The Role of Local Anesthetic Additives In Perineural Analgesia

Ongoing evidence continues to support the finding that postoperative pain remains the greatest concern for patients presenting for surgery.¹ In fact, recent surveys demonstrate that patients continue to suffer moderate to severe pain postoperatively.^2,3

Additionally, patient satisfaction is becoming an increasingly important aspect of health care reimbursements reported via the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey, since the Affordable Care Act established reimbursements based on HCAHPS scores.

Pain after orthopedic surgery may be severe; when uncontrolled, it is the most common reason for readmission after ambulatory orthopedic surgery.⁴ Although perineural analgesia is widely considered the gold standard for postoperative pain control for a wide variety of ambulatory orthopedic procedures, a single-injection nerve block with bupivacaine or ropivacaine lasts less than 24 hours. Compared with a single-injection nerve block, continuous peripheral nerve blockade (CPNB) resulted in lower pain scores up to 48 hours postoperatively, decreased opioid use, decreased nausea, and improved patient satisfaction scores.⁵

However, CPNB is more costly and takes more time to place compared with a single-injection nerve block, and instituting an ambulatory regional analgesia program requires a dedicated team with 24-hour availability to attend to patient questions and follow-ups. CPNB is also not foolproof and is subject to catheter dislodgement, migration, failure, and leakage. Thus, an ambulatory regional analgesia program is not optimal for each patient or each department of anesthesiology.

In this review, I address options for providing the most optimal analgesia for patients undergoing ambulatory orthopedic procedures and the role local anesthetic additives play in perineural analgesia.

Clonidine

Clonidine is an a2-adrenergic agonist that has been widely used as an analgesic adjuvant for more than 20 years.⁶ Clonidine has high lipid solubility allowing easy passage across the blood–brain barrier and interaction at spinal and supraspinal sites. Epidural and intrathecal clonidine produce analgesia when used as a single agent.⁷ Hence, there is a long track record of safety when clonidine is applied to neuronal tissue. Clonidine also has been added to local anesthetics for peripheral blocks.

However, the exact mechanism of its perineural action is unclear; possible explanations include axonal or bloodstream transport to the spinal cord, vasoconstriction, direct action on nerve conduction, or a synergistic effect with local anesthetics. Animal studies have shown clonidine to have a direct effect on nerve impulse conduction, with increased inhibition of A and even more so of C fibers when combined with local anesthetics.^8,9 Still, the exact mechanism of clonidine when administered perineurally is largely unknown and likely a complex and compound interaction of both direct and indirect effects.

What is the effect of clonidine clinically when combined with local anesthetics in perineural analgesia? Numerous studies over 20 years have examined the effect of clonidine in peripheral nerve blockade, but the results remain controversial. In a systematic, qualitative review, McCartney et al identified 27 studies that included 1,385 patients in which clonidine was used as a local anesthetic additive, using doses ranging from 30 to 300 mcg, with 15 supportive results and 12 failing to show benefit.⁶

The literature appears to support clonidine as an adjunct in upper extremity blockade, but few studies were performed involving lower extremity blockade. The most benefit in prolongation of the sensory block occurred when clonidine was combined with intermediate-acting local anesthetics such as mepivacaine and lidocaine.^6,10-13 When comparing the systemic and perineural effects of clonidine as an adjunct to local anesthetic, the literature was again inconclusive.⁶ However, side effects such as hypotension and sedation appear to be limited up to doses of 150 mcg.⁶

A separate review of the literature concluded that perineural clonidine prolonged sensory and motor blockade by about 2 hours for both intermediate- and long-acting local anesthetics, thus making prolongation less significant for long-acting local anesthetics.¹⁴ This review found an increased risk for hypotension, fainting, and sedation with perineural clonidine as well. Thus, based on the currently available literature, clonidine on its own may not be an effective local anesthetic adjunct to prolong perineural analgesia.

Dexmedetomidine

Dexmedetomidine (Precedex, Hospira) also is an α2 agonist with selectivity 8 times greater than clonidine. Its mechanism of action is likely multifactorial when administered perineurally. Dexmedetomidine decreases the release of norepinephrine and causes inhibition of nerve fiber action potentials; centrally, it inhibits substance P in the nociceptive pathway at the dorsal root and activates α2 adrenoreceptors in the locus coeruleus. As with clonidine, animal studies have shown dexmedetomidine causes a prolonged duration of analgesia by blockade of hyperpolarization-activated cation currents.¹⁵ Interestingly, when examining perineural inflammation in rat sciatic nerves, the addition of dexmedetomidine attenuated perineural inflammation when compared with bupivacaine alone.¹⁶

Few studies have examined the effect of dexmedetomidine as a local anesthetic adjunct for perineural analgesia. A review by Abdallah et al, which included 4 studies investigating perineural dexmedetomidine, found that unlike clonidine, dexmedetomidine prolonged the duration of long-acting local anesthetics when used in brachial plexus blocks; however, both sensory and motor blockade were prolonged, which may not be a desirable effect. Additionally, although sensory blockade was prolonged, it did not reach statistical significance.¹⁷

Interestingly, in a smaller study comparing both systemic and perineural dexmedetomidine in combination with ropivacaine in ultrasound-guided ulnar block in healthy volunteers, a profound prolongation of both sensory and motor blockade of approximately 60% occurred in the perineural group, whereas the systemic group showed only a 10% prolongation.¹⁸Dexmedetomidine as a local anesthetic adjunct produced a reversible bradycardia but did not increase the incidence of hypotension or cause any other clinically relevant adverse effect in the limited studies available.¹⁷

Although dexmedetomidine appears to prolong both sensory and motor blockade when used as a local anesthetic additive to peripheral nerve blocks, more studies are needed to support its general use as a perineural adjunct.

Buprenorphine

Buprenorphine is a partial μ-opioid agonist and <03BA> and δ antagonist, and is 25 to 50 times more potent than morphine. As in the case of the additives already discussed, buprenorphine’s mechanism of action in the periphery is controversial, and possibly due to peripheral receptor sites, systemic interaction, or enhancement of local anesthetics.

Candido et al completed several interesting studies involving buprenorphine as a perineural adjunct. They found that the addition of 0.3 mg buprenorphine to a mixture of mepivacaine and tetracaine produced a 3-fold increase in the duration of brachial plexus blockade. Interestingly, a majority of patients in the additive group had complete analgesia and decreased opioid use persisting 30 hours beyond the duration provided by local anesthetic alone (ie, 6 hours).¹⁹ In a follow-up study, Candido et al produced similar results in axillary brachial plexus blockade, showing a 3-fold increase in duration of analgesia with the addition of perineural buprenorphine and a 2-fold increase when compared with patients given systemic buprenorphine injection in combination with the local anesthetic–only block.

Of note, the systemic buprenorphine group in combination with peripheral blockade had a 2-fold increase in analgesia compared with the local anesthetic block.²⁰ The incidence of side effects was comparable for all 3 groups (local anesthetic alone, perineural buprenorphine adjunct, and systemic buprenorphine adjunct). However, when used in lower extremity blockade in combination with bupivacaine, both the perineural and systemic buprenorphine groups had improved analgesia compared with bupivacaine alone but without significant differences between the 2 buprenorphine groups.²¹ Increased nausea and vomiting occurred in both the perineural and systemic buprenorphine groups when compared with bupivacaine alone.²¹

In the limited studies available, buprenorphine appeared to be effective as a local anesthetic additive with acceptable side effects; however, more clinical trials are needed to definitively show benefit and address any possible risks associated with its use.

Dexamethasone

Although dexamethasone’s exact mechanism of action on the peripheral nerve is unknown, it is thought to be mediated by decreasing the release of inflammatory mediators and reducing ectopic neuronal discharge of nociceptive C fibers.²²

Numerous recent studies have focused on the efficacy of dexamethasone as a local anesthetic adjunct and it has gained significant popularity in recent years. Movafegh et al described a greater than 2-fold increase in duration of both sensory and motor blockade when dexamethasone 8 mg was combined with lidocaine for axillary block.²³ Cummings et al showed that dexamethasone 8 mg in combination with ropivacaine prolonged analgesia following interscalene block in 218 patients, from 11.8 to 22.2 hours, whereas the addition of bupivacaine improved duration from 14.8 to 22.4 hours.²⁴ Of note, no adverse effects were noted at 14 days and there was no difference in duration between nerve stimulation or an ultrasound-guidance technique.²⁴

Interestingly, Desmet et al suggested that dexamethasone prolonged duration of analgesia independent of administration while demonstrating decreased analgesic need at 48 hours, improved pain scores, and decreased sleep disturbance with both systemic and peripheral dexamethasone adjuncts to interscalene block when compared with ropivacaine alone in 150 patients.²⁵ Rahangdale et al documented similar results and comparable analgesia when administering perineural versus systemic dexamethasone in sciatic nerve blocks for ankle surgery.²⁶

A recent meta-analysis examined 9 studies with 801 patients, 393 of whom received perineural dexamethasone in doses ranging from 4 to 10 mg. Analgesia was prolonged from 730 to 1,306 minutes when used in conjunction with long-acting local anesthetics and 168 to 343 minutes when combined with intermediate-acting local anesthetics. However, motor block was prolonged as well, from 664 to 1,102 minutes, when dexamethasone was added to the nerve block.²² This may be undesirable in some cases if physical therapy is needed in the early postoperative period. Furthermore, consideration must be given in the ambulatory setting to the risk for falls with such a prolonged motor blockade.

Are Local Anesthetic Additives Safe?

From the limited data that exist, local anesthetic additives appear to be safe, but due to the small number of studies with a minimal number of patients, it is difficult to make a definitive claim regarding their safety, so use in this setting is still considered off-label (Table). It is known that repeated intrathecal injections of betamethasone did not produce spinal neurotoxicity and locally applied corticosteroids have shown no long-term effect on structure, electrical properties, or function of peripheral nerves.^27,28

Table. Key Points Use of clonidine, dexamethasone, buprenorphine, and dexmedetomidine perineurally is off-label. Clonidine in doses up to 150 mcg has limited side effects and prolongs analgesia with intermediate-acting local anesthetics most effectively. Dexmedetomidine prolongs both sensory and motor blockade with potential side effect of reversible bradycardia and no hypotension, but limited studies exist to support routine use. Buprenorphine 0.3 mg prolonged analgesia most effectively in brachial plexus blockade but demonstrated equivocal analgesia as well as side effects to systemic buprenorphine in lower extremity blockade. Dexamethasone 4 to 8 mg prolonged both sensory and motor blockade; however, 2 studies demonstrated equivocal analgesic prolongation with systemic and perineural use. Too few studies exist to definitively determine safety, although no clinical studies resulted in clinically relevant nerve injury. Animal studies do not demonstrate -neurotoxicity when low clinical doses are used in combination with ropivacaine, but dexamethasone demonstrated dose-related neurotoxicity. Limit dexamethasone dose to 1 to 2 mg per peripheral nerve block.

In models of central nervous system ischemia, a-2 adrenoceptor agonists are neuroprotective, whereas clonidine was shown to decrease the response to nerve injury in animal models.¹⁵ As nerve injury is rare and likely secondary to needle trauma, no clinical trial has reported neurotoxicity; given the small sample size, it would require roughly 16,000 patients to show a doubling of the baseline complication rate of 0.4%.²² In animal models, Williams et al showed that ropivacaine was neurotoxic to sensory neurons, whereas high concentrations of adjuvants alone, including buprenorphine, clonidine, and dexamethasone, were significantly less toxic.

Additionally, buprenorphine and clonidine appear safe at estimated clinical concentrations when used in combination with ropivacaine, whereas dexamethasone may have a dose–related neurotoxicity, suggesting the lowest possible dose (1-2 mg per nerve block) should be used.²⁹ A recent study by Williams et al demonstrated that clonidine, buprenorphine, and dexamethasone combined with either bupivacaine or midazolam produced reversible nerve blockade and no long-term deficits in rat sciatic nerves.³⁰

Liposomal Bupivacaine

Liposomal bupivacaine (Exparel, Pacira Pharmaceuticals) is an extended-release formulation of bupivacaine that is designed to allow drug diffusion to occur for up to 72 hours after administration. A single injection of Exparel in patients undergoing bunionectomy or hemorrhoidectomy has been reported to decrease postsurgical pain and delay opioid use for 48 to 72 hours.^31,32

Currently, the FDA has approved Exparel only for surgical site infiltration; however, at press time the manufacturer is awaiting a response from the FDA on its application for a new indication for use in peripheral nerve blockade. A small study in healthy volunteers by Ilfeld et al suggested that Exparel administered via femoral block results in partial sensory and motor block of more than 24 hours for doses greater than 40 mg without significant adverse effects.³³ However, there is little published information regarding the use of Exparel in perineural blockade for postoperative analgesia, and clinical studies must be completed to determine its efficacy.

Conclusion

The results are promising for local anesthetic additives to serve as inexpensive and effective extensions of peripheral blockade and as alternatives to CPNB when their utility is limited by technical challenges, incapability of placement, or limited personnel for management of ambulatory catheters at one’s institution. There are limited clinical studies with small patient cohorts in the literature regarding perineural additives.

The use of all the additives discussed continues to be off-label, which does not preclude their use in clinical practice if based on sound clinical judgment and scientific rationale. Epinephrine is an approved local anesthetic additive, although it has failed to prolong analgesia for long-acting local anesthetics in perineural blockade,³⁴ and recent concerns about its effects on local vasoconstriction of the neural vascular supply, as well as advancements in ultrasound, have diminished its use in this setting.³⁵

Given the off-label use of the additives discussed, more clinical studies of perineural additives must be done to establish efficacy, duration, safety, and side effects. It is also necessary to further determine how these medications compare both perineurally and systemically when administered with a local anesthetic block. When using adjuncts, it is imperative to use a preservative-free formulation as well as the lowest effective dose to reduce the risk for neurotoxicity and unwanted side effects.

At our institution, we frequently use dexamethasone as a perineural adjunct resulting in block prolongation (sensory and motor) to greater than 24 hours when combined with ropivacaine; however, we do not exceed 1 to 2 mg per nerve block and have found no clinically significant adverse events with its use. Although no studies have shown a clinically relevant increase in blood glucose after the perineural use of dexamethasone, we avoid its use in patients with diabetes.

Additionally, we use caution in administering local anesthetic additives perineurally in the setting of preexisting neuropathy. Ultimately, the decision whether to use a local anesthetic additive such as dexamethasone must be based on risk and benefit and should be determined by each clinician in the setting of each individual patient.

In the future, Exparel may prove superior to the local anesthetic additives discussed; however, until more clinical trials determine its utility, consideration of the off-label use of local anesthetic additives discussed may prove effective in prolonging regional analgesia, decreasing opioid requirements, and improving patient satisfaction. Another consideration is the concept of multimodal perineural analgesia, which is the use of medications such as clonidine, buprenorphine, and dexamethasone with or without dilute local anesthetic to provide postoperative analgesia while limiting motor blockade.³⁶

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