BJA Education, 19(9): 276e282 (2019)
doi: 10.1016/j.bjae.2019.05.001
Matrix codes: 1A02,
2G01, 3A09
Perineural adjuncts for peripheral nerve block
N. Desai1,*, E. Albrecht2 and K. El-Boghdadly1
1
Guy’s and St Thomas’ NHS Foundation Trust, London, UK and 2Lausanne University Hospital, Lausanne,
Switzerland
*Corresponding author: Neel.Desai@gstt.nhs.uk
Learning objectives
By reading this article you should be able to:

Describe the limitations of conventional local
anaesthetic agents in peripheral nerve blocks.

Discuss the characteristics of an ideal adjunct to
local anaesthetic agents for perineural use.

Recall the effectiveness, adverse effects and
safety of individual drugs used as perineural ad-
juncts to local anaesthetic agents for peripheral
nerve blocks.
Moderate to severe postoperative pain remains a wide-
spread but still unresolved problem. Poor control of pain is
associated with decreased satisfaction for patients and an
increased incidence of postoperative morbidity and mortality.
The use of local anaesthetic (LA) agents for peripheral nerve
Neel Desai MBChB BSc FHEA FRCA MRCP MRCS PG Cert Med Ed
Dip Reg Anaesth is a consultant anaesthetist at Guy’s and St
Thomas’ NHS Foundation Trust. He has interests in obstetric,
regional, and vascular anaesthesia.
Eric Albrecht MD PD-MER DESA is the program director for regional
anaesthesia at Lausanne University Hospital. He is chairman of the
Regional Anaesthesia Scientific Subcommittee of the European So-
ciety of Anaesthesiology (ESA) and a council representative of Eu-
ropean Society of Regional Anaesthesia (ESRA). His field of research
includes acute postoperative pain, regional anaesthesia, and sleep
apnoea syndrome.
Kariem El-Boghdadly BSc FRCA EDRA MSc is a consultant anaes-
thetist at Guy’s and St Thomas’ NHS Foundation Trust. He is editor
of Anaesthesia Reports and on the editorial board of Anaesthesia. His
research interests include airway management and regional
anaesthesia.
Accepted: 14 May 2019
© 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
For Permissions, please email: permissions@elsevier.com
Advance Access Publication Date: 6 July 2019
Key points

An ideal adjunct for perineural injection would
increase the duration of analgesia without pro-
longing motor block.

Perineural clonidine, dexmedetomidine, and
dexamethasone can increase the duration of
analgesia by a mean period of approximately 2,
4.5 and 4e8 h, respectively.

Perineural clonidine and dexmedetomidine have
been associated with adverse effects such as
bradycardia, hypotension and sedation.

Superiority of the perineural over the systemic
route of adjunct administration is not yet
confirmed.

None of the drugs studied as potential adjuncts
for peripheral nerve block have been approved for
perineural administration.
block (PNB) has long been linked to better pain relief compared
with opioid-based analgesia alone. Nevertheless, the effective-
ness of LAs is limited by their duration of action, which can be
insufficient for adequate postoperative pain control. Patients
who have had a single-shot PNB can sometimes complain of
slightly greater postoperative discomfort between 16 and 24 h
compared with those who have had only systemic analgesics.
Rebound pain may occur after single-shot PNBs, resulting in
unanticipated overnight sleep disturbances, difficulties in
compliance with enhanced recovery and physiotherapy proto-
col, and increased consumption of opioids. The use of opioids is
associated with adverse effects such as constipation, nausea
and vomiting, pruritus and secondary hyperalgesia. Hence,
strategies have been sought to extend the benefits of single-shot
PNBs beyond the maximum of 8e16 h.
A continuous PNB involves the percutaneous insertion of a
catheter adjacent to a peripheral nerve, plexus, or fascial plane,
276

followed by the administration of LA through the catheter.
Benefits include prolonging the duration of a single-shot PNB;,
and reducing pain, supplemental analgesic requirements,
opioid-related adverse effects and sleep disturbances.1 However,
problems include inaccurate catheter tip placement and sec-
ondary block failure;, catheter-related mechanical nerve irrita-
tion, catheter knotting, migration, obstruction or shearing;, fluid
leakage or inflammation at the insertion site of the catheter;,
bacterial catheter colonisation;, infusion pump malfunction;,
myonecrosis with repeated large boluses of bupivacaine;, and
LA systemic toxicity. Given that the introduction of continuous
PNBs in clinical practice necessitates appropriate resource and
service provision to support increased costs, training, and follow
up, its use has been limited. The use of ‘perineural adjuncts’ is an
attractive and technically simple alternative strategy to contin-
uous PNBs in order to extend the benefits of single-shot PNBs.
The term perineural adjuncts refers to the coadministration of
pharmacological agent(s) with LA(s) around a peripheral nerve,
plexus or fascial plane with the aim of affecting the character-
istics of the resulting block. Over time, the number of potential
perineural adjuncts has increased to a wide variety of drugs.
For all adjuncts, the benefits associated with their peri-
neural administration should be weighed against the capacity
for harm. Potential sources of harm include medication errors
associated with the need to combine drugs, the possibility of
extended duration of motor block, the risk of adverse effects,
and the potential for neurotoxicity. Prolonged motor block
could delay ambulation, impede physiotherapy, and increase
the risk of falls, interfering with postoperative recovery. Of
note, falls in the postoperative period are multifactorial in
nature and the relative contributions of decreased motor
strength, joint proprioception, and sensory ability to the risk
of falls has still not been determined.
In this article, we consider how the data for individual
drugs used as perineural adjuncts to LAs in PNBs compares
with the characteristics of an ideal adjunct for perineural use
(Table 1).
Steroids
Dexamethasone
Dexamethasone is a potent long-acting glucocorticoid with
minimal mineralocorticoid activity. Its mechanism of action
after perineural administration could be secondary to
Table 1 Characteristics of an ideal perineural adjunct.
Available as a preservative-free solution
Chemically compatible with LAs and other perineural adjuncts
Proved mechanism of action
Superiority of perineural administration over all other routes of administration
Effective for all nerve blocks and in combination with all short, intermediate, and long acting LAs
Decrease in effective dose of LA
Evidence of dose-response relationship with characteristics of resulting block
Decrease in times to onset of motor and sensory block
Improvement in quality of sensory block
Increase in duration of sensory block to at least 24 h
Absence of prolongation of motor block
Increase in duration of analgesia
Absence of systemic adverse effects including respiratory depression, bradycardia, hypotension, hallucinations, sedation, nausea
and vomiting, and pruritus
Absence of chondrotoxic, myotoxic, and neurotoxic effects
Attenuation of chondrotoxic, myotoxic, and neurotoxic effects associated with LAs
Decrease risk of LA systemic toxicity
Perineural adjuncts
stimulation of glucocorticoid receptors located on the cell
membranes of neurones, increasing the expression of inhib-
itory Kþ channels and thereby decreasing the excitability of
and neuronal transmission in nociceptive unmyelinated C fi-
bres. It may be that its actions are mediated via localised
vasoconstriction or systemic anti-inflammatory effects after
absorption through the vasculature. Dexamethasone must be
administered as a preparation without preservatives such as
benzyl alcohol and propylene, both of which can cause neu-
rolytic effects.2 Unlike bupivacaine and lidocaine, exposure of
ropivacaine to the alkalinity of dexamethasone can result in
crystallisation, demonstrating their in vitro incompatibility.
Several meta-analyses have assessed the efficacy of peri-
neural dexamethasone, mainly in the context of brachial
plexus block but also dental, peribulbar, sciatic nerve, and
transversus abdominis plane blocks. In a systematic review of
29 RCTs, perineural dexamethasone was demonstrated to be
associated with an increase in the mean duration of analgesia
by approximately 4 h when injected with short- or medium-
acting LAs (lidocaine, mepivacaine, or prilocaine) and by 8 h
when injected with long-acting LAs (bupivacaine, levobupi-
vacaine, or ropivacaine).3 Furthermore, perineural dexa-
methasone was related to an increase in the mean duration of
motor blockade by approximately 2.5 h when injected with
short- or medium-acting LAs and by 4 h when injected with
long-acting LAs. Shortening in the times to onset of sensory
and motor block were not clinically significant. Perineural
dexamethasone was shown to decrease pain scores at rest
and on movement, and reduce cumulative morphine con-
sumption at 24 h. In the setting of brachial plexus block, in-
creases in the dose of perineural dexamethasone prolongs the
duration of analgesia in a dose-dependent manner until the
ceiling dose of 4 mg is reached.4
Dexamethasone has been associated with an increase in
postoperative blood glucose concentration in diabetic and
non-diabetic patients.5 Concerns about the potential to cause
delayed wound healing and systemic or wound infection have
not been confirmed in a recent meta-analysis. In one RCT, the
increase in mean serum glucose concentrations with peri-
neural dexamethasone administration was clinically insig-
nificant. Dexamethasone has been linked to a neurotoxic
effect in some but not all in vitro studies.6 However these
findings are subject to the challenges and limitations inherent
in the translation of such results from bench to bedside.
BJA Education - Volume 19, Number 9, 2019 277
Perineural adjuncts
Histopathological or neurobehavioural changes in in vivo
studies and neurological complications in clinical series or
trials have not been reported.7,8 Nevertheless, lack of evidence
of harm is not evidence of absence of harm. In order to
conclusively determine the safety of a perineural adjunct,
given the low incidence of nerve injury after PNB techniques, a
total sample size of approximately 16,000 patients would be
required to show a doubling of the baseline complication rate
of 0.4%.
a2-adrenoreceptor agonists
a2-adrenoceptor agonists are characterised by non-selective
imidazoline derivatives such as clonidine and dexmedetomi-
dine. Clonidine and dexmedetomidine have an a2:a1 activity
ratio of 220:1 and 1620:1, respectively, and hence dexmede-
tomidine is eight times more specific for a2-adrenoceptors
than clonidine.9 Given that a2-adrenoceptors are not located
on the axons of peripheral nerves, the mechanism of action of
a2-adrenoceptor agonists after perineural administration is
likely to be independent of such receptors. In the refractory
phase of an action potential, hyperpolarisation-activated
cation currents normally restore the resting potential of the
neurone, allowing the return of functional activity. Clonidine
and dexmedetomidine block the hyperpolarisation-activated,
cyclic nucleotide-gated channels responsible for these cur-
rents, maintaining the neurone in a hyperpolarised state.
When hyperpolarised, it is unable to generate further action
potentials, thereby inhibiting conduction in Ad and C nerve
fibres and producing analgesia. Clonidine could also work, at
least in part, through localised vasoconstriction mediated via
its less selective activity at a1-adrenoceptors.
Clonidine
In a meta-analysis of 20 RCTs, the efficacy of perineural
clonidine at a dose range of 30e300 mg and most frequently a
dose of 150 mg, was evaluated in the context of mainly brachial
plexus block but also ankle, cervical plexus, femoral, iliohy-
pogastric, ilioinguinal, and sciatic nerve blocks.10 Perineural
clonidine was associated with an increase in the mean dura-
tion of analgesia by approximately 2 h, sensory block by 1.25 h
and motor block by 2.5 h, irrespective of whether
intermediate-acting (lidocaine, mepivacaine, or prilocaine) or
long-acting (bupivacaine or ropivacaine) LAs were injected.
Clonidine also increased the likelihood of adverse effects such
as bradycardia, arterial hypotension, fainting or orthostatic
hypotension, and sedation. Undesirable adverse effects could
preclude the use of perineural clonidine in higher-risk pa-
tients and for procedures associated with changes in HR and
BP; they may also increase the need for perioperative moni-
toring and might interfere with care pathways put in place to
facilitate safe discharge. No evidence of a dose-response
relationship was found for either beneficial or harmful ef-
fects. In an in vitro study, clonidine at estimated clinical con-
centrations and higher concentrations had no effect and an
increased effect in relation to the neurotoxicity of ropivacaine
in rats, respectively.6 In a follow up in vivo study, exposure of
rats to sciatic nerve blocks containing bupivacaine and
clonidine did not result in histopathological or neuro-
behavioural changes.7 The optimal dose of perineural cloni-
dine, at which beneficial effects are maximised and harmful
effects are minimised, has not yet been determined.
278 BJA Education - Volume 19, Number 9, 2019
Dexmedetomidine
In a meta-analysis of 34 RCTs, the efficacy of perineural dex-
medetomidine was reviewed in the setting of brachial plexus
block.11 Perineural dexmedetomidine was demonstrated to be
associated with an increase in the mean duration of analgesia
by approximately 4.5 h, sensory block by 4 h, and motor block
by 3 h. Furthermore, perineural dexmedetomidine was related
to a decrease in the mean time to onset of sensory block by 9
min and motor block by 8 min. Perineural dexmedetomidine
increased the odds of adverse effects such as bradycardia,
hypotension, and sedation. No evidence of a dose-response
relationship was found for either beneficial or harmful ef-
fects. Fewer studies have investigated the administration of
perineural dexmedetomidine in relation to lower limb blocks,
but these have reported similar findings.12 It has been sug-
gested that dexmedetomidine, unlike clonidine, can extend
sensory block without prolonging motor block, producing a
differential sensory motor effect, possibly as a result of a
greater inhibitory effect on Ad and C nerve fibres relative to
motor neurones.13 In an in vivo study examining sciatic nerve
blocks in rats, high dose dexmedetomidine added to bupiva-
caine did not result in histopathological changes and actually
appeared to be neuroprotective with reduced perineural
inflammation.14 This neuroprotective effect could be sec-
ondary to, at least in part, the inhibition of activated nuclear
factor NF-kB, which is responsible for the transcription of pro-
inflammatory cytokines, and the modulation of mast cell
degranulation. Consistent with this, the use of perineural
dexmedetomidine in clinical trials has not been associated
with neurological complications to date. The optimal dose of
perineural dexmedetomidine, at which the duration of sen-
sory block is maximised and the haemodynamic adverse ef-
fects are minimised, has been shown to be 50e60 mg.11
Meta-analyses have suggested perineural dexmedetomi-
dine to be superior to clonidine in terms of indices of block
characteristics, but inferior to dexamethasone (Table 2).15,16
Compared with clonidine, perineural administration of dex-
medetomidine was associated with an increase in the mean
duration of analgesia by approximately 3.5 h, sensory block by
3 h, and motor block by 2.75 h.15 Shortening in the times to
onset of sensory and motor block were not clinically signifi-
cant. Such results may be explained by the more pronounced
inhibitory effect dexmedetomidine has on neuronal action
potentials compared with clonidine. However, perineural
dexmedetomidine increased the likelihood of adverse effects
such as bradycardia and sedation. Conversely, a systematic
review of perineural dexamethasone compared with dexme-
detomidine found an increase in the mean duration of anal-
gesia by approximately 2.5 h without prolongation of either
sensory or motor block and with a decreased risk of hypo-
tension and sedation.16
Adrenaline (epinephrine)
Adrenaline is one of the oldest perineural adjuncts to LAs. It is
widely believed to hasten the onset, increase the duration of
block characteristics, and delay the systemic uptake of LA,
thereby reducing the risk of LA systemic toxicity. It can further
serve as a marker of intravascular injection. Its mechanism of
action after perineural administration is thought to be, at least
in part, related to vasoconstriction secondary to a1-adreno-
ceptor stimulation. In a meta-analysis of five RCTs, perineural
adrenaline was associated with an increase in the mean
 Perineural adjuncts

Table 2 Comparison of the effect of perineural adjuncts on indices of block characteristics and incidence of adverse effects. All data
have been extracted from meta-analyses. ND, no difference; OR, odds ratio; RR, risk ratio.

Outcome Dexamethasone Clonidine Dexmedetomidine Adrenaline Buprenorphine Magnesium

Duration of analgesia þ402 þ123 þ264 þ66 þ518 þ125

(min)
Onset of sensory block 1 2 9 ND ND
(min)
Duration of sensory block þ419 þ74 þ228 þ107
(min)
Onset of motor block (min) 1 ND 8 0.3 1
Duration of motor block þ241 þ141 þ192 þ13 þ90
(min)
Block failure ND ND ND ND
Pain scores at less than or Lower Lower Lower
equal to 24 h
Cumulative postoperative 19 10 Not studied Not studied
opioid consumption at
24 h (mg)
Adverse effects Increase in mean blood Bradycardia Bradycardia (OR Hypertension PONV (RR 5)
glucose concentration (OR 3.1) 7.4) Tachycardia Pruritus (RR 6)
by 3.8 mg dl1 Arterial Sedation (OR 11.8)
hypotension
(OR 3.6)
Orthostatic
hypotension
(OR 2.3)
Sedation (OR
5.1)

duration of analgesia by approximately 1 h.17 Adrenaline can
produce a substantial decrease in blood flow to the peripheral
nerve, particularly when administered in combination with
LA, increasing the susceptibility to neurotoxicity. Guidelines
from the American Society of Regional Anesthesia (ASRA)
recommend modifications of the anaesthetic technique to
include eliminating or reducing the concentration of adrena-
line in patients with acquired peripheral neuropathy. Adverse
effects of perineural administration are tachycardia and hy-
pertension, but these are rare in our experience.
Buprenorphine
Buprenorphine is a partial MOP (m) opioid receptor agonist and
KOP (k) opioid receptor antagonist, which has analgesic and
antihyperalgesic properties. Its mechanism of action after
perineural administration is likely to be secondary to
concentration-dependent block of voltage-gated sodium
channels, inhibiting the generation of action potentials in a
similar manner to LAs, and interaction with MOP opioid re-
ceptors on the axons of unmyelinated C fibres. In a meta-
analysis of 13 RCTs, the efficacy of perineural buprenorphine
was assessed in the context of mainly brachial plexus block,
but also femoral and sciatic nerve blocks.18 Perineural
buprenorphine was associated with an increase in the mean
duration of analgesia by approximately 8.5 h and a slightly
longer duration of motor block of 13 min. Its main adverse
effects were postoperative nausea and vomiting (PONV) and
pruritus. However, none of the patients in the studies
included in the meta-analysis received prophylaxis against
these. Other opioid-related adverse effects were poorly re-
ported. In an in vitro study, buprenorphine at estimated clin-
ical concentrations had no effect in relation to the
neurotoxicity of ropivacaine in rats.6 In a follow-up in vivo
study, exposure of rats to sciatic nerve blocks containing
bupivacaine and buprenorphine did not result in histopatho-
logical or neurobehavioural changes.7
Magnesium
Magnesium is an N-methyl-D-aspartate (NMDA) receptor
antagonist that has been found to increase the excitation
threshold in peripheral nerves, more so in myelinated Ab than
unmyelinated C fibres. Its mechanism of action after peri-
neural administration could be secondary to the effects of its
positive divalent charge on the neuronal membrane or its role
as a physiological calcium antagonist. In a meta-analysis of
seven RCTs, the efficacy of perineural magnesium was eval-
uated in the setting of mainly brachial plexus block, but also
femoral and thoracic paravertebral blocks.19 Perineural mag-
nesium was associated with an increase in the mean duration
of analgesia by approximately 2 h, duration of sensory block
by 1.75 h and duration of motor block by 1.5 h. Perineural
magnesium did not increase the risk of PONV. Studies
examining the safety of magnesium have shown inconsistent
results, with some revealing the potential for neurotoxicity.
Comparison of the perineural and systemic
routes of adjunct administration
It is still uncertain whether the placement of drugs in a peri-
neural and hence more targeted manner improves their effi-
cacy or safety as adjuncts compared with systemic
administration. If the perineural and systemic administration
of drugs were to be equivalent in extending analgesia, then

BJA Education - Volume 19, Number 9, 2019 279

Perineural adjuncts
systemic use would obviate any potential risk of nerve injury
associated with perineural injection.
For dexamethasone, i.v. administration at a dose of 0.1e0.2
mg kg1 has been related to decreased postoperative pain and
opioid consumption.20 Perineural compared with i.v. admin-
istration of dexamethasone in one meta-analysis was asso-
ciated with an overall increase in the mean duration of
analgesia by 3 h, but on subgroup analysis this was statisti-
cally significant only with bupivacaine and not with ropiva-
caine.21 No difference in the incidence of PONV was found
between perineural and i.v. dexamethasone. However, peri-
neural dexamethasone in another meta-analysis did not
provide an incremental benefit over the i.v. route.22 Surpris-
ingly, in a recent study of healthy volunteers, addition of
perineural or i.v. dexamethasone to ulnar nerve block with
ropivacaine did not show any significant benefits over sa-
line.23 These results may not be representative of clinical
practice in the absence of an operative insult. If the mecha-
nism of action of perineural dexamethasone is solely depen-
dent on subsequent systemic distribution, then the lack of an
operative stimulus might have prevented the anti-
inflammatory effects of perineural and i.v. dexamethasone.
In the case of a2-adrenoceptor agonists, the results of studies
comparing the perineural with the i.m. or i.v. route of
administration are inconsistent with regard to the relative
duration of analgesia.13 In a systematic review, perineural
administration of buprenorphine resulted in an increase in
the mean duration of analgesia by 7 h compared with i.m.
administration, but there were no differences in postoperative
pain or PONV.18
Other perineural adjuncts
Hyaluronidase is an enzyme that can be administered in
conjunction with LA to decrease the time to onset of
ophthalmic blocks and provide improved akinesia and anal-
gesia. It degrades hyaluronic acid, a glycosaminoglycan that
attaches to proteoglycans in the orbital connective tissue and
otherwise hinders the spread of LA. Sodium bicarbonate can
reduce the time to onset of neuronal block by alkalinisation
of the solution, increasing its pH closer to the pKa of the LA
and thus favouring the non-ionised form of the LA that is
able to penetrate the peripheral nerve to reach its site of
action.
In view of either conflicting or limited evidence and
worries about their potential for adverse effects or neurotox-
icity, consideration of the administration of other drugs as
perineural adjuncts in PNBs is not encouraged (Table 3).
Our experience of perineural adjuncts
In all patients who are about to undergo soft tissue or super-
ficial operative procedures that are not associated with a
functional limitation, we do not administer i.v. or perineural
adjuncts in combination with PNB. If the operative procedure
is likely to be associated with increased postoperative pain, for
example after surgery involving the bone, or would be ex-
pected to result in a functional limitation, for instance sub-
sequent to hallux valgus correction, we consider perineural
administration of preservative-free dexamethasone at a dose
of 4 mg, or i.v. dexamethasone at a dose of 0.15 mg kg1 or 8
mg. In our experience, after perineural or i.v. dexamethasone
in conjunction with PNB, 90% and 75% of patients remain free
280 BJA Education - Volume 19, Number 9, 2019
Table 3 Summary of evidence for other adjuncts used for
perineural administration.
Adjunct Evidence
Fentanyl Conflicting findings for effectiveness overall
but possible efficacy when administered with
bupivacaine
Adverse effects reported include
hypercapnia, bradycardia, and sedation
Morphine Conflicting findings for effectiveness
No clear demonstration of superiority over
systemic administration
Tramadol Conflicting findings for effectiveness
No clear demonstration of superiority over
systemic administration
Ketamine Lack of demonstrated effectiveness
Significant adverse effect profile including
drowsiness, hallucinations, and nausea
Evidence of in vitro and in vivo neurotoxicity
Midazolam Limited demonstration of effectiveness
Evidence of in vitro and in vivo neurotoxicity
No increase in neurological symptoms after
intrathecal injection in humans
Neostigmine Lack of demonstrated effectiveness
Significant adverse effect profile including
nausea and vomiting
Evidence of in vitro and in vivo neurotoxicity
of pain for more than 24 h after ankle and shoulder surgery,
respectively.
Off-label use of perineural adjuncts in PNB
The concept of licensing of drugs in humans was introduced
to safeguard their effectiveness, quality, and safety in
response to certain examples of drug toxicity, such as pho-
comelia in the developing fetus after the ingestion of thalid-
omide by pregnant women. Once drugs have been licensed by
regulatory authorities such as the European Medicines
Agency, Food and Drug Administration (FDA), and the Medi-
cines and Healthcare product Regulatory Agency (MHRA), the
approved indications, dosing, routes of administration, and
patient populations are specified. However, it is common and
legal for drugs to be prescribed in a manner different to that
recommended in the label or product licence, that is, off-la-
bel.24 Despite its routine use, i.v. dexamethasone for the pro-
phylaxis of PONV, for instance, is an unlicensed indication. It
has been advised by the General Medical Council (GMC) in the
UK that the prescribing of an unlicensed drug may be indi-
cated in the presence of adequate evidence or experience of
using the drug, and where no suitably licensed drug would
otherwise meet the patient’s need. Further guidance on this is
available from the MHRA.25 Similarly, the FDA in the USA has
recommended that the use of an off-label drug must be based
on reasonable scientific rationale and sound clinical judge-
ment.24 Moreover, the GMC has advised that informed con-
sent should be obtained from the patient for the prescription
of an off-label drug.
None of the aforementioned drugs studied as potential
adjuncts in PNB have been approved for perineural adminis-
tration by any of the regulatory agencies. Therefore, their
perineural use remains off-label. Nevertheless, it is unlikely
that a label for perineural administration would ever be

sought by pharmaceutical companies because of the associ-
ated costs, effort and time required. Moreover, generic drugs
may not have the funding foundations needed for a licence to
be pursued. In view of this, with the consistent and supporting
evidence of large and well conducted RCTs, the characteristics
of a prospective adjunct drug must resemble those of an ideal
perineural adjunct, showing convincing clinical benefit over
systemic administration, before routine off-label perineural
use is considered. Until such time, caution is advised.
Current and future directions
Over the last few years, our understanding of the capacity of
individual drugs to act as perineural adjuncts to LAs for PNBs
has continued to progress. Dexamethasone and dexmedeto-
midine are particularly promising, but neither has been
shown so far to be similar enough to an ideal perineural
adjunct to justify their routine perineural use for PNB. Con-
cerns have focused on the adverse effects and the potential for
neurotoxicity of prospective adjunct drugs, and whether
perineural administration is superior to systemic injection.
Studies that have investigated perineural adjuncts to date all
have limitations: these include small size, which increases the
possibility of incorrectly rejecting the null hypothesis and
publication bias; inconsistencies in the definition and the
assessment of outcomes; variations in the method of nerve
location; and the type and volume of LAs used. Further trials
should consider these concerns and limitations and, impor-
tantly, endeavour to use standardised definitions for suc-
cessful outcomes.
Declaration of interest
E.A. has received grants from the Swiss Academy for Anaes-
thesia Research, B. Braun Medical AG, and the Swiss National
Science Foundation to support his clinical research. He has
further received an honorarium from B. Braun Medical AG.
N.D. and K.E. declare that they have no conflicts of interest.
MCQs
The associated MCQs (to support CME/CPD activity) will be
accessible at www.bjaed.org/cme/home by subscribers to BJA
Education.
Supplementary material
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.bjae.2019.05.001.
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