of myalgia with thiopentone compared
with propofol, the NNT was 6 (table 1).
Fentanyl,
3,16,21,26,33,41,44,45,50,51,61
methadone,
36
or me-
peridine
29
was given at induction in 13 trials. In the
others, no opioids were used for induction. The average
incidence of fasciculation was 95.3% with opioids and
94.6% without. The average incidence of myalgia at 24 h
was 53.5% with opioids and 49.2% without. None of
these differences were statistically significant (table 1).
In 9 trials, the dose of succinylcholine was 1 mg/
kg,
16,21,23,26,32,36,46,54,55
and in 25 trials, the dose was
1.5 mg/kg.
3,14,15,22,25,27,29,30,33–35,38,39,41,44,45,48,51,53,55–59,61
The remaining trials used 1.3 or 2.0 mg/kg succinylcho-
line. The average incidence of fasciculation was 98.3%
with 1 mg/kg succinylcholine and 92.0% with 1.5 mg/kg.
The average incidence of myalgia at 24 h was 62.8% with
1 mg/kg succinylcholine and 44.6% with 1.5 mg/kg.
Both differences were statistically significant; for preven-
tion of fasciculation with 1.5 mg/kg succinylcholine
compared with 1 mg/kg, the NNT was 16, and for pre-
vention of myalgia, the NNT was 6 (table 1).
Pretreatments
A large variety of pretreatments were tested: nondepo-
larizing neuromuscular blockers (atracurium,
16,21,30,37,40,
41,46,49,50,53,57,61
cisatracurium,
3,33,44
d-tubocurarine,
12,13,23,
25,29,33,39,41–43,45,51,56,57
gallamine,
12,13,25,48,52
fazadinium,
12,16
metocurine,
13
mivacurium,
18,41,60
pancuronium,
12–14,21,25,31,
38,48,59,62
rocuronium,
26,33,35,41,54,61
vecuronium,
21,22,25,
26,35,41,45
), sodium channel blockers (lidocaine,
24,32,43,52,53
phenytoin
29
), nonsteroidal antiinflammatory drugs (diclofe-
nac,
34
ketorolac,
37
aspirin,
42,46,56
) benzodiazepines (midazo-
lam,
27,45
diazepam
20,22,23,39,51
), vitamins (E,
22,42
C
28
), magne-
sium sulfate,
17,36,58
calcium chloride,
42
dantrolene,
19
dexamethasone,
55
chlorpromazine,
22,42
and succinylcho-
line.
15,48,62
Table 1. Impact of Induction Agent, Opioids, and Different Succinylcholine Doses on Myalgia and Fasciculation
No. of Patients with
Fasciculation/Total No.
of Patients (%)
Relative Risk
(95% CI)
No. Needed
to Treat
(95% CI)
No. of Patients with
Myalgia at 24 h/Total
No. of Patients (%)
Relative Risk
(95% CI)
No. Needed To
Treat (95% CI)
Propofol 99/104 (95.2)
1.00
(0.96–1.05)
68/104 (65.4)
1.33
(1.14–1.55)
6
(4–17)
Thiopentone 725/763 (95.0) 391/795 (49.2)
Opiates at induction 324/340 (95.3)
1.01
(0.98–1.04)
182/340 (53.5)
1.09
(0.96–1.24)
No opiates at induction 521/551 (94.6) 271/551 (49.2)
1 mg/kg SCh 227/231 (98.3)
1.07
(1.04–1.10)
16
(11–28)
145/231 (62.8)
1.41
(1.23–1.61)
6
(4–9)
1.5 mg/kg SCh 521/551 (92.0) 268/601 (44.6)
Subgroup analyses were performed with data from control patients who received succinylcholine without any pretreatment. Data from trials that reported on both
fasciculation and myalgia at 24 h are considered. Numbers needed to treat are shown for statistically significant results.
CI confidence interval; SCh succinylcholine.
Fig. 3. Prevention of succinylcholine-re-
lated fasciculation. For each intervention
that was tested in at least three trials, a
meta-analysis was performed (# num-
ber of analyzed trials). Symbol sizes are
proportional to the number of analyzed
patients. CI confidence interval; NNT
number needed to treat; NSAID nonste-
roidal antiinflammatory drug (aspirin,
diclofenac, ketorolac); benzodiazepine
(diazepam, midazolam); sodium channel
blocker (lidocaine, phenytoin); RB rel-
ative benefit.
879PREVENTION OF SUCCINYLCHOLINE-INDUCED MYALGIA
Anesthesiology, V 103, No 4, Oct 2005
Prevention of Fasciculation
The effect of 12 pretreatments on fasciculation was
tested in at least three trials each (fig. 3). Nonsteroidal
antiinflammatory drugs were not significantly different
from placebo; all other pretreatments were. The NNT
compared with placebo was approximately 10 with ben-
zodiazepines and approximately 4 for cisatracurium and
pancuronium. With magnesium, sodium channel block-
ers (four of five trials tested lidocaine), and the other
nondepolarizing neuromuscular blockers, NNTs were
between 1.2 and 2.5.#
Prevention of Myalgia at 24 h
The effect of nine pretreatments on myalgia at 24 h
was tested in at least three trials each (fig. 4). Benzodi-
azepines had a weak but statistically significant effect on
myalgia; the NNT was approximately 8. With all nonde-
polarizing neuromuscular blockers, there was a statisti-
cally significant effect on myalgia; NNTs were between 6
(pancuronium) and 3 (gallamine, rocuronium). With so-
dium channel blockers (three of four trials tested lido-
caine), the NNT was approximately 3. Best efficacy was
with nonsteroidal antiinflammatory drugs (two trials
tested aspirin, one tested diclofenac); the NNT was 2.5.#
Myalgia at 48 and 72 h
Myalgia at 48 hwas reported in 16 trials.
12,14,15,22,25,29,32,
35–38,41,49,53,59,61
Of 374 controls, 189 (51%) reported
myalgia at 48 h (range, 5– 87%). Myalgia at 72 h was
reported in 8 trials.
16,22,29,30,38,45,49,59
Of 185 controls,
51 (28%) still had myalgia at 72 h (range, 0 60%).
Dose–Response with Nondepolarizing
Neuromuscular Blockers
With most nondepolarizing neuromuscular blockers,
several doses corresponding to 10 –30% of the respective
ED
95
were tested. To test for dose–responsiveness, we
selected those trials that tested neuromuscular blockers
and that reported on myalgia at 24 h
3,12–14,16,21–23,
25,26,29,30,33,35,38,39,41,44 46,48–54,56,57,59,61,62
and plotted
doses versus relative benefits for prevention of myalgia.
There was no clear evidence of dose–responsiveness for
neuromuscular blocking agents (fig. 5). There were not
enough data to allow for sensitivity analyses that ad-
dressed the time point of administration of neuromuscu-
lar blockers on efficacy.
Adverse Effects
Nine trials reported on adverse effects.
3,17,19,23,38,44,51,59,61
Blurred vision, diplopia, heavy eyelids, muscle weak-
ness, difficulty in swallowing, and voice disorder were
significantly more often reported in patients who re-
ceived a nondepolarizing muscle relaxant (table 2). With
pancuronium, dose–responsiveness could be tested with
data from two trials.
38,59
For that purpose, we arbitrarily
divided pancuronium regimens into low (0.21–0.28
mg), medium (0.42– 0.49 mg), and high dose (0.63– 0.7
mg), corresponding to approximately 4, 7, and 10
g/kg,
respectively, for a patient with 70 kg body weight. There
was consistent evidence of dose–responsiveness for
blurred vision, diplopia, heavy eyelids, and muscle weak-
ness. Number-needed-to-harm values were 3.5 or lower
(table 2) with the high-dose regimen. There were not
enough valid data to allow for similar sensitivity analyses for
other adverse effects and for other neuromuscular
blocking agents. Adverse effects with other drugs were
pain on injection and dizziness with diazepam,
23,51
weakness and dizziness with dantrolene,
19
and heat sen
-
sation with magnesium.
17
Discussion
Five main results emerge from this meta-analysis: Two
confirm existing knowledge, and three challenge wide-
spread opinion or provide new insights. First, the inci-
dence of succinylcholine-induced myalgia is high, and
symptoms sometimes last for several days. Second, small
# Details of the meta-analyses are available at: http://www.hcuge.ch/anesthesie/
data. Accessed May 13, 2005.
Fig. 4. Prevention of succinylcholine-re-
lated myalgia at 24 h. For each interven-
tion that was tested in at least three trials,
a meta-analysis was performed (# num-
ber of analyzed trials). Symbol sizes are
proportional to the number of analyzed
patients. CI confidence interval; NNT
number needed to treat; NSAID nonste-
roidal antiinflammatory drug (aspirin,
diclofenac); benzodiazepine (diazepam,
midazolam); sodium channel blocker (li-
docaine, phenytoin); RB relative bene-
fit.
880 SCHREIBER ET AL.
Anesthesiology, V 103, No 4, Oct 2005
doses of nondepolarizing muscle relaxants (i.e., approx-
imately 10–30% of the ED
95
) prevent fasciculation and
myalgia to some extent; however, the risk of potentially
serious adverse effects is not negligible. Third, higher
doses of succinylcholine decrease the risk of myalgia
compared with lower doses, opioids for induction do
not seem to have any impact, and, as to the choice of the
induction agent, it cannot be excluded that there is less
myalgia when thiopentone is used compared with
propofol. Fourth, there is no clear relation between
succinylcholine-related fasciculation and myalgia. Fi-
nally, pretreatment with sodium channel blockers (i.e.,
lidocaine) or nonsteroidal antiinflammatory drugs (di-
clofenac and aspirin) may prevent myalgia.
Fig. 5. Relation between doses of nonde-
polarizing neuromuscular blocking
agents (in milligrams, y-axes) and effi-
cacy in preventing myalgia at 24 h. Sym-
bols are relative benefits with 95% confi-
dence intervals (CI). A relative benefit
greater than 1 indicates less myalgia com-
pared with control. For regimens that
have been tested in more than one trial,
meta-analyses were performed.
Table 2. Analysis of Adverse Effects after Pretreatment with Neuromuscular Blockers Blocking Agents
No. with Adverse Effect/Total No. (%)
Adverse Effect
Experimental
Intervention
Control
Intervention
Odds Ratio
(95% CI)
Number
Needed to Harm References
Blurred vision
Any neuromuscular blocking agent 72/208 (34.6) 3/74 (4.1) 5.76 (3.0–11.1) 3 38,59,61
Pancuronium, low dose* 11/60 (18.3) 3/60 (5) 3.91 (1.25–12.3) 7.5 38,59
Pancuronium, medium dose 23/60 (38.3) 3/60 (5) 7.27 (3.04–17.4) 3 38,59
Pancuronium, high dose 38/60 (63.3) 3/60 (5) 17.6 (7.97–39.0) 2 38,59
Diplopia
Any neuromuscular blocking agent 65/260 (25.0) 5/120 (4.2) 4.99 (2.80–8.88) 5 3,38,44,59
Pancuronium, low dose 4/60 (6.7) 1/60 (1.7) 3.62 (0.59–22.3) 20 38,59
Pancuronium, medium dose 16/60 (26.7) 1/60 (1.7) 8.00 (2.85–22.5) 4 38,59
Pancuronium, high dose 18/60 (30.0) 1/60 (1.7) 9.90 (3.58–27.4) 3.5 38,59
Heavy eyelids
Any neuromuscular blocking agent 155/260 (59.6) 14/120 (11.7) 8.44 (5.38–13.2) 2 3,38,44,59
Pancuronium, low dose 15/60 (25.0) 1/60 (1.7) 7.89 (2.72–22.9) 4 38,59
Pancuronium, medium dose 33/60 (55.0) 1/60 (1.7) 14.0 (6.32–31.1) 2 38,59
Pancuronium, high dose 49/60 (81.7) 1/60 (1.7) 25.8 (12.6–53.1) 1.3 38,59
Weakness
Any neuromuscular blocking agent 89/220 (40.5) 14/100 (14) 5.67 (3.31–9.72) 4 3,38,59
Pancuronium, low dose 7/60 (11.7) 5/60 (8.3) 1.45 (0.44–4.75) 30 38,59
Pancuronium, medium dose 16/60 (26.7) 5/60 (8.3) 3.50 (1.37–8.94) 5.5 38,59
Pancuronium, high dose 30/60 (50.0) 5/60 (8.3) 7.31 (3.34–16.0) 2 38,59
Difficulty in breathing
Any neuromuscular blocking agent 154/308 (6.5) 20/308 (2.6) 2.23 (0.91–5.48) 26 3,38,41,44,59,61
Difficulty in swallowing
Any neuromuscular blocking agent 16/100 (16.0) 2/80 (2.5) 4.45 (1.65 to 12.0) 7 3,41,44
Voice disorder
Any neuromuscular blocking agent 13/80 (16.3) 0/60 (0) 6.71 (2.08 to 21.6) 6 3,44
* Variable doses were converted to fixed doses using average body weights of the study populations as reported in the original trials. Low dose 0.21–0.28mg
(3–4
g/kg, respectively, for 70 kg body weight); medium dose 0.42–0.49 mg (6–7
g/kg, respectively); high dose 0.63–0.70 mg (9–10
g/kg, respectively). Dose
ranges were arbitrarily chosen.
CI confidence interval.
881PREVENTION OF SUCCINYLCHOLINE-INDUCED MYALGIA
Anesthesiology, V 103, No 4, Oct 2005
Our meta-analysis has limitations. Most are related to
weaknesses in the original trials. The average method-
ologic quality of the trials was low. For example, a
minority only reported an adequate method of blinding,
leaving room for observer bias. We do not know
whether these trials were correctly performed but
poorly reported. Also, the size of most trials was limited.
This may partly explain the large variability in event
rates, with some trials reporting less than 20% of con-
trols having myalgia at 24 h and others reporting more
than 80%. Follow-up was 24 h in most trials. This may
not be long enough to provide an adequate view on the
usefulness of pretreatment. Finally, many trials did not
report on drug-related adverse reactions. However, lack
of reporting of adverse reactions does not mean that
none have occurred. For example, we would expect
some cardiac adverse effects in susceptible patients with
lidocaine. Also, the use of nonsteroidal antiinflammatory
drugs such as aspirin may interfere with platelet function.
In particular surgical settings, regular perioperative treat-
ment with these analgesics may not be warranted.
66
Fi
-
nally, potentially serious adverse effects such as difficulty in
swallowing were reported with nondepolarizing neuro-
muscular blocking agents. Relevant data, however, came
from only three studies, with a total of 100 patients who
received pretreatment.
3,41,44
We were unable to provide
reliable information on optimal regimens for each drug.
Pretreatment intervals and tested doses were too diverse.
On average, one half of the patients who received
succinylcholine without pretreatment had myalgia at
24 h and even at 48 h. After 3 days, approximately one
third of patients still experienced muscle pain. It has
been known for a long time that myalgia can last for up
to 1 week.
6,14
The trials did not allow conclusions about
the severity of muscle ache. However, as long as succi-
nylcholine is used in daily clinical practice,
67
there is a
need for an effective treatment against this bothersome
side effect, and this may explain the large number of
published trials dealing with this subject.
Contrary to widespread belief, we were unable to find
a clear relation between the incidence of fasciculation
and myalgia. Clearly, the ability of nondepolarizing mus-
cle relaxants to prevent both seems to link them tightly.
However, benzodiazepines had a favorable effect only
on fasciculation and almost no effect on myalgia, and
nonsteroidal antiinflammatory drugs did not prevent fas-
ciculation but were effective against myalgia. These data
suggest that fasciculation and myalgia may have different
origins. Fasciculation is thought to be related to a
prejunctional agonistic action of succinylcholine on nic-
otinic receptors that results in rapid firing.
68
Nondepo
-
larizing muscle relaxants effectively prevent fascicula-
tion, presumably by blocking presynaptic nicotinic
receptors. The etiology of succinylcholine-induced my-
algia, however, remains obscure. The fact that very dif-
ferent drugs such as diclofenac, lidocaine, or pancuro-
nium all attenuate myalgia to some extent provides
indirect evidence that the origin of succinylcholine-in-
duced myalgia must be, as previously suggested, multifac-
torial.
7,69
The beneficial effect of sodium channel blockers
such as lidocaine may be explained through their cell
membrane–stabilizing properties. The efficacy of nonste-
roidal antiinflammatory drugs suggests that there is an in-
flammatory genesis and that prostaglandins may be in-
volved.
46,70
This assumption, however, is contentious.
55
Patients who received a higher dose of succinylcholine
were less likely to have myalgia compared with those
who received a lower dose. A biologic basis for that
differential effect may be that higher doses of succinyl-
choline reduce forces on muscle spindles and therefore
produce more synchronous muscle contractions and
subsequently less myalgia.
7
However, after administra
-
tion of succinylcholine, biochemical markers of muscle
damage, such as myoglobin or creatine kinase, did not
correlate with the incidence of myalgia.
71,72
Recently
published data suggested that succinylcholine doses as
low as 0.6 mg/kg still provided satisfactory intubation
conditions with a shorter recovery and apnea peri-
od.
73,74
Clinicians will have to make the choice as to
whether it is worthwhile to use a small dose of succinyl-
choline to shorten recovery and apnea period at the
price of increasing the risk of postoperative myalgia. It
has been suggested that a high induction dose of propo-
fol decreases the risk of succinylcholine-induced myalgia.
75
We were unable to confirm this; however, results of the
relevant subgroup analysis should be interpreted carefully
because only a small number of trials that used propofol for
induction could be included. Finally, whether an opioid
was used for induction had no impact on myalgia.
Surprisingly, sodium channel blockers (most trials
tested lidocaine) and nonsteroidal antiinflammatory
drugs including aspirin were among the most efficacious
drug classes to prevent myalgia. However, relatively
small number of patients were tested, and, accordingly,
95% confidence intervals around the relative benefit
point estimates were wide, reflecting some uncertainty
in the degree of efficacy. Not unexpectedly, pretreat-
ment with a small dose of a nondepolarizing muscle
relaxant, perhaps the most popular technique in this
setting, decreased the incidence of myalgia. Almost all
manufactured muscle relaxants were tested in at least
one study, and there was no obvious difference between
specific drugs. All nondepolarizing muscle relaxants had
NNTs for the prevention of fasciculation and myalgia
within a similar range, and 95% confidence intervals
were overlapping. The degree of efficacy seems to be
very similar for all nondepolarizing muscle relaxants.
However, three issues must be discussed in this context.
First, with this technique, the risk of potentially serious
adverse effects is not negligible. Some may be minor,
e.g., heavy eyelids, blurred vision, or diplopia, at worst
causing some discomfort. Others are potentially serious,
882 SCHREIBER ET AL.
Anesthesiology, V 103, No 4, Oct 2005
e.g., difficulty in breathing or swallowing. For pancuro-
nium, the most frequently tested nondepolarizing mus-
cle relaxant in these studies, a consistent and clinically
relevant dose–response for adverse effects became ap-
parent. Approximately 30 of 100 patients present symp-
toms of muscle weakness with 10
g/kg. Approximately
15 of 100 patients are symptomatic at 7
g/kg. The same
degree of risk and a similar dose–response may apply to
all other nondepolarizing muscle relaxants. This assump-
tion is supported by a dose–response analysis for rocu-
ronium that used a pharmacodynamic and pharmacoki-
netic model.
76
Second, and contrary to the data on
adverse effects, there was no clear evidence of dose–
responsiveness for efficacy with any of the nondepolar-
izing muscle relaxants. Therefore, if pretreatment with
one of these drugs is chosen as a strategy to reduce
succinylcholine-induced myalgia, the smallest dose of
each agent that has shown efficacy in these randomized
trials should be given. These doses are unlikely to be above
10% of the respective ED
95
. Finally, a standard dose of
succinylcholine is likely to have a weaker paralyzing effect
after pretreatment with a nondepolarizing muscle relaxant.
Therefore, an increased dose of succinylcholine may be
needed to achieve optimal intubation conditions.
77
Our meta-analysis provides rationale for future research.
First, knowing that pretreatment with nondepolarizing
neuromuscular blocking agents prevents myalgia to some
extent but produces a finite risk of potentially serious
adverse effects begs the question as to whether this
method should still be recommended, and whether further
research is actually warranted with this technique. It may
be worthwhile to try to optimize the effect of dose and
timing of administration of nondepolarizing muscle relax-
ants. Alternative drugs such as lidocaine or nonsteroidal
antiinflammatory drugs seem promising. Among those,
nonsteroidal antiinflammatory drugs are perhaps the most
logical choice, considering their symptomatic analgesic ef-
ficacy in a variety of acute pain syndromes such as strains
and sprains that strongly resemble succinylcholine-induced
myalgia. However, the increased risk of surgical bleeding
must be kept in mind. Second, it may be useful to test
combinations of drugs with different mechanisms to en-
hance efficacy. The origin of myalgia is likely to be multi-
factorial, and it may be naive to believe that one single drug
can completely prevent it. The most effective prevention
may be with a drug combination. Third, it may be a sensible
option to treat muscle pain in patients who complain about
it, rather than to try to prevent it in all patients. The myalgia
is of minor harm only; not all patients, even if untreated, are
affected; and none of the tested pretreatments are univer-
sally effective. There is no rationale why treatment of my-
algia should be less effective than prevention. None of the
retrieved trials examined the treatment of established my-
algia symptoms with, for example, a single dose of a non-
steroidal antiinflammatory drug. Finally, the importance of
pretreatment in the prevention of more serious succinyl-
choline-induced adverse effects, such as hyperkalemia or
an increase in intraocular or intracranial pressure, remains
unclear. There is some evidence that with low-dose miva-
curium, succinylcholine-induced increase in intraocular
pressure may be prevented.
18
However, there is no clear
evidence that succinylcholine increases intracranial pres-
sure in patients with brain injuries,
78
and only limited data
are available for patients with brain tumors.
79
If muscle
fasciculation was a causative factor of these effects, the
prevention of succinylcholine-induced fasciculation may
be an important goal.
In conclusion, nondepolarizing muscle relaxants, lido-
caine, or magnesium may be used for the prevention of
succinylcholine-induced fasciculation. Myalgia may best be
prevented with nondepolarizing muscle relaxants, lido-
caine, or nonsteroidal antiinflammatory drugs. Nondepolar-
izing muscle relaxants should be used cautiously because
the risk of potentially serious adverse effects is not neg-
ligible. There is a lack of relevant data to allow for a
rational risk– benefit analysis for other pretreatments.
The authors thank Nazan Afan, B.S. (Graduate Student, Medical School, Uni-
versity of the Saarland, Homburg, Germany), and Emanuela Morinello, M.D.
(Resident in Anesthesia, Department of Anesthesiology and Critical Care Medi-
cine, University Hospital of the Saarland), for their help in translating Turkish and
Italian reports.
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884 SCHREIBER ET AL.
Anesthesiology, V 103, No 4, Oct 2005
    • "Succinylcholine-induced fasciculation and postoperative myalgia are a well-recognized side effect with the reported incidence of 95% and 50%, respectively [3]. Myalgia after the use of succinylcholine is most frequent on the first postoperative day [11]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Succinylcholine commonly produces frequent adverse effects, including muscle fasciculation and myalgia. The current study identified the optimal dose of rocuronium to prevent succinylcholine-induced fasciculation and myalgia and evaluated the influence of rocuronium on the speed of onset produced by succinylcholine. Methods This randomized, double-blinded study was conducted in 100 patients randomly allocated into five groups of 20 patients each. Patients were randomized to receive 0.02, 0.03, 0.04, 0.05 and 0.06 mg/kg rocuronium as a precurarizing dose. Neuromuscular monitoring after each precurarizing dose was recorded from the adductor pollicis muscle using acceleromyography with train-of-four stimulation of the ulnar nerve. All patients received succinylcholine 1.5 mg/kg at 2 minutes after the precurarization, and were assessed the incidence and severity of fasciculations, while myalgia was assessed at 24 hours after surgery. Results The incidence and severity of visible muscle fasciculation was significantly less with increasing the amount of precurarizing dose of rocuronium (P < 0.001). Those of myalgia tend to decrease according to increasing the amount of precurarizing dose of rocuronium, but there was no significance (P = 0.072). The onset time of succinylcholine was significantly longer with increasing the amount of precurarizing dose of rocuronium (P < 0.001). Conclusions Precurarization with 0.04 mg/kg rocuronium was the optimal dose considering the reduction in the incidence and severity of fasciculation and myalgia with acceptable onset time, and the safe and effective precurarization.
    Full-text · Article · Jun 2014
    • "[3,4] The exact underlying mechanism of succinylcholine-induced myalgia is not known, thus, different pre-treatment modalities have been attempted to reduce the incidence and severity of succinylcholine-induced myalgia. Non-depolarizing neuromuscular blockers, [3] lignocaine, [5] chlorpromazine, [6] benzodiazepines, [4] phenytoin, [7] ketorolac, [8] diclofenac, [9] ABSTRACT Context: Succinylcholine a depolarizing muscle relaxant with rapid onset, predictable course and short duration of action is associated with myalgia. Aim: The aim of this study is to evaluate the efficacy of pregabalin, gabapentin and diclofenac on the incidence and severity of succinylcholine-induced myalgia. "
    [Show abstract] [Hide abstract] ABSTRACT: Context: Succinylcholine a depolarizing muscle relaxant with rapid onset, predictable course and short duration of action is associated with myalgia. Aim: The aim of this study is to evaluate the efficacy of pregabalin, gabapentin and diclofenac on the incidence and severity of succinylcholine-induced myalgia. Settings and Design: Tertiary Care Teaching Hospital. Materials and Methods: A total of 120 patients undergoing laparoscopic cholecystectomy were randomly assigned into three groups: Pregabalin group received 150 mg of pregabalin, gabapentin group received 600 mg of gabapentin and diclofenac group received 100 mg of diclofenac sodium orally 2 h prior to surgery. Anesthesia was induced with fentanyl 3 μg/kg, propofol 2-2.5 mg/kg and succinylcholine 1.5 mg/kg and was maintained with oxygen with sevoflurane in the air and intermittent vecuronium bromide. A blinded observer recorded post-operative pain scores on visual analog scale at different time intervals and myalgia at 24 h. Post-operative pain relief was provided with fentanyl based patient-controlled analgesia. Fentanyl consumption in 24 h was recorded as a primary outcome. Statistical Analysis: Patients' characteristics and total fentanyl consumption were compared using one-way ANOVA followed by post-hoc test. Pain score was compared amongst the groups using Kruskal Wallis test. Results: The myalgia occurred in 15, 14 and 13 patients in pregabalin, gabapentin and diclofenac sodium group respectively (P > 0.85). Patients in diclofenac group had significantly higher fentanyl consumption (674.85 ± 115.58 μg) compared with pregabalin group (601.87 ± 129.57 μg) (95% confidence interval [CI] = 34.8-120.7) and gabapentin group (612.29 ± 105.12 μg) (95% CI = 14.9-170.5). However, there was no significant difference in fentanyl consumption between pregabalin and gabapentin groups (95% CI = -34.8-120.7). There was a significant difference in visual analog score at time points 12, 18 and 24 h among the study groups. Conclusion: Pre-treatment with pregabalin, gabapentin and diclofenac had equal efficacy in reducing the incidence and severity of succinylcholine-induced myalgia. However, pre-treatment with pregabalin and gabapentin decreased post-operative pain scores and fentanyl consumption.
    Full-text · Article · Mar 2014
    • "There are diverse interactions between muscle relaxants and Mg according to the blocking mechanism of depolarizing or non-depolarizing muscle relaxants. Mg prevents muscular fasciculations and reduces the release of potassium outside the cell induced by succinylcholine injection, but it does not affect its onset and duration [23,24] . Mg affects the presynaptic membrane more than the post-synaptic membrane in enhancing blocking effect of non-depolarizing muscle relaxants [25]. "
    Full-text · Article · Jun 2012
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