Adjuvants for Peripheral Nerve
Blockade:
A Review of the Literature
Jonathan Weed, M.D.
Disclosures
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None
Reasons to use adjuvants for
nerve blocks
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Increase duration of action
Increase speed of onset
Increase density or quality of the block
Improve overall analgesic effect
What’s been tried?
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Epinephrine
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Neostigmine
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Sodium bicarbonate
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Verapamil
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α-agonists (clonidine, dexmedetomidine)
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Magnesium
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Ketamine
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NSAIDS (ketorolac)
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Lysine acetylsalicylate
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And probably many more...
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Opioids (fentanyl, sufentanil, morphine,
buprenorphine, nalbuphine, tramadol)
Steroids (dexamethasone,
methylprednisolone)
Midazolam
Do they work?
Epinephrine
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Mechanism: vasoconstriction via α1-activation reduces blood flow to the nerve, decreasing clearance
of the LA and prolonging exposure of the nerve to the LA.
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Epi has been shown to prolong the duration of PNB anesthesia in many studies, however, much more
pronounced with shorter-acting agents:
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70% longer duration with Lidocaine
20% longer duration with Bupivacaine or Ropivacaine
Other benefits:
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Decrease systemic absorption: LA plasma levels 30-50% lower with Epi. Most texts list higher
acceptable LA doses with addition of epinephrine
Can be used as an “intravascular marker” during PNB
Epinephrine
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Dose: 1:200,000 (5 mcg/ml) commonly used for neuraxial, but
lower doses recommended for PNB (1:400,000 or 2.5 mcg/ml)
Concerns:
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Systemic “reaction” (ie, tachycardia, anxiety, etc)
Decreased PNF may be detrimental. ? increased risk for LAinduced nerve injury? Evidence for this is limited, but reduction
in PN blood supply can be significant, and some patients (DM,
HTN, smoking) may be more susceptible to injury.
Sodium Bicarbonate
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Increases the nonionized form of LA, speeding onset; but has
no effect on block duration.
Useful for Lidocaine and mepivacaine, but can cause
precipitation when mixed with bupivacaine or ropivacaine
Data exists supporting its use for neuraxial blockade, but studies
of its use with PNB shows little efficacy.
Clonidine
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α2-agonist (with some limited α1-stimulatory effects)
Has some LA properties, and produces inhibition of
hyperpolarization-activated cation current (Ih current).
Affects C fibers (pain) >> Aα-fibers (motor)
Dose: 100-150 mcg
Side effects (more common with dose > 100 mcg): Bradycardia,
hypotension, sedation.
Clonidine
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Efficacy:
An analgesic benefit has been demonstrated by multiple meta-analyses and
systematic reviews
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Although many studies have examined the effect of clonidine added to PNB, only a
few studies had a control for systemic effects.
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Most dramatic findings by Singelyn, et al: 3 groups (Mepiv alone; Mepiv + clonidine
SQ; Mepiv/clonidine mix). Group 3 showed 2-fold increase in analgesic duration.
Most studies using longer acting LA (bupiv or ropiv) show little or no benefit
Meta-analysis by Popping, et al., estimates that adding clonidine to long-acting LA
nerve blocks extends analgesic effect by approx 100 minutes, on average.
Dexmedetomidine
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Pure α2-agonist.
Likely similar in efficacy to clonidine, but evidence is limited.
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Increased duration of sensory and motor blockade with Bupi/Ropi demonstrated in rat sciatic
nerves
Only 2 human studies:
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Time to rescue analgesia extended with Dex + Bupi (vs Bupi alone) for greater palatine
blocks in children getting cleft palate repair (22hr vs 14hr)
Improved onset time (by 1 minute) and duration (14hr vs 11hr) with 100 mcg Dex + 40 mL
Levobupiv for axillary blocks; but Dex group had episodes of bradycardia requiring Tx
with atropine
****Neither study had systemic Dex control group*****
Opioids
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Use of traditional opioids (ie, fentanyl, morphine, sufentanil,
alfentanil) as adjuncts to LA for PNB is poorly supported by the
literature.
Outcomes of studies examining the effect of perineural opioids (excluding tramadol and
buprenorphine)*
Total Studies
Overall Outcomes
Systemic Control Outcomes
15 Studies
8 Supportive
6 systemic control
(4 supportive, 2 negative)
7 Negative
9 no systemic control
(4 supportive, 5 negative)
*Table 9-1. Hadzic A. Textbook of Regional Anesthesia and Acute Pain Management. 2007. Ch
9, p. 149.
Buprenorphine
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Partial opioid μ-receptor agonist and κ- and δ-receptor antagonist; has both analgesic
and antihyperalgesic properties
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Candido KD, et al, have published several studies using buprenorphine as an additive
for PNB, with varying results.
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2 studies showed significant prolongation of block using buprenorphine as an
adjunct for brachial plexus and axillary blocks, although only 1 of these used a
systemic control (IM inj).
A 3rd, more recent and much larger study, found no difference between
buprenorphine given systemically vs. peripherally with LA
***Important to avoid use in opioid-tolerant patients, as it renders other full opioid
agonists much less effective. May be difficult to treat patients requiring rescue
analgesia.***
Nalbuphine
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Mixed opioid agonist/antagonist. (μ-antagonist; κ-agonist).
Some positive/mixed results as neuraxial adjunct, but no PNB data
available.
Anecdotally, it may lengthen duration and improve analgesia in most
patients, but has some significant drawbacks:
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Since it blocks μ-receptors, patients who need additional/rescue
analgesia require much higher doses of traditional opioids to achieve
desired effect.
In opioid-tolerant patients, administration of nalbuphine can
precipitate acute withdrawal symptoms.
Tramadol
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Weak opioid agonist with some selectivity for the μ-receptor and κ-receptor
Also inhibits norepinephrine reuptake and stimulates serotonin release in the
intrathecal space, which appear to have an analgesic benefit; but no evidence
that this mechanism applies to peripheral nerves
Kapral et al published a study using tramadol with mepivacaine (using
systemic control group) in axillary blocks which demonstrated enhanced
anesthesia and prolonged analgesia.
Overall, however, the clinical data have been largely negative, especially
when combined with long-acting local anesthetics and when systemic control
groups are included.
Dexamethasone
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Limited data available. Rat studies are not supportive. However, 2 human studies showed some
benefits
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Parrington, et al, added 8mg of decadron to mepivacaine for supraclavicular blocks (without
systemic control): extended duration approx 100 min (332 vs 228), but no difference in onset
time.
Vieira, et al., added 8mg of decadron to bupiv/epi/clonidine, and showed significant increase in
both sensory and motor block duration (approx 24hr vs 14hr). No systemic controls, and no
plain LA groups (control group: bupiv/epi/clonidine). Also, pt satisfaction was = in both groups,
despite longer sensory (extended motor block may contribute)
Both studies used relatively large doses, neither had systemic control, and only one used a longacting LA (but control had 2 other additives). Maybe promising, but more data on efficacy and
safety is needed.
***Limit dose or avoid altogether in diabetics patients.***
Midazolam
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Mechanism of action hypothesized to be on GABA-A receptors
in the axons of peripheral nerve trunks.
Very limited data on efficacy for PNB: 2 known studies, both
show improved analgesia when added to bupivacaine brachial
plexus blocks
There are multiple studies showing neurotoxicity when
midazolam is given intrathecally to animals.
***May have analgesic benefit, but evidence is lacking and
potential for neurotoxicity is concerning***
Neostigmine
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Acts on muscarinic receptors which mediate analgesia (dorsal horn of
spinal cord).
Has been shown to produce analgesia when given intrathecally or
epidurally, but studies of it’s use with PNB have produced
disappointing results:
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2 different studies described 500mcg Neostigmine added to LA for
axillary block, with no significant differences.
It has also been tried with lidocaine for IVRA (Bier block), with very
little success.
Verapamil
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L-type calcium channel blocker. Rat studies suggest that L-type Ca
channels may play some role in somatic and visceral pain control.
Verapamil added to intrathecal and epidural lidocaine exhibits
prolonged analgesic effects.
Only 1 study exists in which it was given as a PNB additive:
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Lalla, et al. added it to lido/bupi brachial plexus blocks, showing only
30 min additional sensory block (but no difference in analgesic
effect)
***appears to have limited role in PNB, but more data needed***
NMDA antagonists
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Both ketamine and magnesium have NMDA-blocking effects,
and some evidence exists that these receptors may play a role
in the PNS as well as the CNS (as previously described).
No known studies using either drug with peripheral nerve
injections exist, but multiple studies show improved analgesic
effects when they are combined with lidocaine for IVRA.
COX inhibitors
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Ketorolac and lysine acetylsalicylic acid have been added to
lidocaine for IVRA, as well, with successful prolongation of
analgesia.
No known studies involving PNB.
Comments
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Strongest case could be made for clonidine, buprenorphine, or
dexamethasone, although drawbacks exist
In general, very little conclusive data exists for any LA adjunct in PNB
Very large % of data is flawed: poor control groups, small # of pts, use of
short-acting LA only, etc.
If extended duration is intended, consider long-acting LA and/or CNB
Always consider risk/benefit ratio.
Patient selection.
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2.
Sinnott CJ, Cogswell LP, et al. On the mechanism by which epinephrine potentiates lidocaine’s peripheral nerve block. Anesthesiology 2003;98:181-188.
3.
Neal JM. Effects of epinephrine in local anesthetics on the central and peripheral nervous systems: neurotoxicity and neural blood flow. RAPM 2003;28(2):124-134.
4.
Singelyn FJ, Dangoisse M, et al. Adding clonidine to mepivacaine prolongs the duration of anesthesia and analgesia after axillary brachial plexus block. Reg Anesth
1992;17:148-150.
5.
Popping DM, Elia N, et al. Clonidine as an adjuvant to local anesthetics for peripheral nerve and plexus blocks: a meta-analysis of randomized trials. Anesthesiology.
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6.
Brummett CM, et al. Perineural dexmedetomidine added to ropivacaine causes a dose-dependent increase in the duration of thermal antinociception in sciatic nerve
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7.
Obayah GM, et al. Addition of dexmedetomidine to bupivacaine for greater palatine nerve block prolongs postoperative analgesia after cleft palate repair. Eur J
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8.
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9.
Candido KD, et al. Buprenorphine added to the local anesthetic for brachial plexus block to provide postoperative analgesia in outpatients. Reg Anesth pain Med.
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10.
Candido KD, et al. Buprenorphine added to the local anesthetic for axillary brachial plexus block prolongs postoperatvie analgesia. Reg Anesth Pain Med.
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11.
Candido KD, et al. Buprenorphine enhances and prolongs the postoperative analgesic effect of bupivacaine in patients receiving infragluteal sciatic nerve block.
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12.
Kapral S, et al. Tramadol addd to mepivacaine prolongs the duration of an axillary brachial plexus blockade. Anesth Analg 1999;88:853-856.
13.
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