8411-MAS

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Intrathecal magnesium as analgesic adjuvant for spinal

anesthesia: a meta-analysis of randomized trials
J. P. RAMÍREZ, S. G. TRUJILLO, C. ALCANTARILLA

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Department of Anesthesiology, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain

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O ABSTRACT

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Background. The efficacy and safety of intrathecal magnesium as analgesic adjuvant has been tested by several clini-
cal trials in recent years. We performed a meta-analysis of the available literature.
Methods. Randomized clinical trials comparing a 50 to 100 mg dose of intrathecal magnesium sulfate versus placebo
in addition to an intrathecal local anesthetic and/or opiate for a below-umbilicus procedure were included. Medline,

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LILACS, Cochrane Library and Google Scholar databases were searched. A random analysis was performed and het-
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erogeneity was tested for. The size of the effect for quantitative outcomes was calculated as standard mean difference
(SMD, neutral=0); and as odds ratio (OR, neutral=1) for dichotomous outcomes.
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Results. Twelve studies totaling 817 patients were included. The “time to first analgesia request” was at least 35
minutes longer when intrathecal magnesium was included in the intervention (SDM 0.94, 95%CI 0.51 to 1.37,
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P<0.001). The “onset time to sensory block” (SDM 0.64, 95%CI 0.15 to 1.12, P=0.01) and the “time to maximal
motor block” (SDM 0.97, 95%CI 0.28 to 1.67, P=0.006) were 2.4 minutes slower with intrathecal magnesium.
There was no difference in “time to full motor recovery, incidence of pruritus, postoperative nausea and vomiting,
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bradicardia, low blood pressure and urinary retention”. No cases of respiratory depression or neurotoxicity were
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recorded in these studies.

Conclusion. The inclusion of 50 to 100 mg of intrathecal magnesium in a spinal anesthetic prolongs opiate analgesia
duration; no safety concerns have been identified by the included clinical studies but additional evidence is advised.
(Minerva Anestesiol 2013;79:1-2)
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Key words: Magnesium - Analgesia - Meta-analysis as topic.

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M agnesium ion is a natural calcium an-

tagonist that acts on different neuron
ity to decrease intra- and postoperative analgesic
consumption to certain extent without modify-
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channels involved in antinociception mecha- ing pain scores 2 with some increased incidence
nisms. It inhibits calcium entry into the cells of bradycardia and slowing effect on neuromus-
via non-competitive blockade of the dorsal cular transmission.3 A dose of 40 mg·kg-1 before
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horn N-methyl-D-aspartate (NMDA) receptor, induction followed by 10 mg·kg-1·h-1 is adequate

which modulates or prevents central pain sensi-
tization. Therefore, there is a theoretical role for
exogenously given magnesium sulfate to act as
analgesic adjuvant. When the ion has been used
intravenously, the obtained results as analgesic
adjuvant have shown a limited capacity. There is
no clear evidence about its efficacy as a preven-
tive analgesia agent.1 It seems to have a capac-
for this purpose without having undesirable he-
modynamic effects.4 The explanation given for
the limited pain-sparing effect as IV agent 5 is
that magnesium does not cross the blood-brain
barrier 6 and, therefore, no action upon NMDA
receptors should be expected. Conceivably, di-
rect intrathecal (IT) administration could im-
prove its performance as analgesic adjuvant. Not

Vol. 79 - No. 4 MINERVA ANESTESIOLOGICA 1

RAMÍREZ Intrathecal magnesium: a meta-analysis

until recently, several randomized controlled tri-
als (RCTs) have explored this possibility in terms
of efficacy and safety.
We conducted a meta-analysis of RCT’s stud-
ying the anesthetic features of the spinal block
when IT magnesium is used adjunct to either IT
local anesthetics and/or IT opiates as well as the
possible benefits for postoperative analgesia.
Materials and methods
was considered. The authors were not contacted
for unpublished data.
The abstracts of the obtained citations were
reviewed by two independent researchers to
exam whether they met the inclusion and exclu-
sion criteria. The same two independent authors
analyzed the quality of the included RCTs fol-
lowing the Jadad score 7 (a minimum of 3 out
of 5 points was required) and the Cochrane
Collaboration tool for risk of bias 8 (Table I). A
hand-search of the references was added, as well.
The two authors extracted the relevant data from

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Methods
the included studies. Any discrepancy was solved
Electronic searches in Medline, LILACS, by a third author. Data from RCTs containing

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Cochrane Library and Google Scholar data- more than two groups was extracted compar-
bases were carried out using the medical sub- O ing the group containing IT magnesium and
ject headings, text words and Boolean operators the control group (containing sodium chloride

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“intrathecal” and “magnesium” and “clinical or water). The primary objective was to evaluate
trial” up to December 2011. Our inclusion cri- the IT magnesium (Mg) as analgesic adjuvant.
teria were: controlled RCTs whose anesthetic The outcomes to be analyzed for that purpose

intervention included IT local anesthetic and/
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or IT opiate in addition to either intrathecal
magnesium sulfate as analgesic adjuvant or pla-
cebo. Exclusion criteria were preclinical stud-
ies, other purposes of the IT technique differ-
ent than analgesia/anesthesia (studies about
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were the “time to first analgesia” request since
the spinal technique was performed, followed by
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the “consumption of postoperative analgesics”
and “subjective pain scale”. The subjective pain
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scale was measured with the visual analogue scale
(VAS), or the verbal rating scale (VRS) over a

magnesium as protective agent against neural range 0 to 10. Other outcomes to be analyzed
injuries were excluded) and surgical procedures were the “onset time to sensory block” meas-
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above the diaphragm. No language exclusion ured both as time to reach the T10 level and/or
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Table I.—Quality of reports assessment.

JJADAD SCORE RISK OF BIAS ANALYSIS
EDouble blind

Free of other
Randomized

concealment
Withdrawls

Incomplete
Jadad total

generation

Allocation

addressed
Sequence

reporting
outcome
Blinding
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selective
Free of

bias

Buvanendran 9 2 0 1 3 + + - + + +
Ozalevli 10 2 2 1 5 + + + + + +
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Arcioni 11 2 2 1 5 + + + - + ?
Lee 12 1 2 1 4 ? + + + + -
Shoeibi 13 2 2 1 5 + + + - + +
El-Kerdawy 14 1 1 1 3 ? ? ? + + +
Dayioglu 15 1 2 1 4 ? + + + + +
Ghrab 16 2 2 0 4 + + + + + +
Malleeswaran 17 2 2 1 5 + + + + + +
Unlugenc 18 2 2 1 5 + + + + + +
Khalili 19 2 2 1 5 + + + + + +
Shukla 20 2 2 1 5 + + + + + +
Borgia 21 1 1 1 3 ? ? ? - - -

2 MINERVA ANESTESIOLOGICA ?? 2013

Intrathecal magnesium: a meta-analysis RAMÍREZ
time to reach the highest dermatomal level, the
“highest dermatomal level” assessed by pin-prick
exam, the “time to two segments regression”
from the previous highest dermatomal level, the
“time to maximal motor block” measured on the
modified Bromage scale (range 0 to 3; 3 is no
movement of legs; 2 is movement of feet; 1 is
movement of Knee; 0 is elevation of hips), the
“time to full motor recovery” as the time to re-
cover a Bromage of 0, the incidence of “pruritus,
postoperative nausea and vomiting (PONV),
bradicardia, low blood pressure, urinary reten-
tion and neurotoxicity”.
Statistical analysis
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The size of the effect for quantitative outcomes
was extracted from mean and standard deviation
plus group size. As the scale of the variable could
vary among the studies, the size of the effect was
calculated as standard mean difference (SMD)
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with its 95% confidence interval (CI) and P
value. SMD divides the raw mean difference
in each study by the standard deviation. When
data was shown as median, range and size of the
group, a validated method was used to calculate
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mean and standard deviation.22 A neutral SMD
for the outcome was 0; a CI crossing 0 was con-
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sidered not significant; P values were significant
if <0.05. The size of the effect for dichotomous
outcomes was calculated from incidence and size
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of the groups and expressed as odds ratio (OR),
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95% CI and p value. An OR of 1 represented a
neutral effect for the outcome; a CI including 1
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was considered not significant, as well as p val-
ues above 0.05. The choice for fixed vs. random
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analysis was decided in favor of the random anal-
ysis because data was considered to be extracted
from different statistical populations (different
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surgical procedure, different magnesium dose,
different local anesthetic and/ or opiate included
in the spinal procedure). Heterogeneity analysis
was performed computing Cochrane’s Q and P
value (P<0.1 meant heterogeneity) and I2 (its
value represented the % of real dispersion at-
tributable to the observed values; we consid-
ered >50% consistent with heterogeneity) but
they were not used as criteria to decide which
type of analysis should be done. We performed
Vol. 79 - No. 4 MINERVA ANESTESIOLOGICA 3
a funnel plot for the outcome “time to the first
analgesia request”, to assess the publication bias
risk. The statistical analysis was conducted with
the program Comprehensive Meta Analysis V2
(BiostatTM, Englewood, USA). This report was
issued following the PRISMA checklist.23
Results
Our research rendered 54 citations. After dis-
carding duplicates and reviewing the abstracts
for adequate inclusion and exclusion criteria,
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18 RCTs were retrieved. Six of the RCTs were
ruled-out after a full review of the study: Youssef
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et al.24 and Ghatak et al.25 used the adjuvant
magnesium via epidural space, Mageed et al.26
focused in a different outcome (fast-track cardiac
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anesthesia), Marzouk et al.27 was a dose-finding
study instead placebo-controlled and Ouerghi et
al.28 was a study of analgesic consumption for
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lung resection. Borgia et al.21 was ruled out as
consequence of the risk of bias analysis, which
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offered many unanswered issues and lack of data.
The search flowchart is represented in Figure 1.
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We considered 12 RCTs for our meta-analysis
(Table II), totaling 817 patients: 412 receiving
IT magnesium sulfate and 405 receiving a pla-
cebo, usually sodium chloride except Shoeibi et
al.13, who used water. Seven of the RCTs added
IT magnesium sulfate to both an opiate (usually
fentanyl except Arcioni et al.’s study,11 which in-
cluded sufentanil; Ghrab et al.’s study 16 includ-
ed IT morphine in addition to fentanyl) plus a
local anesthetic (bupivacaine in all cases). Five
RCTs included only local anesthetics added to
magnesium: bupivacaine three times (Unlugenc
et al.,18 Khalili et al.19 and Shukla et al.20), lido-
caine once (Shoeibi et al.13) and tetracaine once
(Lee et al.12). Buvanendran et al.9 report was
the only RCT including IT fentanyl-only asso-
ciated to magnesium. There were three studies
considering more than two comparison groups.
We decided to compare the groups whose re-
spective interventions were identical except the
IT Mg versus placebo, and disregarded the other
intervention (Arcioni et al.11 included epidural
magnesium, Ghrab et al.16 had a distinct group
without morphine and Shukla et al.20 included
dexmedetomidine in a third group).
RAMÍREZ Intrathecal magnesium: a meta-analysis

P<0.001). Ghrab et al.16 included morphine in

Electronic search of the intervention, which prolonged analgesia very
MEDLINE, LILACS, significantly with or without IT magnesium; if
Cochrane that study was excluded of the analysis, the an-
Library and Google algesia duration period still favored the IT Mg
Scholar
group in 34.5 minutes as average (SDM 0.91,
returned 54 citations
95% CI 0.44 to 1.33, P<0.001). There were four
studies with usable data that did not include IT
opiates but only local anesthetics in addition to
IT Mg (Shoeibi et al.,13 Unlugenc et al.,18 Kha-
36 citations
6 citations removed after full text
exam: lili et al.19 and Shukla et al.20). For these studies
the average difference was still 31 minutes longer

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removed after abstracts were • 2 epidural magnesium

screened for inclusion and

• 1 fast-track cardiac RCT time period to ask for analgesia in favor of IT
exclusion criteria
• 1 lung resection Mg patients, but such result stays at the verge of

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• 1 dose-finding study significance (SDM 0.62, 95%CI -0.03 to 1.27;
P=0.063). If we apply a fixed model for sub-
bias
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• 1 unfavorable risk of

group analysis based on the similarity of the no-

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opiate IT intervention, the result is significant
in favor of a longer duration with IT Mg (SDM
0.60. 95% CI 0.35 to 0.84, P<0.001). Three of

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12
the studies (Arcioni et al.,11 Ghrab et al.,16 and
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Randomized Clinical
Khalili et al.19) used a dose of (or very close to)
Trials included in the
meta-analysis
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100 mg of Mg sulfate. The rest used the same
dose used by Bunavendran et al.9 The attribut-
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able size effect when the 100 mg dose was used
was not significant (SDM 0.75, 95% CI -0.21 to
Figure 1.—Search flowchart.
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1.71; P=0.5) compared to the full meta-analysis

for the outcome “time to first analgesia request”;
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Table III summarizes main results. The out- this subgroup outcome analysis was based on the
come “time to first analgesia request” since the two studies with usable data (Ghrab et al.16 and
procedure was performed was 85 minutes longer Khalili et al.19) out of three. “Postoperative con-
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as average if IT Mg was included in the interven- sumption of analgesics” information was offered
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tion (Figure 2; SDM 0.94, 95% CI 0.51 to 1.37, in different ways by the studies (see Table IV for
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Table II.—Descriptive data of the included randomized clinical trials.

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N. N.
First autor Year Ref. Population included Mg dose Opiate Local anesthetic
control Mg
Buvanendran 2002 9 Labor analgesia 25 25 50 mg Fentanyl 25 µg None
Ozalevli 2005 10 Lower extremity orthopedic 50 50 50 mg Fentanyl 25 µg Bupi 10 mg
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Arcioni 2007 11 Knee/hip replacement 30 23 94.5 mg Sufentanil 8 µg Bupi 15 mg

Lee 2007 12 Knee replacement 30 30 50 mg None Tetracaine 10 mg
Shoeibi 2007 13 Cesarean section 40 40 50 mg None Lidocaine 75 mg
El-Kerdawy 2008 14 Lower extremity orthopedic 40 40 50 mg Fentanyl 25 µg Bupi 10 mg
Dayioglu 2009 15 Knee arthroscopy 30 30 50 mg Fentanyl 10 µg Bupi 6 mg
Ghrab 2009 16 Cesarean section 31 34 100 mg Fentanyl 10 µg Bupi 10 mg
morphine 100 µg
Malleeswaran 2009 17 Cesarean section/preeclampsia 30 30 50 mg Fentanyl 25 µg Bupi 10 mg
Unlugenc 2009 18 Cesarean section 30 30 50 mg None Bupi 10 mg
Khalili 2011 19 Lower extremety orthopedic 39 40 100 mg None Bupi 15 mg
Shukla 2011 20 Lower abdominal and lower limb 30 30 50 mg None Bupi 15 mg
Mg: magnesium; Ref.: reference; bupi: bupivacaine.

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Intrathecal magnesium: a meta-analysis RAMÍREZ

Table III.—Main time outcomes.

Difference SDM 95% CI P value
minutes
Time to first analgesia request 85 0.98 0.51 to 1.37 <0.001
Time to first analgesia request without morphine 34.5 0.91 0.44 to 1.33 <0.001
Time to first analgesia request only IT local anesthetic 31 0.60 0.35 to 0.84 <0.001
Onset time to sensory block 2.4 1.15 0.56 to 2.74 0.001
Time for two segments regression non signif. 0.54 -2.4 to 1.32 0.175
Onset time to motor block 2.4 0.97 0.28 to 1.67 0.006
Time to full motor recovery Non signif. 0.52 -0.11 to 1.15 0.101
SDM: standard mean difference.

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Figure 2.—Time to first analgesia request.

details): some recorded IV analgesics (opiates P<0.001) based on four studies (Ozalevli et al.,10
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or NSAIDs), some PO medication and some Ungulenc et al.,18 Khalili et al.19 and Shukla et
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other recorded epidurally-given analgesics. Two al.21). The “highest dermatomal level” examined
studies considered a 24 hours period for anal- by pin-prick was shown in very different ways
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ysis, two studies considered a 36 hours period among the studies and therefore we couldn’t syn-
and two other mentioned an unspecified “total thesize a quantitative comparison. The summary
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postoperative period”. Therefore, it could not be (IT Mg vs. no IT Mg groups) is: Ozalevli et al.10
computed as a single size effect data, but it was T7 vs. T6; Lee et al.12 T6(3-12) vs. T6(3-12);
evident (Table IV) that the consumption was less Shoeibi et al.13 T4/T6:24/16 vs. 27/13; Dayi-
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in the IT Mg group in everyone of the studies
that offered these data, sometimes up to 50%
reduction (Arcioni,11 Lee 12 and El-Kerdawy 14)
and. “Subjective pain” assessment at rest showed
lower scores for the IT Mg group (Table IV;
SDM 0.7; 95% CI 0.28 to 1.13; P=0.001).
“Onset time to sensory block” was prolonged
with IT magnesium when measured to reach
a T10 dermatomal level (2.4 minutes average
difference) (SDM 1.15, 95%CI 0.56 to 1.74,
oglu et al.55 T7(4-10) vs. T7 (4-10); Ghrab et
al.16 T4/above T4:30/4 vs. 24/7; Malleeswaran
et al.17 T4/T6:14/16 vs. 21/9; Unlugenc et al.18
T4(2-5) vs. T4(2-5). But the time necessary to
achieve whatever higher level was reached was
longer with the IT Mg intervention (Figure 3;
SDM 0.64, 95% CI 0.15 to 1.12, P=0.01). The
necessary time to decrease two segments its high-
est dermatomal level was an outcome considered
by 6 studies, and resulted in a non significant

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RAMÍREZ Intrathecal magnesium: a meta-analysis

Table IV.—Postoperative consumption of analgesics and subjective pain evaluation.

Postoperative analgesic consumption Subjective pain evaluation
First Author IT Mg No IT Mg
IT Mg No IT Mg Scale Mean Mean
Mean±SD Mean±SD (range)±SD (range)±SD
Buvanendran NR VAS 0 (0-4) 1 (0-9)
Ozalevli NR NR
Arcioni i.v. morphine (mg) over 36 hours 20±3.3 39±4.7 VAS 1.9 (1.1-2.8) 2.3 (1.6-3.0)
Lee PCEA 0.2 % ropivacaine/morphine 0.2±0.5 0.4±0.7 VRS rest 4.3±2.5 4.1±2.4
(50 µg/ml) epidural number of VRS motion 6.9±2.1 7.2±2.4
rescues at 36 hours in addition to an
infusion at 2 ml/h
Shoeibi NR NR

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El-Kerdawy PCEA fentanyl (µg) at 24 hours 252 409 VAS 2 (0-8) 3 (0-9)
Dayioglu Total 50mg p.o. tramadol number 2±1 2.6±1.4 NR
of tablets
Ghrab NR VAS rest 0.9±0.7 1.6±0.9

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VAS motion 1.7±0.9 2.8±1.1
Malleeswaran
Unlugenc
i.m. Diclofenac (mg) over 24h
NR
O 147±55 182±58 VRS
NR
0.9 (0.8-1) 1 (0.8-1.1)

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Khalili Total (i.v. plus p.o.) tramadol (mg) 97±33 138±51 NR
NR: not reported; IT: Mg intrathecal magnesium; LA: local anesthetic; VAS: visual analogue scale; VRS: verbal rating scale; PCEA: patient con-
trolled epidural analgesia.

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Figure 3.—Onset time to highest dermatomal level.

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difference (SDM 0.54, 95% CI -0.24 to 1.32,
P=0.175). The time to achieve the highest motor
block degree was 2.4 minutes slower for the IT
Mg patients based on four studies (El-Kerdawy
et al.,14 Malleeswaran et al.,17 Unlugenc et al.18
and Shukla et al.20), (Figure 4; SDM 0.97, 95%
CI 0.28 to 1.67, P=0.006). Bromage score was
higher among the IT Mg patients (SDM 0.84,
95% CI 0.55-1.14, P<0.0001) based on three
studies (Ozalevli et al.,10 Lee et al.12 and Ghrab
et al.16). Full motor recovery was not significant-
ly different in regard to the IT Mg intervention
(Figure 5; SDM 0.52, 95% CI -0.11 to 1.15,
P=0.101). Three studies that included only a
local anesthetic without an opiate associated to
the IT Mg considered this outcome (Khalili et
al.,19 Unlugenc et al.18 and Shukla et al.20) and
rendered a non-significant 35 minutes average

6 MINERVA ANESTESIOLOGICA ?? 2013

Intrathecal magnesium: a meta-analysis RAMÍREZ

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Figure 4.—Motor onset time.

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Figure 5.—Full motor recovery.

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shorter motor block duration for patients with- (1 Ozalevli et al.,10 1 Unlugenc et al.18) but it
out IT Mg (SDM 0.69, 95% CI -0.88 to 2.25, was not significant (OR 3.08, 95%CI 0.31 to
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P=0.390). The other two no-IT-opiate-included
studies did not look into this outcome.
There was neither difference in pruritus (Fig-
ure 6; OR 0.67, 95%CI 0.43 to 1.03, P=0.069)
nor in PONV incidence (Figure 7; OR 0.83,
95%CI 0.5 to 1.36. P=0.458). There were no
cases of respiratory depression reported in our
included studies. There were two cases of bradi-
cardia reported by the 5 studies that considered
this outcome. Both happened in IT Mg patients
30.29, P=0.335). The incidence of low blood
pressure showed no significant differences (OR
0.71, 95%CI 0.42 to 1.18, P=0.182). There was
no difference in urinary retention based on two
studies, Lee et al.12 and Dayioglu et al.15 (OR
0.25, 95%CI 0.04 to 1.66, P=0.152). There were
no neurologic complications recorded among
the 10 studies that reported such outcome.
We framed a funnel-plot (Figure 8) to ana-
lyze the publication bias for the primary out-

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RAMÍREZ Intrathecal magnesium: a meta-analysis

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Figure 6.—Pruritus.
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Figure 7.—Postoperative nausea and vomiting.

come, “time to first analgesia request”. Most of meta-analyses based on a relatively low number
the included studies show a good precision. The of studies and in such case it is more difficult
publication bias is reasonably absent. This is a to obtain meaningful funnel-plot symmetry. The

8 MINERVA ANESTESIOLOGICA ?? 2013

Intrathecal magnesium: a meta-analysis RAMÍREZ
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Figure 8.—Funnel plot.
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fail-safe analysis reveals that there would be need
to be 30 missing studies for every observed study
for the effect to be nullified.
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Discussion
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Our meta-analysis concludes that the inclu-
sion of 50 to 100 mg of IT Mg in a spinal an-
esthetic acts as an effective and safe analgesic
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adjuvant. IT Mg offers a longer period (at least
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half an hour) of postoperative analgesia free of
rescue medication in addition to less subsequent
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postoperative consumption of analgesics (at least
during 24 to 36 hours; the postoperative con-
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sumption of analgesics could not be computed
as a size effect data due to the disparity of the
used agents, but a direct look to the figures leaves
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no doubt it was decreased in all the included
studies), and no difference in the incidence of
side-effects. Whether this is a significant find-
ing for clinical practice or not, is debatable. A
direct comparison with a standard IT analgesic
adjuvant as fentanyl is advisable. A recent meta-
analysis including epidural magnesium inter-
ventions, despite, the increased heterogeneity of
their sample, is coincidental with ours in most
variables.
Vol. 79 - No. 4 MINERVA ANESTESIOLOGICA 9
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Magnesium is involved in anesthetic and an-
algesic mechanisms in the central nervous sys-
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tem.29 It has been reported in a systematic review
of intravenous Mg RCTs 2 an inverse relation be-
tween magnesium concentration in cerebral spi-
nal fluid (CSF) and consumption of analgesics.5
Direct intrathecal injection of magnesium sul-
fate would overcome theoretical difficulties for
the ion to reach the dorsal horn target in suffi-
cient doses without systemic toxicity side-effects.
Magnesium has a capacity to act as an antago-
nist both on N-type voltage-gated ionotropic and
NMDA ligand-gated spinal metabotropic recep-
tor. Whereas for the later function needs a mag-
nesium CSF concentration of 10 µM to be effec-
tive,30 for the former no clear-cut dose has been
advanced, although a plasmatic concentration of
4.8 mM/L has been found effective to block N-
type channel at nerve terminals.31 It is usually
assumed that the adjuvant properties of IT Mg
are mediated by NMDA receptor antagonism.
NMDA receptor channels contain ligand-gated
ion currents at glutamatergic synapses. Noxious
stimulation leads to the release of glutamate and
aspartate neurotransmitters, which bind to the
NMDA receptor and promotes intracellular sig-
naling. Blockade of these receptors may inactive
RAMÍREZ Intrathecal magnesium: a meta-analysis
wind-up phenomenon, long-term synaptic plas-
ticity and central sensitization.32 Analgesic con-
sumption and pain scores at rest have not been
related with central sensitization but it has to do
with wind-up phenomenon and hyperalgesia.33
NMDA antagonists as magnesium and others
are known to synergize with opiates.34 The ma-
jority of the IT interventions considered in our
meta-analysis studies added magnesium to both
a local anesthetic and an opiate.
Some of these RCTs spinal intervention did
not include opiates, but only a local anesthetic
associated to Mg. In these instances the 31 min-
utes difference in “time to the first analgesia” re-
quest with versus without IT Mg showed a trend
towards significance (P=0.06) using the random
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analysis. If a fixed analysis was used (and it could
make sense to use it based on the close similarity
of the interventions) the outcome difference be-
came significant (P<0.001). This conclusion was
based in four studies; three of them used bupi-
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vacaine and one lidocaine. This later one (Shoe-
ibi et al.13) showed a 48 minutes longer time free
of analgesics when IT Mg was associated to lido-
caine (P<0.001).
Although the adjuvant benefit seems related
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to its NMDA receptor antagonism, the onset
delay when magnesium was added could also
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indicate there is a modulation of the neuronal
electrical conduction blockade. High doses of IT
magnesium produce an intense neuronal block
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per se,35 reversible in 1 hour without sequel.
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Lower concentrations may interact with N-type
calcium channel activity that mediates pain sig-
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naling. N-type calcium channels are highly con-
centrated in the synaptic terminals they make in
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the dorsal horn of the spinal cord (laminae I and
II).36 These primary afferents (mainly C-fibers
and Aδ-fibers) are implicated in the sensation
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of a variety of noxious painful stimuli. Block
of high voltage-gated N-type calcium channel
currents dramatically inhibits the release of neu-
ropeptides as substance P and calcitonin gene-
related peptides from sensory neurons.37 If half
the calcium channels are blocked, the release of
transmitter might be reduced to about 10% of
the control value. This mechanism would not re-
quire the magnesium ion to synergize with opi-
ates in order to act as analgesic adjuvant. In fact,
10 MINERVA ANESTESIOLOGICA ?? 2013
glutamatergic receptors are known targets of lo-
cal anesthetics, as well.38 We cannot conclude
or reject from the available data that there is a
benefit associated to incremental IT Mg doses.
As consequence, additional studies on the 100
mg dose or higher are still needed to rule out a
dose-related benefit.
There has been concern about the safety of
the magnesium sulfate injection in the intrath-
ecal space. The studies included in our meta-
analysis detected no problems, including respi-
ratory depression and neurotoxicity. It has been
F
reported an accidental IT injection of 1000
mg.39 The patient developed an intense mo-
A
tor block that resolved in 90 minutes without
neurotoxic sequels in long-term follow-up. The
preclinical evidence has been summarized else-
IC
where.40 Eight studies were reported, and seven
of these detected no neurotoxicity. Saeki et al.41
studied the possible protective effect of IT mag-
D
nesium as protection for ischemic spine injury
in rabbits. He found no protection and reported
E
a possible neurological injury associated with
Mg. Another animal model of spinal ischemia
M
42 has revealed a neuroprotective capacity for IT
Mg, producing less glutamate release into CSF
obtained by microdialysis, better motor func-
tion and lesser destruction of neurons assessed
by histopathology. The lowest doses used in
these animal experiments were equivalent to the
highest doses used in human trials. Although
the clinical data do not show neurotoxicity con-
cerns, there is still a reasonable doubt consider-
ing the mentioned animal study. This needs to
be clarified before definitive recommendations
can be done.
Conclusions
There is an adjuvant effect of IT Mg for spinal
anesthetics that include a local anesthetic and an
opiate or opiates alone. There is not enough evi-
dence to argue definitely in favor of that same
capacity when the spinal anesthetic only in-
cludes a local anesthetic. May be lidocaine has a
particular analgesic interaction with IT Mg, but
this needs further clarification in future studies.
The amount of heterogeneity among the stud-
ies was considerable, but it was accounted for by
Intrathecal magnesium: a meta-analysis RAMÍREZ
the random type of analysis used, which elevates
the threshold to find significant results in meta-
analytic studies. The postoperative consumption
of analgesics could not be computed as a size ef-
fect data due to the disparity of the used agents,
but a direct look to the figures leaves no doubt
about it. The number and size of the clinical tri-
als should increase before definite recommenda-
tions can be done, ruling out safety concerns.
This meta-analysis suggests that the addition
of 50 to 100 mg of IT Mg could be useful when
a spinal anesthetic has to be used, particularly
for outpatient surgery (more analgesia-time free
of rescue pain-killers, less postoperative amount
of these agents and no prolongation of the mo-
tor blockade without increasing the incidence of O
side-effects as pruritus, PONV, urinary reten-
tion, etc), but the evidence in that specific target
population is not available thus far.
There is no evidence that Mg is harmful to
spinal tissue, but studies focused specifically on
O
this issue would be advisable. The capacity of IT
Mg as neuroprotective agent for chronic post-
operative pain and for TNS needs additional
search.
R
Key messages
VA
—— Clinical studies show magnesium is
effective and safe as intrathecal adjuvant;
P
advantages compared to other available adju-
R
vants are unclear; some safety concern from
preclinical studies should be clarified before
E
recommendations can be done.
IN
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An abstract of the present paper was presented at the European Society of Regional Anesthesia (ESRA), Bordeaux, France, September
2012.
P

Conflicts of interest.—Dr. Pascual-Ramírez has a research grant by the Fundación Mutua Madrileña for an intrathecal magnesium clinical
R

trial to be started on 2013.

Received on November 2, 2012. - Accepted for publication on January 22, 2013.
Corresponding author: J. P. Ramírez, Hospital General Universitario de Ciudad Real, c/Besana, 2b 13170 Miguelturra, Spain. E-mail:
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pascrib@hotmail.com
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12 MINERVA ANESTESIOLOGICA ?? 2013