96 MINERVA ANESTESIOL OGICA January 2014R E V I E WAnno: 2014 Mese: JanuaryVolume: 80No: 1Rivista: MINERV A ANESTESIOLOGICACod Rivista: Minerva… [629462]

96 MINERVA ANESTESIOL OGICA January 2014R E V I E WAnno: 2014
Mese: JanuaryVolume: 80No: 1Rivista: MINERV A ANESTESIOLOGICACod Rivista: Minerva AnestesiolLavoro: titolo breve: Intrathecal and systemic adjuvants to spinal block
primo autore: STAIKOU
pagine: 96-112
Single-shot subarachnoid anesthesia is a popu-
lar regional modality, as it is relativ
ely easy
to perform, and pro
vides a fast and dense neu-
ral block with small doses of local anaesthetics
(LAs). Nev
ertheless, it is a non-titratable tech-
nique, and thus, the block and analgesia can-
not be potentiated or extended in duration, if
needed.
Intrathecal adjuvants are combined with LAs
in order to potentiate the spinal block and pro-
long analgesia.1-13 Also, they allow a reduction of
the LA dose,14 thus enabling a faster reco very of
motor function and voiding, and consequently
a faster discharge. Various systemic and inhala-tional adjuvants have also been tested for their
efficacy to impr
ove subarachnoid block.15-23
This review presents the intrathecal, systemic
and inhalational adjuvants that have been stud-
ied for their impact on subarachnoid block, spe-
cifically on the onset, height, quality and dura-
tion of sensory (SB) and motor block (MB), and
also on the duration and quality of analgesia.
Significant side effects and safety issues are also
described.
We conducted a MEDLINE® literature search
using the terms “intrathecal adjuvants
”, “system-
ic adjuvants
”, “opioids
”, “fentanyl
”, “alfentanil
”,
“sufentanil
”, “morphine
”, “pethidine
”, “diamor-The effects of in trathecal an d sy stemic
ad
juvants on su
barachnoid bl
ock
C. STAIKOU, A. PA RASKEVA
Department of An esthesia, Are taieio Ho spital, Me dical Sc hool, Un iversity of At hens, At hens, Gre ece
A B S T R A C T
Various intrathecal and systemic adjuvants to local anaesthetics have been found to impro ve the quality and extend
the duration of spinal block. Intrathecal opioids are the most frequently used; the lipophilic fentanyl and sufentanil
enhance and moderately prolong the sensory block, whereas the hydr
ophilic morphine significantly prolongs spinal
analgesia. Nausea/v
omiting, pruritus, urinary retention and respirator
y depression are possible side effects. Adr
ener-
gic agonists, such as adrenaline and phenylephrine may prolong the block due to vasoconstriction, while clonidine
and dexmedetomidine accelerate the onset and prolong the duration of block and analgesia. Hypotension, sedation
and respirator
y depression have been repor
ted with clonidine. Other intrathecal adjuvants, such as midazolam, keta-
mine and neostigmine may also impro
ve the quality of block and prolong analgesia, but are not popular because of
their adverse effects. Intrathecal magnesium sulphate mainly potentiates the analgesic action of intrathecal opioids,
without significant side effects. A positive impact on spinal analgesia has also been suggested
– from animal studies
– for intrathecal calcium channel blockers, while the analgesic efficacy of intrathecal nonsteroidal anti-inflammatory
drugs remains questionable. Sev
eral drugs may also affect the spinal block characteristics after systemic administra-
tion. Opioids enhance, alpha-2 agonists and ketamine prolong the block, magnesium sulphate reduces postoperative
analgesic consumption and nimodipine may delay the regr
ession of sensory block. Nitr
ous oxide inhalation has also
been found to enhance the level of sensory spinal block. Ev
en though opioids are the most popular adjuvants to
spinal local anaesthetics, a variety of drugs given intrathecally or systemically, can accelerate, impro
ve and extend
the spinal block. (M
inerva Anestesiol 2014;80:96-112)
Key words: A
djuvants, anesthesia – Anesthesia, spinal – I
ntrathecal injections – I
ntravenous injections.
COPYRIGHT© 2014 EDIZIONI MINERVA MEDICA
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use isnot permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo ,
or other proprietary information of the Publisher.

INTRATHECAL AND S yST EMIC ADJUVANTS TO SPINAL BLOCK ST AIKOU
Vol. 80 – N
o. 1 MINER
VA ANESTESIOL
OGICA 97phine”, “tramadol”, “epinephrine ”, “nor epine-
phrine”, “phenylephrine
”, “clonidine
”, “dexme-
detomidine
”, “benzodiaz
epines”, “midaz
olam”,
“ketamine”, “neostigmine
”, “nonster
oidal anti-
inflammatory drugs
” “calcium channel block-
ers
”, “magnesium
”, “baclofen”, “cor
ticosteroids”,
“nitr
oglycerin”, “nitr
ous oxide
”, “v
olatiles”, “and
“local anaesthetics”, “spinal block”, “subarach-
noid block” Clinical studies with <10 patients
per group
, volunteer studies with <8 subjects,
case repor
ts/series, and articles in languages
other than English wer
e excluded. Randomised
controlled trials (RCT
) were preferr
ed, while an-
imal/experimental studies wer
e used only when
clinical data wer
e lacking. We identified 113 ar-
ticles suitable to be included in the revie
w. Addi-
tionally
, 8 studies wer
e found by manual search-
ing. T w
enty-six articles pro
viding information
about mechanisms of action and safety profile of
the studied agents wer
e also used. In total, 147
articles (105 R
CT) w
ere included in the r
eview.
Intrathecal adjuvants
Opioids
Intrathecal opioids impro
ve the spinal block
(T
able I), while sparing the LA dose.3, 5, 14 Selec-
tiv
e spinal opioid analgesia -with omission of the
LA- has also been advocated in clinical practice.
Its advantage is the selective inhibition of pain
pathways without sympathetic or motor block-
ade, thus ensuring cardio
vascular stability and
early ambulation.24
Opioid antinociception is mediated via acti-
v
ation of opioid receptors located in substantia
gelatinosa.24 Opioids act both pre- and posty-
naptically; they inhibit the prosynaptic release
of excitator
y neurotransmitters (i.e
., substance
P), while postynaptically interfer
e with K+-
currents resulting in neuronal hyperpolariza-
tion.24, 25 They may also enhance the descending
inhibitory pathways and the release of acetylcho-
line and adenosine.25 Impairment of the central
perception of noxious stimuli, and a decrease of
spinal blood flow with subsequent reduction of
LA blood absorption may play a r
ole, too
.
Intrathecal fentanyl at doses 10-50 μg has
been found to prolong the duration,1, 2, 26-29 and increase the upper SB level in healthy volun-
teers 29 but not in parturients.26 It also improves
the quality of spinal block intraoperatively
,27, 30-32
without delaying MB resolution.1, 2, 29 These
proper
ties render fentanyl suitable for cases re-
quiring fast postoperative mobilization, while
it is probably not ideal when prolonged anal-
gesia is needed, due to its modest duration of
action.33 Doses ranging from 6.25 to 15 μg pro-
long analgesia by up to 2h after caesarean deliv-
er
y (CD),1, 3, 27, 31, 34 without additional benefit
from large doses.1, 34 Fentanyl short-lasting anal-
gesia is further indicated by the lack of reduction
of postoperative pain intensity 30 and analgesic
requir
ements after 4-6 h.3, 30 Moreover, a 63%
increase in morphine consumption between 6
and 23 h after CD has been attributed to acute
opioid tolerance induced b
y fentanyl.30
Intrathecal sufentanil accelerates the on-
set,28, 35 improves the quality 31 and prolongs the
duration of SB induced by bupivacaine,28 but
not by the relativ
ely short acting mepivacaine.26
It accelerates the establishment of MB,26 but does
not affect its resolution.1, 28 It potentiates the in-
traoperativ
e and prolongs postoperative analge-
sia,26, 28, 31, 32, 35 by 4-5 h.26, 28 For surgical an-
esthesia,4, 28, 31, 32, 35, 36 mostly in CD,4, 31, 32, 35, 36
doses ranging from 1.5 to 7.5 μg have been used,
though larger doses -up to 10 μg- have been re-
por
ted in labour analgesia.37 A dose-independent
effect on LA sparing,14 and also on duration of
analgesia 4, 14 and supplementary requir ements 4
has been demonstrated.
I
ntrathecal morphine pro
vides adequate and
prolonged analgesia,35, 38-41 without affecting
the level or duration of SB and MB.38 In par-
turients undergoing CD, morphine 0.1-0.2 mg,
impro
ves the quality,42 prolongs the duration of
postoperative analgesia 36, 38 by up to 25 h,38 re-
duces the 24 h morphine consumption 42 and in-
cr
eases patient satisfaction.42 In patients under-
going hip arthr
oplasy, morphine 0.05 mg does
not pro
vide adequate postoperative analgesia,41
while doses ranging from 0.1 to 0.3 mg exhibit
similar efficacy in reducing postoperative opioid
consumption.40, 41 Also, analgesia is prolonged
to a similar extent by 0.1 or 0.2 mg.41 Neverthe-
less, nausea/vomiting 40 and pruritus 41 are more
frequent with larger doses. Thus, although the
COPYRIGHT© 2014 EDIZIONI MINERVA MEDICA
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use isnot permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo ,
or other proprietary information of the Publisher.

STAIKOU INT RATHECAL AND S yST EMIC ADJUVANTS TO SPINAL BLOCK
98 MINERVA ANESTESIOL OGICA January 2014In CD, even large doses, such as 0.2 mg/kg, do
not significantly affect the level of SB,44 time to
reach the highest dermatome 44 and regression
of SB and MB.44 Smaller doses (7.5-10 mg) im-
pr
ove and moderately prolong the duration of optimal dose is unkown,43 doses ranging from
0.1 41 to 0.2 40 mg probably repr esent the best
balance betw
een safety and efficacy
.
Though not popular, pethidine has been used
in clinical practice as adjuvant to spinal LAs. Table I.—Effects of intrathecal opioid adjuvants on subarachnoid block.
Intrathecal opioidEffect on sensory block,
motor block and analgesiaD oses studied Local anesthetic used Sources of evidence
Fentanyl –SB: faster onset 28
–prolonged duration 1, 2, 26-29
–higher peak lev el 29
–improved quality 30, 31
–MB: no significant effects 1, 2, 29 faster
onset 26 improved muscle relaxation 32
–Analgesia: impr oved IO
(doses≥12.5 μg) 27, 30, 32, 34 prolonged
duration 2, 3, 26-29, 31, 32, 34min: 2.5 μg
max: 50 μg
2.5-50 μg 1
5-10 μg 26
7.5-15 μg 34
10 μg 31
15 μg 3, 27
20 μg 2, 29, 32
25 μg 28, 30Bupivacaine 1, 28, 30-32, 34
Lidocaine 2, 3, 27
2-Chloroprocaine 29
Mepivacaine 26RCT, N.=56 1
R-cross over, N.=8 vol 2
RCT, N.=28 3
RCT, N.=100 26
RCT, N.=40 27
RCT, N.=90 28
R-cross over, N.=8 vol 29
RCT, N.=60 30
RCT, N.=80 31
RCT, N.=72 32
RCT, N.=75 34
Sufentanil –SB: faster onset 28, 35 prolonged
duration 28
–MB: faster onset 26 prolonged
duration 28
–Analgesia: impr oved
IO 4, 31, 32 prolonged
duration 4, 14, 28, 31, 32, 35 reduced
analgesic consumption PO 4, 31min: 1.5 μg max:
7.5 μg
1.5-5 μg 4
2.5 μg 32
2.5- 5 μg 31
2.5-7.5 μg 35
5 μg 28, 36Bupivacaine 4, 14, 28,
31, 32, 35, 36
Mepivacaine 26RCT, N.=100 4
RCT, N.=150 14
RCT, N.=100 26
RCT, N.=90 28
RCT, N.=80 31
RCT, N.=72 32
RCT, N.=80 35
RCT, N.=54 36
Morphine –SB: no effects 38
–MB: no effects 38
–Analgesia: impr oved IO 38 prolonged
duration 36, 38, 39, 41
–improved PO/lo wer VAS
scores 39, 41, 42
–reduced analgesic consumption
PO 40-42
*0.05 mg: produces no effective
analgesia 41min: 0.05 mg
max: 0.3 mg
0.05-0.2 41
0.1 42
0.1-0.3 40
0.2 36, 38, 39Bupivacaine 36, 38-42 RCT, N.=54 36
RCT, N.=34 38
RCT, N.=60 39
RCT, N.=80 40
RCT, N.=60 41
RCT, N.=60 42
Pethidine –SB: pr olonged duration 45 higher peak
level 46/no effect on median level 45
–Analgesia: impr oved IO 46 prolonged
duration 45, 46
–no effect on analgesic consumption
PO 45
*Addition of pethidine 0.2 mg/kg to
bupivacaine -morphine (10.5/0.15 mg)
has no effect on SB/MB (lev
el, time to
peak lev
el, r
egression) 44min: 7.5 mg max:
0.2mg/kg
7.5 mg 46
10 mg 45
0.2 mg/kg 44Bupivacaine 44-46 RCT, N.=40 44
RCT, N.=40 45
RCT, N.=50 46
Diamorphine –SB: no effect on lev el 5, 49
–Analgesia: no effect 49/improved
IO 5, 51 prolonged duration 5, 51
reduced analgesic consumption PO 51min: 0.2 mg
max: 0.5 mg
0.2-0.5 mg5
0.3 mg 51 0.4 mg 49Bupivacaine 5, 49, 51 RCT, N.=200 5
RCT, N.=80 49
RCT, N.=75 51
T ramadol –Analgesia: pr olonged duration 52, 53
–improved PO/lo wer VAS scor es 53min: 20 mg
max: 25 mg
20 mg 53
25 mg 52Bupivacaine 52, 53 RCT, N.=40 52
RCT, N.=50 53
SB: sensory block; MB: motor block; VAS: Visual Analogue Scale; IO: intraoperatively; PO: postoperatively; RCT : Randomised Controlled T rial;
N. number of patients; v
ol: v
olunteers.
COPYRIGHT© 2014 EDIZIONI MINERVA MEDICA
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use isnot permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo ,
or other proprietary information of the Publisher.

INTRATHECAL AND S yST EMIC ADJUVANTS TO SPINAL BLOCK ST AIKOU
Vol. 80 – N
o. 1 MINER
VA ANESTESIOL
OGICA 99long-acting opioids combined with LAs.54 The
incidence is quite low
er for short-acting opio-
ids (0-25%) 54 or when opioids are administered
alone, i.e., 1.8% and 11.6% for pethidine and
morphine, respectiv
ely.43, 47 Uterine hyperactiv-
ity and fetal heart rate abnormalities have been
observ
ed in parturients receiving relativ
ely large
doses (7.5 μg) of sufentanil for labor analgesia.55
Last, sedation/respirator
y depression is mostly
related to morphine.43Although quite rare,42, 43
it remains the major safety concern regar
ding in-
trathecal opioids.
A
lpha-adrenergic agonists
The direct acting alpha-adrenergic agonists,
have long been used as adjuvants to spinal LAs
in order to prolong the spinal blockade (T
able
II). Their effect is mainly attributed to spinal
vasoconstriction and subsequent decrease of LA
systemic absorption, while a direct antinocicep-
tiv
e action via spinal alpha-adrenergic receptors,
especially the alpha- 2 type, may also exist. The
central alpha-2-adrenergic agonists, activate al-
pha-2-adr
energic receptors in substantia gelati-
nosa and also spinal opioid receptors.56 Antinoc-
iception is probably related to the suppression of
C-fiber neurotransmitters
’ release and increased
potassium conductance leading to hyperpolari-
sation of post-synaptic dorsal horn neur
ons.56
The addition of epinephrine 0.1-0.5 mg to
various LAs prolongs both SB and MB 57-63
dose-dependently,58 but without affecting the
onset time or the upper level of block.58, 64, 65
Inter
estingly, the time for SB to reach T4 in-
cr
eases,66 and SB height decreases 67 when epine-
phrine is added to a bupivacaine/opioid mix-
tur
e.66, 67 However, prolongation of bupivacaine/
opioid induced labor analgesia,67 and reduction
of additional analgesic requir
ements have been
repor
ted.68 Also, epinephrine impro ves intra-
operativ
e anesthesia /analgesia and reduces the
need for supplements.63, 69 Nonetheless, it seems
to have no efficacy in selective spinal analgesia
without LAs; it has offered no benefit to gynae-
cologic surgical patients 70 or laboring parturi-
ents 71 receiving morphine 70 or sufentanil 71 an-
algesia. Epinephrine side effects include flu-like
symptoms,59 increased nausea and pruritus when anesthesia and analgesia by 1.5-2h,45, 46 without
reducing the 24h morphine consumption 45 after
CD. Inter
estingly, sole intrathecal pethidine 5%
at ver
y high doses (0.5 mg/kg) has been found
to induce SB and MB.47 Long lasting analgesia
of 5-8.5 h has been repor
ted with doses 0.5-1
mg/kg after perineal surgery and CD.47, 48 The
extremely wide range of doses (7.5 mg-1 mg/kg)
may explain the different efficacy of pethidine
repor
ted in clinical studies.
I
ntrathecal diamorphine 0.2-0.5 mg does
not significantly affect spinal block characteris-
tics,5, 49 but significantly potentiates intraopera-
tiv
e analgesia.5, 50, 51 Also, improved 5, 50, 51 and
long-lasting 5, 51 postoperative analgesia up to
11.5 h,5 with concomitant decrease of 24 h mor-
phine consumption 50, 51 has been demonstrated
for these doses. As both analgesic and side effects
are dose-dependent,5 a dose of 0.4 mg possibly
repr
esents a safe and efficacious choice.5
T ramadol exerts its antinociceptive effects by
activating opioid receptors and also by inhibit-
ing the reuptake of norepinephrine and serot-
onin, thus suppressing pain transmission in the
spinal cord. T ramadol 25 mg combined with
bupivacaine pro
vides labour analgesia of about
2 h, but the incidence of vomiting may reach
25%.52 A lower dose, such as 20 mg, is probably
preferable, since it reduce pains and prolongs an-
algesia after gynaecological surgery
, without any
side effect, such as nausea/vomiting, pruritus, or
respirator
y depr
ession.53
Comparative studies have shown that suf-
entanil prolongs analgesia more than fenta-
nyl,26, 31 while morphine is superior to both 36, 39
regar
ding the quality and duration of postop-
erativ
e analgesia. No significant differences wer
e
found among these opioids regar
ding their ef-
fects on SB and MB.36, 39 Diamorphine has also
been found superior to fentanyl, in terms of pro-
longed analgesia 51 and reduced postoperative
morphine consumption.50, 51
Intrathecal opioids have been associated with
several troublesome side effects. Nausea and
vomiting are quite common,5, 32, 45 especially
with pethidine.45 Pruritus, another frequent
symptom,2, 14, 28-30, 34, 37, 40-43 seems to increase
along with the administered dose.4, 5, 41 Urinary
retention occurs in 25-36% of patients receiving
COPYRIGHT© 2014 EDIZIONI MINERVA MEDICA
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use isnot permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo ,
or other proprietary information of the Publisher.

STAIKOU INT RATHECAL AND S yST EMIC ADJUVANTS TO SPINAL BLOCK
100 MINERVA ANESTESIOL OGICA January 2014cal norepinephrine; doses 5-15 μg added to tet-
racaine do not affect the onset of SB or its upper
level, but significantly prolong the duration of
both SB and MB.74 No significant haemody-
namic effects have been repor
ted for these dos-
es.74
The effect of vasoconstrictors on spinal block
is largely determined by the drug combination
and doses used.58 Among LAs, bupivacaine 73
and lidocane 65 seem to be the least influenced. combined with opioids,71 and a high incidence
(>20%) of MB in laboring par
turients.68
Intrathecal phenylephrine at a dose of 5 mg
prolongs more than 70% 58 the duration of
SB 58, 72 and MB 58 induced by tetracaine,58, 72
but not by bupivacaine.73 In either case, the on-
set time,58 the upper SB level 72 or the time to
reach it 58 are not affected. The incidence of tran-
sient neur
ologic symptoms may ex
ceed 12%.72
Limited clinical data exist regar ding intrateh-Table II.—Effects of alpha-adrenergic agonists and selective alpha-2-agonists on subarachnoid block.
Intrathecal adjuvantEffect on sensory block,
motor block and analgesiaD oses studied Local anaesthetic used Sources of evidence
Alpha-agonists
Epinephrine –SB: no effect on onset 58, 64, 65
–no effect on peak lev el 65 no effect 65/
prolonged duration 57, 60-62, 72
–MB: no effect on onset 58, 64, 65
prolonged duration 57-62
–Analgesia: impr oved IO 63, 69
prolonged duration 63
–reduced analgesic consumption
PO 69min:12.5 μg
max: 0.6 mg
12.5 μg 64
0.1-0.5 mg 61
0.2 mg 60-63, 65, 69 71, 72
0.3 mg 57
0.4-0.6 mg62
0.5 mg 58Procaine 57
Tetracaine 58, 69
2-Chloroprocaine 72
Bupivacaine 60, 61, 64
Lidocaine 62, 63, 65RCT, N.=62 57
RCT, N.=30 58
R-cross over,
N.=18 v
ol 59
RCT, N.=63 60
RCT, N.=96 61
RCT, N.=80 62
RCT, N.=78 63
RCT, N.=50 64
RCT, N.=29 65
RCT, N.=60 69
RCT, N.=40 71
Phenylephrine –SB: no effect on onset 58 no effect on
peak lev
el 72, 73
–no effect 73/prolonged duration 58,72
–MB: no effect on onset 58 prolonged
duration 58, 725 mg 58, 72, 73 Bupivacaine 73
Tetracaine 58, 72RCT, N.=30 58
RCT, N.=160 72
RCT, N.=30 73
Norepinephrine –SB: no effect on onset 74 no effect on
peak lev
el 74
–prolonged duration 74
–MB: pr olonged duration 74min:5 μg
max:15 μg
5-15 μg 74Tetracaine 74 RCT, N.=80 74
Alpha 2-agonists
Clonidine –SB: faster onset 6 prolonged
duration 6, 76-81, 83 higher peak level 79
–MB: faster onset 83 prolonged
duration 6, 76, 77-80, 82, 83
–Analgesia: impr oved IO 77, 82
prolonged duration 76, 78-80 improved
PO/low
er VAS scor
es 76, 79-81min: 15 μg
max: 150 μg
15 μg 78
15-30 μg 79, 82
15-75 μg 77
30 μg 83
37.5-150 μg 76
45-75 μg 80
75 μg 81
100 μg 6Bupivacaine 76, 79-83
Ropivacaine 77
Lidocaine 6
2-Chloroprocaine 78RCT, N.=90 6
RCT, N.=80 76
RCT, N.=120 77
R-crossover, N.=8 vol 78
RCT, N.=45 79
RCT, N.=60 80
RCT, N.=106 81
RCT, N.=75 82
RCT, N.=60 83
Dexmedetomidine –SB: faster onset 84, 85 no effect on
peak lev
el/time to r
each 86
–prolonged duration 84-88
–MB: faster onset 84, 85 prolonged
duration 84-88
–Analgesia: pr olonged duration 86
impro
ved PO/lo
wer VAS scor
es 86
reduced analgesic consumption PO88min: 5 μg
max: 10 μg
5 μg 86-88
5-10 μg 84
10 μg 85Bupivacaine 84, 85, 87, 88
Ropivacaine 86RCT, N.=66 84
RCT, N.=90 85
RCT, N.=60 86
RCT, N.=76 87
RCT, N.=60 88
SB: sensory block; MB: motor block; VAS: Visual Analogue Scale; IO: intraoperatively; PO: postoperatively; LA: local anesthetic; RCT : Ran-
domised Contr
olled T rial; N. number of patients; v
ol.: v
olunteers.
COPYRIGHT© 2014 EDIZIONI MINERVA MEDICA
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use isnot permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo ,
or other proprietary information of the Publisher.

INTRATHECAL AND S yST EMIC ADJUVANTS TO SPINAL BLOCK ST AIKOU
Vol. 80 – N
o. 1 MINER
VA ANESTESIOL
OGICA 101are not significantly affected.86 Although clini-
cal data are limited, dexmedetomidine seems to
be a potent analgesic; even low doses, such as 5
μg, prolong analgesia by 4 h,86 and significantly
reduce postoperative pain intensity 86 and 24h
analgesic consumption.88 Regarding its safety
profile, for doses up to 10 μg, it has not been
associated with adverse effects, such as nausea/
vomiting, pruritus,86, 88 sedation,83, 84, 86, 88 respi-
rator
y depression 86, 88 or significant hypotension
or brady
cardia.83, 84, 86-88
Benzodiazepines: midazolam
Midazolam suppresses the sensory and motor
excitability of spinal neurons 89 via enhancing
gamma aminobutyric acid (GABA) activity in
the central nerv
ous system (CNS). When added
to intrathecal LAs it prolongs the duration of
SB,8, 9, 90 with no effect on MB regr ession,8, 10
(T
able III). It also impro
ves the quality 8, 9, 90-93
and prolongs postoperative analgesia.8-10, 90, 91
Although the optimal dose is not clearly deter-
mined, midazolam <1 mg probably has no ef-
fect on SB or analgesia,90, 93 while the commonly
used doses (1-2 mg) result in moderate prolon-
gation of analgesia by 0.5-2.3 h, after CD 90 or
general surger
y.9
Midazolam has also been combined with oth-
er spinal adjuvants; a dose of 2 mg potentiates,
but prolongs modestly (by less than 1 h) fentanyl
10 μg analgesia in labouring parturients, without
adverse effects on mothers and neonates.94 Also,
in adult surgical patients, the addition of mid-
az
olam to bupivacaine/ketamine,11 but not to
bupivacaine/clonidine,95 significantly prolongs
analgesia (by 6h),11 possibly due to a midazolam-
ketamine synergistic interaction.
A
lthough mi
dazolam ap
pears to be sa
fe,8, 9, 90, 93
it is no
t po
pular in ev
eryday pr
actice, pa
rtly be
–
cause of an is
sue th
at wa
s ra
ised ab
out po
ssible
ne
urotoxicity.89, 96 Nevertheless, th ere ar e no
cl
inical fin
dings in hu
mans to re
late do
ses ≤2 mg
of pr
eservative fr
ee mi
dazolam wi
th in
creased
ri
sk of ne
urotoxicity.10, 89, 90, 94 , 97 Except from
a mi
ld tr
anquility,91, 92 midazolam ha s no t be en
as
sociated wi
th re
spiratory/cardiovascular si
de ef
–
fects,8, 9, 90, 94 significant sedation,8, 9, 90-92, 94 or uri-
nary re
tention.8, 90The dose affects the degree of vasoconstriction,
which is associated with block prolongation, but
also with neurologic complications due to local
ischaemia and/or increased exposure of the neu-
ral tissue to the L
A.72
Regarding ce ntral al pha-2-adrenergic ag o-
nists, in
trathecal cl
onidine im
proves th
e qu
al-
ity an
d pr
olongs sp
inal an
esthesia an
d an
al-
gesia.75, 76 It has been co mbined wi th va rious
LA
s, in do
ses 15
-150 μg
.6, 7, 75-83 It accelerates
th
e on
set,6, 83 and prolongs do se-dependent-
ly 75, 76, 82 both SB 6, 76-81, 83 and MB,6, 76-83 (Ta-
ble II
). In th
e ab
sence of op
ioids, cl
onidine
ha
s li
mited eff
ects on po
stoperative an
alge-
sia in ob
stetric an
d ad
ult su
rgical po
pula-
tion.76, 79-81 Even large do ses (7 5 81-150 μg 76)
pr
olong an
algesia by ab
out 2.
5 h,76 without re-
d
ucing th
e 24 h an
algesic ne
eds.81 Conversely,
it
s ad
dition to a bu
pivacaine/morphine mi
x-
ture si
gnificantly de
creases bo
th pa
in in
tensity
an
d 24 h mo
rphine co
nsumption af
ter or
tho-
pedic su
rgery.7
The optimal dose of intrathecal clonidine is
not known.75 A dose of 150 μg may be used to
prolong spinal anesthesia in long-lasting proce-
dur
es,76 where MB prolongation is acceptable.
In ambulatory surgery
, smaller doses (15-30 μg)
are preferr
ed to impro
ve the quality of spinal an-
esthesia/analgesia.77, 79, 82 Nevertheless, even such
low doses may also prolong the MB 78, 79, 83 and
delay ambulation.78
Side effects include hypotension,75, 77, 83 seda-
tion 6, 77 and urinary retention.78, 79, 82 It is not
clear if the incidence of arterial hypotension in-
cr
eases 77, 80 or not 75, 76 with larger doses, while
occurrence of bradycar
dia seems to be unaffected
by clonidine.75, 80 Time to void increases even
with small doses;78, 79, 82 a prolongation by 10-
25% has been observ
ed after addition of cloni-
dine 15-30 μg to bupiv
acaine.82
The combination of dexmedetomidine 3-10
μg with intrathecal bupivacaine or ropiv
acaine
significantly accelerates the onset time 84, 85 and
prolongs dose-dependently 84, 85 the duration of
SB 83-88 and MB.83-88 Even the smallest dose (3
μg) may delay the regr
ession of MB by about 1.5
h,83 rendering the drug unsuitable for ambula-
tor
y surgery
. Regar
ding other block characteris-
tics, the upper SB level or the time to reach it
COPYRIGHT© 2014 EDIZIONI MINERVA MEDICA
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STAIKOU INT RATHECAL AND S yST EMIC ADJUVANTS TO SPINAL BLOCK
102 MINERVA ANESTESIOL OGICA January 2014Table III.—Effects of miscellaneous intrathecal adjuvants on subarachnoid block: midazolam, magnesium, ketamine, neostig-
mine, nonsteroidal anti-inflammatory drugs (NSAIDs), calcium channel blockers, baclofen and dexamethasone.
Intrathecal adjuvantEffect on Sensory block,
Motor block and AnalgesiaD oses studiedLocal anaesthetic and/or
opioid
usedSour ces of evidence
Benzodiazepines
Midaz
olam –SB: no effect on peak lev el 9 prolonged
duration 8, 9, 90
–MB‡: no effect on duration 8/prolonged
duration 9
–Analgesia: impr oved IO 9 prolonged
duration 8, 9, 90-92 improved PO/lower
VAS scor
es 8, 9, 91-93 reduced analgesic
consumption PO 90
‡A meta-analysis by Ho et al. found no
impact on motor block duration10min: 0.5 mg
max: 2 mg
0.5-1 mg 93
1 mg 9
1-2 mg 90
2 mg 91, 92Bupivacaine 8, 9, 90, 91
Lidocaine 92, 93RCT, N.=30 8
RCT, N.=40 9
RCT, N.=60 90
RCT, N.=44 91
RCT, N.=40 92
RCT, N.=45 93
Magnesium –SB: delay ed onset 100, 101, 105*, 106*/ no
effect 104* prolonged duration 100-102, 106*/
no effect 104*
–MB: delay ed onset 100, 101, 105* / no
effect 104* prolonged duration 100/no
effect104*
–Analgesia: impr oved IO 67 prolonged
duration 99, 102 improved PO/lower VAS
scores 99
–reduced analgesic consumption
PO 12, 99, 100, 103, 105*, 106*
* Mg combined with bupivacaine alonemin: 50 mg
max: 100 mg
50 mg 99-105*
94.5 mg 12
100 mg106*Bupivacaine 104-106
Bupivacaine +
Fentanyl 99-102
Levobupivacaine +
sufentanil 12
Fentanyl + morphine 103RCT, N.=120 12
RCT, N.=80 99
RCT, N.=60 100
RCT, N.=100 101
RCT, N.=60 102
RCT, N.=58 103
RCT, N.=90 104
RCT, N.=90 105
RCT, N.=79 106
Ketamine –SB: faster onset 110, 111 faster peak level
establishment 111
–MB: faster onset 111, 112
–shorter duration 109, 110 decreased
intensity 110
–Analgesia: no significant effects 11, 109, 111min: 0.05 mg/
kg
max: 25 mg
0.05 mg/kg 111
0.1 mg/kg 11, 110
25 mg109Bupivacaine 11, 109-111 RCT, N.=60 11
RCT, N.=30 109
RCT, N.=40 110
RCT, N.=90 111
Neostigmine –SB: faster onset122/no effect 116, 121 no
effect on highest lev
el13, 116, 119 no effect
on duration 116, 121
–MB: no effect on the
onset 116, 121 prolonged duration 13, 122/no
–effect 116, 121
–Analgesia: impr oved IO 13 prolonged
duration13, 116,121,122 improved PO/lower
VAS scor
es13,116, 122
–reduced analgesic consumption
PO 13,116,119min: 5 μg
max: 100 μg
5 μg 119
25 μg 116
50 μg 13
50-100 μg 122
100 μg 121Bupivacaine 13, 116 119, 121
Tetracaine 122RCT, N.=80 13
RCT, N.=79 116
RCT, N.=48 119
RCT, N.=36 121
RCT, N.=60 122
NSAIDs
Ketorolac –SB: no effect 135
–Analgesia: no effect 1350.5-2 mg 135 Bupivacaine 135 (3 studies) 135
–open label, N.=15
–R-cross o
ver,
N.=12 v
ol
–RCT
, N.=30
Calcium channel
blockers
–Verapamil (
V)
–Diltiaz
em (D)
–Nicar
dipine (N) –SB (
V+LA): potentiation 136 prolonged
duration 136
–MB (
V+LA): potentiation 136 prolonged
duration 136
–Analgesia ( V+LA): impr obe 136
prolonged duration 136
–Analgesia ( V, D, N): potentiation of
spinal morphine antinociception 137V: 50 μg 136, 137
D: 100 μg 137
N: 20 μg 137Tetracaine 136
Lidocaine 136Animal study (rats) 136
Animal study (rats) 137
Baclofen –Analgesia: pr olonged duration 138
impro
ved PO/lo
wer VAS scor
es 138
–reduced analgesic consumption PO 138100 μg 138 Bupivacaine 138 RCT, N.=60 138
Dexamethasone –SB: no effect on onset 139
–no effect on peak lev el 139 prolonged
duration 139
–Analgesia: pr olonged duration 1398 mg 139 Bupivacaine 139 RCT, N.=50 139
SB: sensory block; MB: motor block; VAS: Visual Analogue Scale; IO: intraoperatively; PO: postoperatively; RCT : randomised controlled trial; N.
number of patients; v
ol: v
olunteers.
COPYRIGHT© 2014 EDIZIONI MINERVA MEDICA
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INTRATHECAL AND S yST EMIC ADJUVANTS TO SPINAL BLOCK ST AIKOU
Vol. 80 – N
o. 1 MINER
VA ANESTESIOL
OGICA 103unsuitable for use as sole spinal anaesthetic.108
yet, it may still repr
esent an attractive adjuvant
due to its cardio
vascular stability,11, 111 and LA
sparing effects.109, 110 The addition of 0.05-0.1
mg/kg to intrathecal bupivacaine accelerates the
onset of SB and MB 110, 111 and the establish-
ment of upper SB level.111 On the other hand,
it may reduce the intensity 110 and duration of
MB,109 while the duration of analgesia 11, 109, 111
and postoperative analgesic consumption 109 are
probably not affected (
Table III).
I
n most clinical studies ketamine ≤0.1 mg/kg
has been used, since large doses (≥ 25 mg) re-
sult in significant side effects without impro
ved
efficacy.109 Central adverse effects include seda-
tion, dizziness, nystagmus, nausea/v
omiting and
psychomimetic symptoms.108, 109 Furthermore,
concerns about possible neuroto
xicity have
been raised, especially regar
ding repeated doses
or continuous administration.112 Preservatives
such as chlorobutanol are neuroto
xic, thus only
preser
vative-free ketamine should be used in-
trathecally
.113 Even though histological findings
in animals receiving repeatedly preser
vative-free
ketamine indicate a safe profile,114 the issue has
not been adequately clarified.
N
eostigmine
The spinal anti-nociceptive effects of neostig-
mine are associated with inhibition of metabo-
lism and subsequent accumulation of spinal ace-
tylcholine,115, 116 while endogenous nitric oxide
(NO) may also be implicated.117
Neostigmine 10-100 μg used as sole intrathe-
cal agent produces no sensory or motor block-
ing effects.118 Also, doses 5-100 μg added to LAs
do not affect the upper level,13, 116, 119, 120 or the
onset time or regr
ession of SB 116, 121 (Table III).
The findings regar
ding MB are inconclusive;
no effect on the onset and regr
ession 116, 121 or
significant prolongation of MB 13, 122 have been
repor
ted for similar doses used in CD,13, 116
gynecological 121 or general surgery .122 Lower-
extr
emity weakness 120, 123 and decreased deep
tendon reflex
es 123 have been observ ed, especially
after doses >100 μg.123
Regarding analgesia, ve ry la rge do ses (≥ 150
μg
) of ne
ostigmine al
one are ne
eded to pr
o-Magnesium
Magnesium is a non-competitive antagonist
at N-methyl-D-aspartate (NMDA) receptors
and its intrathecal antinociceptive proper
ties are
related to a voltage-dependent blockade of spinal
NMDA receptors.98 Most human data concern
the addition of intrathecal magnesium to a LA/
opioid mixture.99-102 Doses of 50-100 mg do not
affect the level of SB,102 but significantly delay
the onset and regr
ession of both SB 100-102 and
MB 100 (Table III). A significant prolongation of
time to ambulation, as repor
ted after knee ar-
thr
oscopy,102 probably renders magnesium un-
suitable for ambulatory surgery
.102 The quality
of anesthesia and intra- and postoperative anal-
gesia is significantly impro
ved,99, 102 along with
a reduction of postoperative analgesic requir
e-
ments;12, 99, 100, 103 a 50% or more decrease in
36h morphine consumption has been repor
ted
after major surger
y.12, 103
The effects of magnesium on spinal anesthesia
/analgesia are less pronounced when combined
solely with a LA.104 The findings are somewhat
contradictory; no effect,104 or a delay in the on-
set 105, 106 and regression of SB 106 have been re-
por
ted for doses 50-100 mg.104-106 Nevertheless,
these effects are probably of limited clinical sig-
nificance, as the mean duration of anesthesia /
analgesia is not affected in either case.105, 106 Fur-
thermore, intrathecal magnesium, even without
opioid supplementation, may still reduce sig-
nificantly the postoperative analgesic consump-
tion.105, 106
Magnesium seems to be a safe spinal adju-
v
ant, since no side effects, or neurological com-
plications or systemic toxicity have been repor
t-
ed.12, 99, 101, 103
Ketamine
Ketamine is significantly involv
ed in spinal
nociception acting as a non-competitive an-
tagonist at the dorsal horn NMDA-receptors.107
As sole intrathecal agent, it produces SB and
MB at doses ≥0.7 mg/kg.108 Nevertheless, the
short duration of anesthesia, along with a high
incidence of inadequate analgesia (50%) and
psychomimetic effects (30%) render ketamine
COPYRIGHT© 2014 EDIZIONI MINERVA MEDICA
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means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use isnot permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo ,
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STAIKOU INT RATHECAL AND S yST EMIC ADJUVANTS TO SPINAL BLOCK
104 MINERVA ANESTESIOL OGICA January 2014Non-steroidal anti-inflammatory drugs (NSAIDs)
The spinal antinociceptive action of NSAIDs
is mainly related to the inhibition of cycloo
xy-
genase and consequently prostaglandin pro-
duction.125 Muscarinic cholinergic pathways
and spinal acetylcholine release may also be in-
v
olved.126
The vast majority of data regar ding intrathecal
NSAIDs are based on animal studies. In rats, ke-
tor
olac 0.15-0.6 mg has been found to increase
anti-nociception by up to 50-60% maximum
possible effect in the tail flick response laten-
cy
.127 Also, repeated administration of 0.05-0.4
mg produces analgesia, with 0.15 mg being the
maximum effective dose.128 Conversely, no anal-
gesic efficacy has been demonstrated for ketoro-
lac in rat models of acute pain produced by
thermal stimulation;129, 130 even a dose of 0.3 mg
results in low-lev
el analgesia.130 No rise of the
pain threshold to mechanical noxious stimuli
has been found after intrathecal administration
of ketoprofen, phenylbutazone, salicylic acid
and tolfenamic acid in sheep, suggesting that
NSAIDs have no direct spinal effects.131 The ab-
sence of an actual peripheral tissue injury could
possibly explain the ineffectiveness of NSAIDs
in thermal and mechanical stimuli, since their
main action is anti-inflammatory
.130 This ex-
planation is in accordance with the finding that
intrathecal celecoxib decreases the acute inflam-
mator
y pain in rats, but has minimal effects on
pain pr
oduced b
y thermal stimuli.132
A possible synergism between NSAIDs and
other analgesics has also been investigated in
animal models. In mice, cyclo
xyenase-2 inhibi-
tors enhance the analgesic action of intrathecal
morphine; this effect is more prominent with
pareco
xib, less with meloxicam and even less
with nimesulide.133 Contradictory are the avail-
able data on ketorolac-clonidine combination;
a synergistic antinociceptive interaction129 or
antagonism resulting in poor clonidine analge-
sia,127 have both been reported.
Limited evidence from human studies (T
a-
ble III) has shown that intrathecal ketorolac has
no intrinsic effect on sensory
, motor function
and deep tendon reflex
es of the low
er extremi-
ties.134 Also, a dose of 2 mg added to bupivacaine du
ce an eff
ect, as de
monstrated in he
althy vo
l-
unteers.123 However, its co mbination – ev en
in sm
all do
ses –
wi
th ot
her sp
inal an
algesics is
pr
obably us
eful, al
though th
e fin
dings are no
t
co
nsistent.120, 124 According to Ow en et al., th e
ad
dition of ne
ostigmine 10 μg to a mi
xture of
bu
pivacaine/fentanyl 25 μg
/clonidine 30 μg
,
si
gnificantly pr
olongs (b
y >4
0 mi
n) th
e du
ra-
tion of la
bour an
algesia.120 On the other ha nd,
D’
Angelo et
al. fo
und th
at th
is do
se do
es no
t
aff
ect th
e qu
ality or du
ration of la
bour an
alge-
sia in
duced by bu
pivacaine/sufentanil 10 μg
/
clonidine 50 μg
.124 The discrepancy in fin dings
ma
y be ex
plained by th
e di
fferent st
udy de
–
signs, reg
arding th
e po
tency an
d do
se of op
io-
ids, an
d al
so th
e do
se of cl
onidine. Al
though
a sy
nergistic ac
tion be
tween ne
ostigmine an
d
op
ioids ma
y ex
ist, th
e an
ticipated be
nefits ma
y
be ob
scured by ot
her, co
ncomitantly ad
minis-
tered ag
ents.
Doses 25-100 μg impro
ve the quality of in-
tra- and postoperative analgesia.13, 116, 122 The
vast majority of studies in obstetric and gen-
eral surgical population, have shown signifi-
cant prolongation of analgesia 13, 116, 118, 121, 122
(by >4 h),116, 121, 122 lower postoperative pain
scores,13, 116, 122 and reduced analgesic consump-
tion.13, 116, 118, 119 Although larger doses (100 μg)
have been associated with increased duration
and better quality of analgesia than smaller ones
(50 μg),122 the reduction of postoperative mor-
phine consumption is dose-independent for the
dose range 10-100 μg.118
Regarding other effects, neostigmine could
possibly counteract the LA-induced hypotension
via increasing the spinal acetylcholine and the
sympathetic tone.115 The haemodynamic chang-
es are dose-dependent:123 no effect is observ ed
with doses ≤25 μg,116 less LA-induced hypoten-
sion with 100 μg,121 while increased blood pres-
sur
e and heart rate 123 have been reported with
doses >200 μg.
S
everal dose-dependent side effects,13, 118, 123
such as sever
e nausea/vomigint,116 ,123, 124 uri-
nar
y retention,123 dizziness, sweating/distr ess,13,
116, 120-122 even hallucinations, have been re-
por
ted.123 Doses ≤25 μg should probably be
preferr
ed since they are both effective and well
tolerated.13, 118, 119
COPYRIGHT© 2014 EDIZIONI MINERVA MEDICA
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(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use isnot permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo ,
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INTRATHECAL AND S yST EMIC ADJUVANTS TO SPINAL BLOCK ST AIKOU
Vol. 80 – N
o. 1 MINER
VA ANESTESIOL
OGICA 105studies are lacking and their safety profile is not
adequately established.
B
aclofen
Baclofen is a GABAB-receptor agonist, mainly
used in the management of spasticity. With re-
gar
d to its effects on LA-induced spinal block,
the data are scarce.138 In patients undergoing
total knee arthr
oplasty, the addition of baclofen
100 μg to bupivacaine has been associated with
less postoperative opioid consumption, reduced
pain intensity at 42-72 h and a significantly
low
er incidence of chronic pain at 3 months.138
No significant side effects wer
e repor
ted in this
study.138
Corticosteroids
Corticosteroids are commonly administered
neuraxially for the treatment of chronic pain
conditions. Nev
ertheless, there are limited data
regar
ding their impact on the spinal block in-
duced by LAs. In orthopaedic surgical patients,
the addition of dexamethasone 8 mg to bupi-
v
acaine has been found to prolong the dura-
tion of SB, without affecting its onset time, or
its maximum level.139 Dexamethasone may also
prolong significantly postoperative analgesia (by
more than 3 h),139 without any significant ad-
v
erse effects r
eported.139
Systemic adjuvants
Various systemic adjuvants have been investi-
gated for their effects on spinal block (T
able IV).
Systemic opioids enhance the spread 15-17 and
delay the regr
ession of SB,140 without affecting
MB characteristics.140 Intravenous fentanyl 15-17
and nalbuphine17 increase by 3-4 cm the upper
level of SB induced by bupivacaine 15 or lido-
caine.16, 17 Notably, this effect is rev ersed with
nalox
one.16, 17
Intravenous ketamine 0.15 mg/kg has been
associated with a higher level and prolonged
duration of the SB induced by intrathecal bupi-
v
acaine.141 Also, this dose impro ves 18 and pro-
longs 18, 141 postoperative analgesia, thus result-
ing in r
educed analgesic consumption.18, 141does not affect the onset, spread and duration
of SB.135 Furthermore, the drug has been found
ineffective as analgesic when tested in healthy
volunteers 134 and surgical patients.135 The inten-
sity of acute postoperative pain or time to first
morphine dose or the total amount consumed
in 24h are not affected.135 Similarly, in chronic
pain patients the analgesic efficacy of the drug
has been found comparable to placebo.135 In-
ter
estingly, pain is reduced in patients with high
levels of PGE2 in their cerebrospinal fluid, prob-
ably because ketorolac efficacy is associated with
spinal cycloo
xygenase activity.135 Further investi-
gation in this area is needed to clarify if specific
subpopulations can actually benefit from spinal
NSAIDs.
Regar
ding the safety of intrathecal NSAIDs,
the available data are limited. In rats, ketorolac
tromethamine has not been associated with neu-
r
otoxicity, behavioral or histopathological chang-
es, even after multiple intrathecal injections
of large doses, such as 0.4 mg.128 In humans,
ketorolac has not been related to neuroto
xicity
or other serious side effects;134, 135 nevertheless,
more studies are requir
ed to confirm the safety
profile of intrathecal NSAIDs.
C
alcium channel blockers
The efficacy of intrathecal calcium channel
blockers in potentiating the spinal block and an-
algesia produced by LAs and opioids has been
demonstrated in animals.136, 137 These effects are
probably explained by the fact that LAs inhibit
not only sodium, but also presynaptic calcium
channels which stimulate the release of neuro-
transmitters, and that opioids exer
t inhibitory
actions on voltage-dependent calcium-chan-
nels.136, 137 Intrathecal verapamil, diltiazem and
nicardipine -used alone- do not produce any
sensory or motor blocking or antinociceptive
effects.136, 137 Nevertheless, when a small dose
(50 μg) of verapamil is added to lidocaine or tet-
racaine, it potentiates and prolongs both SB and
MB 136 (Table III). Also, verapamil, diltiazem
and nicardipine exhibit a synergistic interaction
with spinal morphine, resulting in significantly
impro
ved analgesia.137 Calcium channel block-
ers are not used in clinical practice, since human
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or other proprietary information of the Publisher.

STAIKOU INT RATHECAL AND S yST EMIC ADJUVANTS TO SPINAL BLOCK
106 MINERVA ANESTESIOL OGICA January 201450 mg/kg bolus follow ed by 15 mg/kg/h infu-
sion does not affect the level of bupivacaine-in-
duced SB or the duration of spinal analgesia, but
has been associated with reduced pain and anal-
gesic consumption up to 48 h postoperativ
ely.21
Among the used NSAIDs, given at clinically
relev
ant doses, intravenous tenoxicam has been
found to produce no effect on the level of SB
induced by lidocaine.143 This lack of efficacy
may be – at least partly
– attributed to the low
lipophilicity of the drug and subsequent mini-
mal CNS concentrations achieved after its in-
trav
enous administration. The analgesic effects
of NSAIDs are mainly exer
ted via peripheral
mechanisms, and no synergism with the LAs is
likely to exist in the CNS.I
ntravenous clonidine 3 μg/kg 19 significantly
prolongs the duration of SB and MB induced
by bupivacaine.19 Intravenous dexmedetomi-
dine 0.5 μg/kg has been associated with a higher
block level and significant prolongation of SB
and analgesia, resulting in decreased analgesic
consumption postoperatively
.20 This dose does
not affect the duration of MB induced by bupi-
v
acaine,20 while larger doses, such as 1 μg/kg
bolus follow
ed by 0.4 μg/kg/h infusion, signifi-
cantly prolong both SB and MB induced by the
short-acting prilocaine.142 Although intravenous
dexmedetomidine seems to be generally well tol-
erated, it has been associated with sedation and
increased incidence of brady
cardia.142
Magnesium sulphate given intravenously as Table IV.—Effects of systemic adjuvants and nitrous oxide on subarachnoid block.
Systemic adjuvantEffect on sensory block, motor block
and analgesiaD oses studied Local anesthetic usedSources of
evidence
Opioids
Fentanyl (F)
N
albuphine (N)
D
iamorphine (D) –F , SB: higher peak lev el 15-17
–N, SB: higher peak lev el 17
–D, SB: delay ed r egression 140
–D, MB: no effect 140F: 50 μg IV 15
F: 50-150 μg IV 17
F: 100 μg IV 16
F: 150 μg IV 143
N: 10-20 mg IV 17
D: 5 mg IV 140Lidocaine 16, 17, 143
Bupivacaine 15, 140RCT, N.=60 15
RCT, N.=71 16
RCT, N.=68 17
RCT, N.=20 140
RCT, N.=60 143
Ketamine –SB: pr olonged duration 141 higher
peak lev
el 141
–Analgesia: pr olonged
duration 18, 141 improved PO/
low
er VAS scor
es 18
–reduced analgesic consumption
PO 18,1410.15 mg/kg IV18, 141 Bupivacaine 126 127
RCT, N.=90 18
RCT, N.=60 141
Clonidine –SB: pr olonged duration 19
–MB: pr olonged duration 193 μg/kg IV19 Bupivacaine 19 RCT, N.=78 19
Dexmedetomidine –SB: pr olonged duration 20, 142
higher peak lev
el 20
–MB: pr olonged duration 142
–Analgesia: pr olonged duration 20
reduced analgesic consumption
PO 200.5 μg/kg IV20
1 μg/kg (+ 0.4 μg/kg/h) IV142Bupivacaine 20
Prilocaine142RCT, N.=75 20
RCT, N.=60 142
Magnesium –SB: no effects on peak lev el 21
–Analgesia: impr oved PO/lo wer
VAS scor
es 21
–reduced analgesic consumption
PO 2150 mg/kg (+ 15mg/kg/h)21Bupivacaine 21 RCT, N.=40 21
Tenoxicam –SB: no effects on peak lev el 143 40 mg143 Lidocaine143 RCT, N.=60 143
Nimodipine –SB: delay of r egression 22 20 mg22 Lidocaine22 RCT, N.=50 22
Nitroglycerin+ opioid –SB: no effects on duration 145
–Analgesia: pr olonged duration 144
–reduced analgesic consumption
PO 1445 mg/day Bupiv acaine/
sufentanil144
Bupivacaine/
fentanyl145RCT, N.=56 144
RCT, N.=120 145
Nitrous oxide –SB: higher peak lev el 23 50% (10 min)23 Lidocaine23 RCT, N.=60 23
SB: sensory block; MB: motor block; VAS: Visual Analogue Scale; IO: intraoperatively; PO: postoperatively; IV: intravenously; RCT : randomised
controlled trial; N.: number of patients.
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(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use isnot permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo ,
or other proprietary information of the Publisher.

INTRATHECAL AND S yST EMIC ADJUVANTS TO SPINAL BLOCK ST AIKOU
Vol. 80 – N
o. 1 MINER
VA ANESTESIOL
OGICA 107requirements.144 Spinal block ch aracteristics ar e
pr
obably no
t aff
ected, as no eff
ect on SB re
gres-
sion ha
s be
en de
monstrated.145 Such low doses
ha
ve no
t be
en as
sociated wi
th si
de eff
ects.119, 144
Inhalational adjuvants
Data from animal studies suggest that volatile
anaesthetics suppress spinal neuron excitability;
intrathecal liquid sevoflurane at doses 0.05-0.1
mL/kg produces a dose-related, rev
ersible SB
and MB, without consciousness impairment, in-
dicating an action limited at spinal level.146 Re-
garding nitrous oxide (N2O), its antinociceptive
effects are mainly mediated via activation of de-
scending noradrenergic inhibitory neurons, and
of GABA
ergic neur
ons in the dorsal horn.147Regarding calcium channel blockers, an intra-
v
enous infusion of nimodipine 2 mg/h has been
found to delay the regr
ession of the lidocaine-in-
duced SB.22 It should be noted though, that the
maximum difference found between nimodipine
and control group was 1.1 cm, indicating a sta-
tistically
, but probably not clinically, significant
effect.
Ni
troglycerin is an NO ge
nerator po
ssibly
aff
ecting sp
inal no
ciception th
rough th
e NO
–
cGMP sy
stem. Al
though tr
ansdermal ni
troglyc-
erin 5 mg
/day la
cks an
y an
algesic effi
cacy it
self,
it si
gnificantly pr
olongs th
e an
algesia in
duced
by sp
inal op
ioids 144, 145 and clonidine.119 The
ma
ximum eff
ect is ob
served wi
th su
fentanil,
wi
th a 14 h av
erage eff
ective an
algesia an
d si
g-
nificant re
duction of th
e 24 h re
scue an
algesic
Table V.—Summary of the effects of adjuvants on spinal block and analgesia, safety/tolerance and clinical use.
DrugEffect
on sensory blockEffect
on motor blockEffect
on analgesiaS afety / tolerance Clinical use
INTRATHECAL
Fentanyl +++ – + ++ +++
S
ufentanil +++ – ++ ++ +++
Morphine – – +++ +++ +++
Pethidine – – ++ ++ +
Diamorphine – – +++ ++ ++
T ramadol – – + ++ +
Epinephrine +++ +++ – ± +
Phenylephrine +++ +++ – ± +
Nor
epinephrine +++ +++ – ± –
Clonidine +++ +++ + ++ +++
Dexmedetomidine +++ +++ ++ +++ ++
M
idazolam ++ – + ± ++
Magnesium ++ ++ ++ +++ +
Magnesium/opioid +++ +++ +++ +++ ++
Ketamine + + – ± +
Neostigmine – ± ++ + +
NSAIDs – – – ID –
Ca++channel blockers* ++ ++ ++ ID –
Baclofen ID ID ++ +++ +++
Dexamethasone + ID ++ ++ ++
SySTEMIC
Opioids ++ – ID ++ ++
K
etamine + ID ++ ++ ++
Clonidine + + + ++ ++
Dexmedetomidine + + + + +
Magnesium – – + + +
NSAIDs – – ++ ++ ++
Ca++channel blockers + – ID ID –
Nitr
oglycerine/opioid – – ++ + –
Inhalational
Nitr
ous o
xide + – + ++ +++
* animal studies only, (+++): significant, (++): moderate, (+): limited, (-): absent; ID: inadequate data; NSAIDs: nonsteroidal anti-inflammatory
drugs.
COPYRIGHT© 2014 EDIZIONI MINERVA MEDICA
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use isnot permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo ,
or other proprietary information of the Publisher.

STAIKOU INT RATHECAL AND S yST EMIC ADJUVANTS TO SPINAL BLOCK
108 MINERVA ANESTESIOL OGICA January 2014Conclusions
Various intrathecal and systemic adjuvants
can potentiate the spinal block and prolong an-
algesia. Ev
en though opioids are the most pop-
ular adjuvants, several other drugs can also ac-
celerate, potentiate and extend the spinal block.
Apar
t from their efficacy, these drugs
’ safety pro-
file should be carefully considered before their
clinical use.
K
ey messages
—Various intrathecal and systemic ad-
juv
ants to local anaesthetics potentiate the
spinal block, impro
ve and prolong analgesia
and reduce the postoperative analgesic con-
sumption.
—Although used in clinical practice, the
majority of adjuvants are not licensed for in-
trathecal use.
—A potential risk of neuroto
xicity
should be considered for the intrathecal ad-
juv
ants, especially those with no adequately
established safety pr
ofile.
—A dose pro
viding the optimal balance
between efficacy and side-effects should be
preferr
ed for both intrathecal and systemic
adjuvants.
References
1. Hunt CO, Naulty JS, Bader AM, Hauch MA, Var tikar JV,
Datta S
et al. Perioperativ
e analgesia with subarachnoid
fentanyl-bupivacaine for cesarean deliver
y. Anesthesiology
1989;71:535-40.
2. Liu S, Chiu AA, Carpenter RL, Mulr
oy MF , Allen HW,
Neal JM
et al. Fentanyl prolongs lidocaine spinal anesthesia
without prolonging reco
very. Anesth Analg 1995;80:730-
4.
3. P
almer CM, Voulgar
opoulos D, Alves D. Subarachnoid
fentanyl augments lidocaine spinal anesthesia for cesarean
deliver
y. R
eg Anesth 1995;20:389-94.
4. D
emiraran
y, Oz
demir I, Kocaman B,
yucel O. Intrathecal
sufentanil (1.5 microg) added to hyperbaric bupivacaine
(0.5%) for elective cesarean section pro
vides adequate
analgesia without need for pruritus therapy. J Anesth
2006;20:274-8.
5. S
aravanan S, Robinson AP , Qay
oum Dar A, Columb
MO, Ly
ons GR. Minimum dose of intrathecal diamor-
phine requir
ed to prev
ent intraoperative supplementation
of spinal anesthesia for Caesarean section. Br J Anaesth
2003;91:368-72.
6. D
obrydnjov I, Samar
ütel J. Enhancement of intrathecal
lidocaine by addition of local and systemic clonidine. Acta
Anaesthesiol Scand 1999;43:556-62.In clinical practice, inhalation of 50% N2O
for 10 minutes has been found to enhance the
cephalad spread of intrathecal lidocaine, result-
ing in an SB level elevation by 5.6 cm (T
able
IV). This effect is rev
ersible, with a relativ
ely
rapid regr
ession of the SB after N2O discontinu-
ation.23
Safety and clinical considerations
Among the adjuvants used in clinical prac-
tice (T
able V), only morphine and baclofen are
appro
ved for intrathecal administration by the
Food and Dr
ug Administration. All the others
are used off-label, most of them safely. Nev
er-
theless, the suitability for intrathecal use should
be indicated by the drug manufacturer
. Whilst
preser
vatives increase the risk of adverse effects,
“pr
eservative free
” formulations are not always
safe. Other factors, such as solution stability, me-
dia and additives are also important. Although
efficacy is a desired objective, it is not justified
when safety issues arise.
L
imitations of the study
Randomised controlled studies wer
e mainly
included in the present revie
w in order to in-
cr
ease the strength of evidence; never
theless,
data are in some points inadequate or contradic-
tor
y, and thus inconclusive. D
ifferences in study
designs, drug doses/combinations, and studied
populations/procedur
es may have played a role.
Also, most studies are not standardised regar
ding
the tools and characteristics of the technique and
block. This is partly due to lack of a universally
accepted methodology for neuraxial block as-
sessment, which would be probably helpful for
a more systematic and standardised approach of
relev
ant data.
F
urther investigation is probably needed to
differentiate the clinically significant from the
scientifically interesting findings. Ev
en though
the available data are not clear enough to sup-
por
t specific recommendations, the information
contained in this revie
w may contribute to a bet-
ter understanding of the efficacy and safety of
the pr
esented adjuv
ants.
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This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
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means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use isnot permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo ,
or other proprietary information of the Publisher.