Curr Pain Headache Rep (2017) 21:6
DOI 10.1007/s11916-017-0604-1
OTHER PAIN (N VADIVELU AND A KAYE, SECTION EDITORS)
Adjuvant Agents in Regional Anesthesia
in the Ambulatory Setting
Veerandra Koyyalamudi 1 & Sudipta Sen 2 & Shilpadevi Patil 2 & Justin B. Creel 2 &
Elyse M. Cornett 2 & Charles J. Fox 2 & Alan D. Kaye 3
# Springer Science+Business Media New York 2017
Abstract
Purpose of Review A majority of surgical practice has in-
volved ambulatory centers with the number of outpatient op-
erations in the USA doubling to 26.8 million per year. Local
anesthesia delivery provides numerous benefits, including in-
creased satisfaction, earlier discharge, and reduction in un-
planned hospital admission. Further, with the epidemic of opi-
oid mediated overdoses, local anesthesia can be a key tool in
providing an opportunity to reduce the need for other analge-
sics postoperatively.
Recent Findings Adjuvants such as epinephrine and clonidine
enhance local anesthetic clinical utility. Further,
dexmedetomidine prolongs regional blockade duration ef-
fects. There has also been a significant interest recently in
the use of dexamethasone. Studies have demonstrated a sig-
nificant prolongation in motor and sensory block with peri-
neural dexamethasone. Findings are conflicting as to whether
intravenous dexamethasone has similar beneficial effects.
However, considering the possible neurotoxicity effects,
which perineural dexamethasone may present, it would be
prudent not to consider intravenously administered dexameth-
asone to prolong regional block duration. Many studies have
also demonstrated neurotoxicity from intrathecally adminis-
tered midazolam. Therefore, midazolam as an adjuvant is
This article is part of the Topical Collection on Other Pain
* Charles J. Fox
cfox1@lsuhsc.edu
1
Department of Anesthesiology, Mayo Clinic, Phoenix, AZ, USA
2
Department of Anesthesiology, LSUHSC-Shreveport,
Shreveport, LA, USA
3
Department of Anesthesiology, LSUHSC-NO, New Orleans, LA,
USA
not recommended. Magnesium prolongs regional block dura-
tion but related to paucity of studies as of yet, cannot be rec-
ommended. Tramadol yields inconsistent results and ketamine
is associated with psychotomimetic adverse effects.
Buprenorphine consistently increases regional block duration
and reduce opioid requirements by a significant amount.
Future studies are warranted to define best practice strategies
for these adjuvant agents.
Summary The present review focuses on the many roles of
local anesthetics in current ambulatory practice.
Keywords Ambulatory . Pain . Analgesia . Regional
blockade . Adjuvants . Peripheral nerve
Introduction
The role of ambulatory surgery has grown, comprising 65% of
American surgical practice in 2012. The number of outpatient
operations in the USA has increased from 12.3 to 26.8 million
per year in the past few decades. The use of peripheral nerve
blockade (PNB) offers multiple benefits in line with the goals
of modern-day outpatient surgery. These benefits allow pa-
tients to be discharged home in less time with higher satisfac-
tion and potential reduction in the incidence of unplanned
hospital admission.
Drug overdose is the leading cause of accidental death in
the USA, with 47,055 lethal drug overdoses in 2014, of which
18,893 were related to prescription pain relievers. Regional
blockade with local anesthetics (LA) has been shown to re-
duce the amount of opioids required postoperatively and may,
therefore, play a significant role in alleviating opioid depen-
dence postoperatively. This need to address opioid abuse in
the community makes regional blockade a valuable tool.
6 Page 2 of 10
Role of Regional Blockade in Ambulatory Surgery
In the surgical setting, regional anesthesia has been shown to
reduce post-procedural pain and need for opioid medications,
as well as to minimize adverse effects, such as nausea and
vomiting. These benefits allow patients to be discharged home
in less time with higher satisfaction and potentially reduce the
incidence of unplanned hospital admissions and expenditure
[1–3].
Based on the American Society of Addiction Opioid
Addiction 2016 Facts & Figures, drug overdose is the leading
cause of accidental death in the USA, with 47,055 lethal drug
overdoses in 2014 of which 18,893 were related to prescrip-
tion pain relievers [4]. In fact, since 1999, the amount of pre-
scription opioids sold in the USA has nearly quadrupled as has
the deaths from prescription opioids, despite no change in
reported pain from Americans [5]. Regional blockade with
LA reduces the amount of opioids required postoperatively
[6] and may play a significant role in alleviating opioid de-
pendence postoperatively.
Commonly Used Local Anesthetics for Regional
Blockade and Limitations
Local anesthetics vary with regard to onset of action, duration
of action, and degree of motor blockade. Lidocaine is the most
widely used LA because of its inherent potency and rapid
onset. However, lidocaine is the most likely to cause transient
neurological symptoms when administered into the intrathecal
space [7] and because of a short duration of action, may not be
the preferred LA for regional blockade in most circumstances.
Chloroprocaine has an onset and duration shorter than that
of lidocaine. Chloroprocaine’s rapid half-life of 20–40 s
makes it the least systemically toxic LA. In the early 1980s,
reports surfaced of prolonged motor and sensory deficits with
inadvertent intrathecal chloroprocaine injections. However,
several studies have since proven its safety with appropriate
dosages and preservative free preparations, which has led to a
recent resurgence in chloroprocaine’s popularity [8, 9].
Bupivacaine’s slower onset and longer duration of action
than lidocaine. Bupivicaine’s principle limitation is its
cardiotoxicity [9], which is the greatest among all clinically
used LA. In response to the cardiotoxicity of bupivacaine,
levobupivacaine was developed, essentially removing the tox-
ic right sided enantiomer from the preparation. Further, a one
carbon modification resulted in ropivacaine. Ropivacaine
shares a similar pharmacological profile to bupivacaine with
less toxicity. Animal experiments have shown ropivacaine to
be less cardiotoxic than bupivacaine or its fractionated S-en-
antiomer, levobupivacaine [10, 11]. Ropivacaine at lower dos-
ages (concentrations) has been found to have a motor sparing
effect, minimizing the undesirable effects a motor block may
Curr Pain Headache Rep (2017) 21:6
have on ambulation [10]. Thus, ropivacaine provides distinct
advantages, which has made it a popular choice for both epi-
dural and PNB.
Adding Many Adjuvant Agents Provides Benefit
Drug lipophilicity increases both potency and duration by in-
creasing affinity to lipid membranes. However, this hydropho-
bicity comes at the cost of increasing systemic toxicity, there-
by directly correlating with a decreased therapeutic index [11].
The use of adjuvant agents, when co-administered with
LA, may improve speed of onset, safety, and/or duration of
analgesia. Adjuvant agents decrease LA toxicity via two pri-
mary mechanisms. Synergistic analgesia can result in de-
creases in serum drug levels that minimize the potential for
systemic toxicity. Alternatively, vasoconstrictors achieve a
similar effect by confining the LA to its desired site of action
delaying systemic absorption.
Ideally, LA would have an immediate onset of action and a
prolonged duration. One method which has attempted to ob-
tain such anesthesia is the combination of a quicker onset
agent with a longer acting agent. However, both Gadsden et
al. and Roberman et al. have disproved the efficacy of such
combinations, showing no clinical differences in block onset
or duration [12, 13]. Additionally, mixing agents can lead to
unpredictable blockade characteristics, which can further
complicate the delivery of anesthesia [14].
Adjuvants Commonly Used in Regional Blockade
Drugs That Hasten Onset
Bicarbonate
The pKa of a local anesthetic is the pH at which a LA is
present in equal proportions of ionized and non-ionized form.
It is the non-ionized LA form that has a higher ability to cross
neuronal membranes [15–17]. Commercially prepared LA so-
lutions are acidic in nature with LA molecules present in a
predominantly ionized state. Adding an alkaline to a LA in-
creases the amount of LA in non-ionized form and therefore,
should decrease the onset of action by hastening diffusion to
the site of onset in the peripheral nerve [15]. However, in
clinical practice, there has been mixed results related to has-
tening onset of sensory and motor blockade. Studies have
demonstrated adding 4 meq sodium bicarbonate to 40 ml
1.4% mepivacaine, containing epinephrine (1:200,000), de-
creased the onset of interscalene brachial plexus blockade.
[16]. Similar findings of decreased latency were found when
bicarbonate was added to mepivacaine for axillary brachial
plexus [18, 19] and femoral and sciatic nerve blocks [20].
Curr Pain Headache Rep (2017) 21:6
Studies on the alkanization of lidocaine have demonstrated
conflicting results. It produced a quicker onset of motor block
in median nerve blocks [21] and axillary brachial plexus
blockade [20]. However, Chow et al. could not find a signif-
icant clinical advantage for axillary brachial plexus blockade
with buffered lidocaine [18]. Buffering of 1.5% lidocaine re-
vealed a similar lack of benefit with respect to block onset
time when used for femoral and sciatic nerve blocks (onset
was actually delayed) [20].
Another concern is the precipitating effects of the addition
of sodium bicarbonate to the LA solution. The addition of
bicarbonate may cause precipitation, and this may result in
the injection of particulate free base along with the solution
[22, 23]. Caution must be advised when buffering bupivacaine
and ropivacaine as much smaller quantities are required to
cause precipitation when compared with lidocaine [15]. In
fact, higher concentrations of ropivacaine (0.75 to 1%) should
never be buffered due a very low threshold for precipitation
[15].
To summarize, the inconsistencies in the effect of buffering
on block onset, the tendency for precipitation with commonly
used local anesthetics and the relatively minor benefit (for
example, onset time of mepivacaine-epinephrine when buff-
ered improved from 2.7 to 1 min) [16] precludes the routine
addition of sodium bicarbonate to LA solutions when
performing a PNB. The greatest utility for bicarbonate is in
the obstetric population where laboring patients may suddenly
have fetal deceleration and/or distress resulting in emergent
caesarian section, seconds of onset can be the difference of a
successful epidural block or the need for general endotracheal
intubation in a subpopulation known for challenging airways
related to physiological changes of pregnancy such as swell-
ing of the airway and weight gain.
Drugs Added to Reduce Local Anesthetic Toxicity
Epinephrine
Co-administration of epinephrine with a LA decreases the rate
of uptake into the plasma after perineural injection. As a result,
the amount of LA that can be safely given with epinephrine
substantially increases related to the presumed added benefit
of decreasing LA systemic toxicity.
Braid demonstrated an 18% decreased average plasma li-
docaine concentration when 5 μg/ml of epinephrine was
added to 2% lidocaine solution while performing an intercos-
tal nerve block [24]. Schierup demonstrated similar results of
decreased mepivacaine concentration in maternal venous
blood when 5 μg/ml of epinephrine was added to 1%
mepivacaine (20 ml) for pudendal nerve blocks during second
stage of labor [25]. Both intercostal and pudendal nerve
blocks are performed in highly vascular spaces with
Page 3 of 10 6
significant systemic absorption of local anesthetic. Co-admin-
istration of epinephrine with LA substantially increased the
amount of local anesthetic which can be administered in such
high vascular spaces with lesser risk of local anesthetic sys-
temic toxicity.
However, adding epinephrine to ropivacaine has been
found to have no effect on limiting the systemic absorption
of ropivacaine. Hickey, et al. concluded no effect on
ropivacaine’s peak plasma concentration and time to peak
plasma concentration when 5 μg/ml of epinephrine was added
to ropivacaine 0.5% during placement of a subclavian
perivascular brachial plexus block [25].
Drugs Added to Prolong Duration of Action
Epinephrine
Epinephrine can be administered locally, neuraxially and
around peripheral nerves. Addition of epinephrine has been
shown to prolong duration of action of LA. Epinephrine by
virtue of vasoconstrictive properties reduces clearance of co-
administered drugs [26].
In addition to local vasoconstriction, neuraxially adminis-
tered epinephrine prolongs duration of action by directly bind-
ing to the alpha-receptors [26]. Niemi et al. demonstrated ef-
ficacy of epinephrine with a minimum effective concentration
of 1.5 μg/ml when used with a LA and opioid thoracic epidu-
ral infusion [27, 28].
Addition of epinephrine to prolong PNB varies depending
on the type of LA used. Dogru et al. studied the effects on
motor block, sensory block, and hemodynamic parameters of
low dose (25 μg) and high dose (200 μg) epinephrine when
mixed with 1.5% lidocaine to perform axillary brachial plexus
block. Motor and sensory block were both prolonged by 25
and 40 min respectively in the high dose (200 μg) epinephrine
group. Systolic blood pressure and heart rate were significant-
ly higher in the high dose epinephrine group. Low dose epi-
nephrine group (25 μg) prolonged motor and sensory block
minimally by 10 and 30 min, respectively [23].
Epinephrine (200 μg) when used as an adjunct with 1%
mepivacaine (40 ml), while performing infraclavicular brachi-
al plexus block, prolonged motor duration of the bock by
60 min [29]. Epinephrine (200 μg) was an inferior adjunct
to prolong block duration (p less than 0.001), when added to
0.25% bupivacaine (40–50 ml) to perform a supraclavicular
block in a study performed on 60 patients when compared
with 150 μg clonidine (994.2 ± 34.2 vs 728.3 ± 35.8 min)
[30].
Ropivacaine is a unique LA with intrinsic vasoconstrictive
properties. The addition of epinephrine results in no major
effect on the time of onset, duration of action, or in limiting
systemic absorption of ropivacaine [31, 32]. Epinephrine
(1:200,000) when added to ropivacaine while performing a
6 Page 4 of 10
femoral block for total knee replacement did not alter the
duration of analgesia [33].
Addition of sodium bicarbonate to epinephrine containing
LA solutions rapidly degrades the epinephrine. Robinson et al.
demonstrated undetectable levels of epinephrine after 24 h
when sodium bicarbonate was added to a LA mixture of 2%
lidocaine with 5 μg/ml epinephrine [27].
Potential concerns of neurotoxicity by reducing endoneural
blood flow have limited the use of epinephrine as an adjunct
for prolonging duration of action of PNB [28]. This is partic-
ularly important in patients who are at higher risk for nerve
injury, diabetes, hypertension, and smoking [34–36].
Clonidine
Clonidine produces analgesia in the neuraxial space through
alpha-2 agonism. However, the analgesic effects of peripher-
ally administered clonidine when used as an adjunct with PNB
are not attributed to alpha-2 agonism. Clonidine inhibits hy-
perpolarization activated cation current in C fibers and A-al-
pha fibers. This cation current normally functions to restore
resting potential of the nerve from the hyperpolarized state to
generate the next action potential. Effects of clonidine are
more sensory specific as the inhibition is more pronounced
on the C fibers (pain) than the A-alpha fibers (motor) [37, 38].
Poppin et al. conducted a meta-analysis of 20 studies where
30–300 μg of clonidine was used as an adjunct with PNB. The
duration of analgesia and sensory block was prolonged by
about 2 h; duration of motor block was also increased.
Increased risk of arterial hypotension, orthostatic hypotension,
bradycardia, and sedation was noted [31].
A qualitative systematic review of 27 studies where cloni-
dine was used with PNB demonstrated a marginally greater
number of positive trials (15 studies) for prolonging analgesic
duration when used with intermediate acting LA (e.g.,
mepivacaine and lidocaine, less supportive evidence with
levobupivacaine and bupivacaine). Side effects of clonidine
in this analysis were limited if doses were used up to 150 μg
[32].
Based on the above two studies, both authors have recom-
mended to use 0.5 μg/kg of clonidine up to a maximum dose
of 150 μg to avoid systemic side effects.
Dexmedetomidine
Dexmedetomidine is a lipophilic alpha-2 methyl derivative
with an alpha2: alpha1 receptor affinity ratio of 1620:1; seven
times greater receptor affinity when compared with clonidine
[39].
A meta-analysis of four studies using dexmedetomidine as
an adjunct demonstrated an increase in mean motor block
duration by 268 min and mean sensory block duration by
284 min. Time to first analgesia requirement was 345 min.
Curr Pain Headache Rep (2017) 21:6
The effect on prolonged sensory block duration was not sta-
tistically significant. No significant hypotension was noted at
the doses of dexmedetomidine used (30 μg, 100 μg, 0.75 μg/
kg, 1 μg/kg) in the four studies. Reversible bradycardia was
however noted in about 7% of patient’s receiving perineural
dexmedetomidine [40].
Agarwal and Fritsch conducted two independent studies
where adding 100 μg of dexmedetomidine to bupivacaine
(30 ml solution of 0.325% bupivacaine) supraclavicular
blocks and 150 μg dexmedetomidine to ropivacaine (12 ml
solution of 0.5% ropivacaine) interscalene blocks prolonged
the duration of these blocks by 8 and 4 h, respectively [41, 42].
An investigation on human volunteers undergoing ultra-
sound guided ulnar nerve blocks demonstrated a 200-min pro-
longation of analgesia when dexmedetomidine was added to
ropivacaine (3 ml ropivacaine 0.75% with perineural 20 μg
dexmedetomidine). Systemic dexmedetomidine (systemic
20 μg dexmedetomidine with perineural 3 ml ropivacaine
0.75%) increased duration in analgesia by 50 min [35].
In another volunteer study, addition of dexmedetomidine to
ropivacaine (10 mL of a solution containing 0.5% ropivacaine
with 1 μg/kg of dexmedetomidine) prolonged the duration of
tibial nerve blockade by 5 h [36].
Most authors recommend using 1 μg/kg of
dexmedetomidine with ropivacaine or bupivacaine as an ad-
junct to PNB. Caution must be exercised in patients where
bradycardia and hypotension can be of concern.
Dexamethasone
Dexamethasone acts by possible attenuation of the small, un-
myelinated, slow conducting C fiber responses in a dose-de-
pendent manner leading to increased duration of selective
sensory blockade and thus prolongation of PNB. Other theo-
ries for its mechanism of action include anti-inflammatory or
immune suppressive actions [37]. It can also cause vasocon-
striction on topical application to the skin related to its action
on glucocorticoid receptors. Steroids bind to intracellular re-
ceptors and modulate nuclear transcription. It is also speculat-
ed that along with local effects, the systemic effects of steroids
may play a role in its prolonged analgesia [48••].
In a recent systematic review of 14 studies involving 1022
patients, Knezevic et al. came to the conclusion that the addi-
tion of dexamethasone to a brachial plexus block significantly
reduced opioid consumption at 24 h and significantly im-
proved postoperative pain scores at 48 h with no increase in
complication rates. However, perineural adjuvant dexametha-
sone delayed the onset of sensory and motor block and
prolonged the duration of motor block [38]. In another similar
meta-analysis, investigators found a significant improvement
in postoperative nausea and vomiting with an approximate
doubling of the duration of postoperative analgesia [43]. A
prospective, randomized, double blinded study comparing
Curr Pain Headache Rep (2017) 21:6
1.5% lidocaine with 2 ml (8 mg) dexamethasone vs 1.5%
lidocaine with 2 ml of saline as control for axillary brachial
plexus blockade showed significant prolongation in the dura-
tion of both sensory and motor blockade by approximately 1
to 2.5 times with no much change in onset of sensory and
motor blockade [44].
Few studies have examined the effects of dexamethasone
on lower extremity PNB. When added to bupivacaine for sci-
atic nerve blocks, addition of 10 mg of dexamethasone
showed a significant reduction in pain at 24 h but not at
48 h. But the injection of dexamethasone in this study was
directed at least 2 cm from the sciatic nerve questioning
whether injection lead to any neural penetration and neural
effects [45]. In the same study, addition of dexamethasone
showed lack of effect in ankle blocks [45]. Eight milligrams
of dexamethasone added to 0.5% bupivacaine followed by a
continuous infusion prolonged the duration of analgesia pro-
vided by femoral nerve blockade by about 7 h (25.7 ± 3 h, vs
18.8 ± 4 h) with a reduction in opioid requirements [46]. In
this study, the addition of dexamethasone improved pain con-
trol on the first postoperative day, but no difference in the pain
score was detected on days 2 or 3 [46]. Addition of dexameth-
asone to paravertebral blocks with 0.25% bupivacaine [41]
and transversus abdominal plane blocks [42] with 0.5%
ropivacaine demonstrated similar increases in duration of an-
algesia and reduction in opioid consumption.
Studies have shown that intravenous administration of
dexamethasone may cause prolongation of PNB [47].
However, studies that have tried to elucidate whether system-
ically administered dexamethasone would have similar anal-
gesic effects as perineural administration found conflicting
results. When added to a supraclaviular brachial plexus block-
ade with 0.5% bupivacaine, an equivalent increase in duration
of analgesia was observed [48••]. Similar equivalent findings
were demonstrated with interscalene brachial plexus blockade
with 0.5% ropivacaine and with sciatic nerve blockade with
0.5% bupivacaine and epinephrine [49–51]. However, a re-
cent multicenter randomized control trial involving 150 pa-
tients undergoing ultrasound guided infraclavicular blockade
showed that 5 mg of perineural dexamethasone as an adjuvant
provided a longer duration of motor and sensory block when
compared to 5 mg injected intravenously [52]. Studies by
Kawanishi et al. and Chun et al. showed a similar superiority
with perineural administration [53, 54].
Currently, there is not much data to on the adverse effects
of adding dexamethasone to the peripheral nerve blockade.
Parrington et al. showed no difference in the postoperative
neurological sequelae with or without addition of dexametha-
sone to mepivacaine 2 weeks after block placement [55].
Numerous other studies have not shown any increase in clin-
ical evidence of neurotoxicity when administered perineurally
in doses usually used in clinical practice [51–53]. In contrast,
in vitro studies have demonstrated a neurotoxic effect [56, 57].
Page 5 of 10 6
Considering beneficial effects of intravenous dexamethasone,
more studies are required to evaluate the safety of dexameth-
asone in perineural administration before recommending ad-
ministration for perineural administration. Lastly, it should be
used with caution in diabetic patients related to the risk of
hyperglycemia. Also patients with prolonged infection, use
of dexamethasone may be detrimental related to its anti-in-
flammatory effects [58].
Midazolam
Midazolam, a water soluble benzodiazepine acting on the
GABA-A receptors in the axons of peripheral nerve trunks,
is an indirect GABA receptor agonist. Another speculated
mechanism of action is on the peripheral benzodiazepine re-
ceptors [59]. Midazolam decreases unmyelinated C fiber con-
duction but does not completely ablate C wave conduction in
non-neurotoxic doses.
Intrathecal use of midazolam in multiple animal studies has
shown that it is neurotoxic and hence, use should best be
avoided as an adjuvant to local anesthetics in perineural ad-
ministration [60–62].
Magnesium
The exact mechanism of action of magnesium is not clear but
attributed to interaction with calcium channels and NMDA
receptors. The calcium channel blockers have anti nociceptive
effects which have been demonstrated in animals. It is an
NMDA receptor antagonist and mediates calcium influx into
neurons. Magnesium has shown to decrease peripheral nerve
excitability [63, 64].
Addition of magnesium to intravenous regional anesthesia
for chronic limb pain management by Tramer and Glynn dem-
onstrated improvement in quality of blockade and prolonged
the duration of analgesia. Magnesium decreased intraopera-
tive opioid consumption and tourniquet pain. Magnesium im-
proved the quality of anesthesia and prolonged the time for
first postoperative analgesic requirement. Overall, the addition
of magnesium to local anesthetic is effective both for perineu-
ral and intravenous regional anesthesia [65].
In a recent meta-analysis of randomized controlled trials, Li
et al. evaluated seven trials involving 493 patients.
Investigators concluded that the addition of magnesium as
an adjuvant to PNB prolonged the postoperative duration time
of analgesia, sensory, and motor block [49]. Though results
look promising, more studies are required to evaluate the safe-
ty and effectiveness of magnesium in PNB.
Tramadol
Studies suggest that tramadol exerts analgesic effects by both
agonist activity at the μ-opioid receptor and other non-opiod
6 Page 6 of 10
actions. It causes serotonin release, has weak μ-opioid recep-
tor stimulating activity, inhibits of norepinephrine reuptake,
and blocks sodium channels [20, 66•, 67].
When used as an adjunct in PNB, there have been incon-
sistencies in results with regards to the duration of block.
Addition of 100 mg tramadol to 0.5% bupivacaine for an
interscalene block for patients undergoing shoulder arthrosco-
py increased the duration of the block from 7.6 ± 2.9 to 14.5 ±
4.0 h. In the same study, intramuscular administration of tram-
adol also showed an increase in the duration of analgesia by
10.1 ± 5.3 h [50]. However, in another retrospective study, a
significant increase in block duration was seen with
buprenorphine added as an adjunct, but not with the addition
of tramadol, to an interscalene block with 0.75%
levobupivacaine [51].
Conflicting results were seen when tramadol was used as
an adjunct for axillary brachial plexus block. Two studies
demonstrated an increase in duration of block. Addition of
200 mg (but not 100 mg) of tramadol to an axillary brachial
plexus block with 1.5% lidocaine and 1:200,000 epinephrine
increased the duration of sensory block and time to first rescue
analgesic (265 ± 119 min vs 126 ± 48 min). However, this
came at the expense of a significant increase in block onset
time [68]. Kapral et al. observed a significant increase in du-
ration when 100 mg of tramadol was added to mepivacaine
1% for brachial plexus block [53]. Three studies examining
the addition of tramadol to an axillary brachial plexus block
revealed no increase in duration of block. A decrease in dura-
tion of axillary brachial plexus block was observed in patients
undergoing hand surgery when tramadol 100 mg was added to
a mixture of 30 mL of levobupivacaine 0.5% and 10 mL of
lidocaine hydrochloride 2% [54]. In another study, the addi-
tion of tramadol to 40 mL of mepivacaine 1.5% for axillary
brachial plexus block produced no difference relative to pla-
cebo in the duration of sensory or motor blockade, but was
associated with a decrease in requests for pain medication
postoperatively [69]. A study by Kesimci et al. found no in-
crease in duration of axillary brachial plexus block when tram-
adol was added to 0.75% ropivacaine [56].
Ketamine
Ketamine is an NMDA receptor antagonist and is known to
possess analgesic and hypnotic effects. Animal studies have
demonstrated that ketamine causes a reversible depression of
compound action potential in frog sciatic nerve [57]. In toad
sciatic and tibial nerve, ketamine has been demonstrated to
depresses amplitude, conduction velocities, and increases
threshold to stimulation [70]. It is therefore quite conceivable
that ketamine may be of use in peripheral nerve blockade.
However, the few studies that have been published have
not shown much promise. In a study of 60 patients, Lee et al.
added 30 mg of ketamine to 30 ml of 0.5% ropivacaine for an
Curr Pain Headache Rep (2017) 21:6
interscalene brachial plexus block with no improvement in the
onset or duration of sensory block. The use of ketamine was
associated with a high incidence of psychotomimetic adverse
effects [71•]. The use of ketamine for Bier block (intravenous
regional anesthesia) has been described. When ketamine 0.3
or 0.6% was used for a Bier block, though the degree of
anesthesia achieved was satisfactory and on par with
prilocaine, a significant number of subjects suffered from psy-
chotomimetic adverse effects. In summary, the use of keta-
mine as an adjunct in peripheral nerve blockade is not
recommended.
Buprenorphine
Buprenorphine is a highly lipophilic opioid agonist-antago-
nist. Buprenorphine is a partial μ-receptor agonist and appears
to have a local-anesthetic-like capacity to block voltage gated
Na+ channels [60]. A characteristic feature of buprenorphine
is the presence of a ceiling effect on respiratory system depres-
sant effects, but not on analgesia [61].
Numerous studies have consistently shown the use of
buprenorphine as an adjunct to significantly prolong periph-
eral nerve blocks. When compared with morphine,
buprenorphine as an adjunct to a supraclavicular brachial
plexus block with 0.5% bupivacaine provided better analgesia
and a significantly longer duration of analgesia [62]. In anoth-
er study by Bazin et al., adding buprenorphine 3 μg/kg in-
creased the mean duration of satisfactory analgesia to 20
(14–34 h) from 11.5 (8–15) hours without an opioid [63].
Candido et al. evaluated the effect of adding buprenorphine
to a shorter acting LA. When adding 3 μg/kg of
buprenorphine to 1% mepivacaine and 0.2% tetracaine with
epinephrine 1:200,000 for a subclavian perivascular brachial
plexus block, the mean duration of postoperative analgesia the
buprenorphine group (17.4 ± 1.26 h) was three times greater
than that in plain local anesthetic group.(5.3 ± 0.15 h) [64].
The same investigators found similar results in block prolon-
gation when buprenorphine was added as an adjunct to axil-
lary [72] and subgluteal sciatic [73] nerve blocks. Behr et al.
demonstrated a significant increase in interscalene block du-
ration with addition of epineural buprenorphine [66•]. In a
more recent randomized study, addition of dexamethasone
and buprenorphine as an adjuvant significantly increased
block duration in sciatic nerve blocks with 0.25% bupivacaine
[67].
Conclusion
Adjuvants play a beneficial role in PNB. They have been used
successfully in anesthetic practice to hasten the onset of sur-
gical block, reduce the toxicity related to LA administration,
and prolong the duration of motor and sensory blockade.
Curr Pain Headache Rep (2017) 21:6
Though the addition of bicarbonate may hasten block onset
clinical results have not been consistent. Hastening the block
by a few minutes may or may not add much clinical and
operational benefit (perhaps most relevant in obstetric pa-
tients), and precipitation is a potential concern. Epinephrine
as an adjuvant has been proven to reduce plasma levels of
local anesthetics and prolong slightly the duration of lidocaine
and mepivacaine, but not ropivacaine nerve blocks. Clonidine
seems to have a similar analgesic and block prolonging effect
as epinephrine. However, the side effects of clonidine (hypo-
tension, bradycardia, sedation) may preclude use. In contrast,
dexmedetomidine prolonged PNB effects by many hours.
Studies showed a significant prolongation in motor and sen-
sory block with perineural dexamethasone. Findings were
conflicting as to whether intravenous dexamethasone has sim-
ilar effects. However, considering the possible neurotoxicity
affects that perineural dexamethasone may present, it would
be prudent not to consider intravenously administered dexa-
methasone to prolong block duration. Studies have demon-
strated neurotoxicity from intrathecally administered midazo-
lam. Magnesium has been found to prolong block duration but
due to paucity of studies, cannot be recommended. Studies
involving tramadol showed inconsistent results and ketamine
has been found to be associated with psychotomimetic ad-
verse effects. Buprenorphine has been found to consistently
increase block duration by a significant amount.
It is important to note that though many of these adjuvants
may serve their purpose, the Federal Drug Administration
does not approve their use as an adjuvant and there is a pro-
pensity for side effects and neurotoxicity. More studies are
needed to evaluate these effects.
Compliance with Ethical Standards
Conflict of Interest Veerandra Koyyalamudi, Sudipta Sen, Shilpadevi
Patil, Justin B. Creel, Elyse Cornett, Charles J. Fox, and Alan D. Kaye
declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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