Adjuvants for Peripheral Nerve Blockade: A Review of the Literature

1. Adjuvants for Peripheral Nerve Blockade: A Review of the Literature • Jonathan Weed, M.D.

2. Disclosures • None

3. Reasons to use adjuvants for nerve blocks • Increase duration of action • Increase speed of onset • Increase density or quality of the block • Improve overall analgesic effect

4. What’s been tried? • Epinephrine • Sodium bicarbonate • α-agonists (clonidine, dexmedetomidine) • Opioids (fentanyl, sufentanil, morphine, buprenorphine, nalbuphine, tramadol) • Steroids (dexamethasone, methylprednisolone) • Midazolam • Neostigmine • Verapamil • Magnesium • Ketamine • NSAIDS (ketorolac) • Lysine acetylsalicylate • And probably many more...

5. Do they work?

6. Epinephrine • 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. • Epi has been shown to prolong the duration of PNB anesthesia in many studies, however, much more pronounced with shorter-acting agents: • 70% longer duration with Lidocaine • 20% longer duration with Bupivacaine or Ropivacaine • Other benefits: • 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

7. Epinephrine • 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: • Systemic “reaction” (ie, tachycardia, anxiety, etc) • Decreased PNF may be detrimental. ? increased risk for LA-induced 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.

8. Sodium Bicarbonate • 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.

9. Clonidine • 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.

10. Clonidine • Efficacy: • An analgesic benefit has been demonstrated by multiple meta-analyses and systematic reviews • Although many studies have examined the effect of clonidine added to PNB, only a few studies had a control for systemic effects. • 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.

11. Dexmedetomidine • Pure α2-agonist. • Likely similar in efficacy to clonidine, but evidence is limited. • Increased duration of sensory and motor blockade with Bupi/Ropi demonstrated in rat sciatic nerves • Only 2 human studies: • 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*****

12. Opioids • 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)* *Table 9-1. Hadzic A. Textbook of Regional Anesthesia and Acute Pain Management. 2007. Ch 9, p. 149.

13. Buprenorphine • Partial opioid μ-receptor agonist and κ- and δ-receptor antagonist; has both analgesic and antihyperalgesic properties • Candido KD, et al, have published several studies using buprenorphine as an additive for PNB, with varying results. • 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.***

14. Nalbuphine • 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: • 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.

15. Tramadol • 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.

16. Dexamethasone • Limited data available. Rat studies are not supportive. However, 2 human studies showed some benefits • 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 long-acting 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.***

17. Midazolam • 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***

18. Neostigmine • 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: • 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.

19. Verapamil • 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: • 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***

20. NMDA antagonists • 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.

21. COX inhibitors • Ketorolac and lysine acetylsalicylic acid have been added to lidocaine for IVRA, as well, with successful prolongation of analgesia. • No known studies involving PNB.

22. Comments • 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.

23. Brummett CM, Williams BA. Additives to local anesthetics for peripheral nerve blockade. Int Anesthiol Clin. 2011;49(4): 104-116. • Sinnott CJ, Cogswell LP, et al. On the mechanism by which epinephrine potentiates lidocaine’s peripheral nerve block. Anesthesiology 2003;98:181-188. • 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. • 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. • 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. 2009;111: 406-415. • Brummett CM, et al. Perineural dexmedetomidine added to ropivacaine causes a dose-dependent increase in the duration of thermal antinociception in sciatic nerve block in rat. Anesthesiology 2009;111:1111-1119. • Obayah GM, et al. Addition of dexmedetomidine to bupivacaine for greater palatine nerve block prolongs postoperative analgesia after cleft palate repair. Eur J Anaesthesiol 2010;27:280-284. • Esmaoglu A, et al. Dexmedetomidine added to levobupivacaine prolongs axillary brachial plexus block. Anesth Analg 2010;111:1548-1551. • Candido KD, et al. Buprenorphine added to the local anesthetic for brachial plexus block to provide postoperative analgesia in outpatients. Reg Anesth pain Med. 2001;26:352-356. • Candido KD, et al. Buprenorphine added to the local anesthetic for axillary brachial plexus block prolongs postoperatvie analgesia. Reg Anesth Pain Med. 2002;27:162-167. • Candido KD, et al. Buprenorphine enhances and prolongs the postoperative analgesic effect of bupivacaine in patients receiving infragluteal sciatic nerve block. Anesthesiology. 2010;113:1419-1426. • Kapral S, et al. Tramadol addd to mepivacaine prolongs the duration of an axillary brachial plexus blockade. Anesth Analg 1999;88:853-856. • Parrington SJ, et al. Dexamethasone added to mepivacaine prolongs the duration of analgesia after supraclavicular brachial plexus blockade. Reg Anesth Pain Med. 2010;35:422-426. • Van Elstraete AC, et al. Neostigmine added to lidocaine axillary plexus block for postoperative analgesia. Eur J Anaesthesiol 2001;18:257-260. • Bone HG, et al. Enhancement of axillary brachial plexus block anesthesia by coadministration of neostigmine. Reg Anesth Pain Med 1999;24:405-410. • Lalla RK, Anant S, et al. Verapamil as an adjunct to local anesthetic for brachial plexus blocks. MJAFI 2010; 66: 22-24. • Hadzic A. Textbook of Regional Anesthesia and Acute Pain Management. 2007. Ch 9, p. 145-155.