Opioids

Opioids are sometimes added to local anesthetics to increase efficacy and extend the duration of the block. The efficacy of peripherally injected opioids is likely due to a combination of factors, including direct effects on opioid receptors in the periphery, anti-inflammatory effects, systemic absorption, and action at the spinal cord due to slow retrograde axonal transport along the nerve.^4-6

Directly applying opioids to a peripheral nerve at high concentrations can produce analgesia that is not naloxone-reversible and is thought to be a nonspecific local anesthetic-like action.⁴ In addition, opioid mu and kappa receptors are present on the distant peripheral terminals of C fibers, and these receptors increase in number and become activated when there is inflammation at the site.^4-6 Opioids attenuate the excitability of peripheral nociceptive terminals of primary afferent neurons during inflammation by inhibiting high-voltage activated calcium channels, which decreases the propagation of action potentials and the release of C fiber excitatory transmitters, such as substance P.^4-6

Morphine is often used in intra-articular and epidural blocks, along with local anesthetics, and seems to provide additional analgesia in people and dogs.^7-9 Buprenorphine has been shown to extend the duration of analgesia with brachial plexus and epidural blocks in people, compared with local anesthetic administration alone.^10-13 Epidural morphine and buprenorphine have induced thermal nociception in cats, but morphine antinociception lasted longer and was more intense.¹⁴ The mechanism for the increased efficacy and duration of analgesia with peripherally administered opioids appears to be related to the lipophilicity of the opioid since the highly lipophilic buprenorphine provided a longer duration of satisfactory analgesia in people after a brachial plexus block than did the less lipophilic sufentanil.¹³ The anti-inflammatory effects of opioids likely also play a role in prolonging analgesia.⁵ Minimal adverse affects are associated with the peripheral administration of opioids because doses administered peripherally result in low plasma concentrations in most species.^2,5

Alpha₂ agonists

Alpha₂ agonists, such as medetomidine, can be added to local anesthetic blocks to extend the duration and increase the efficacy of the block.^15-18 Alpha₂ agonists likely exert these effects through several mechanisms, including vasoconstriction, resulting in decreased systemic absorption of local anesthetics; facilitation of C fiber blockade by the local anesthetic; and action at the spinal cord due to slow retrograde axonal transport along the nerve.¹⁷ Norepinephrine is a principal neurotransmitter in the sympathetic nervous system that is also involved in nociception through alpha₂-adrenergic receptors expressed on peripheral sensory neurons. In pathological pain states, such as neuropathic pain and inflammation, nociceptors develop increased sensitivity to norepinephrine, and peripheral antinociception is likely mediated through these peripheral alpha₂-adrenergic receptors.^17,18

Clonidine has been used for intra-articular, epidural, intrathecal, intravenous regional, and peripheral nerve blocks in people.^17,18 Medetomidine provided effective analgesia when administered epidurally in goats, cows, dogs, and cats and extended the duration of radial nerve blockade with mepivacaine in dogs.^15,19-22 Dexmedetomidine (Dexdomitor—Pfizer Animal Health) has potentiated and prolonged the effects of intrathecal and epidural local anesthetics in rats, sheep, guinea pigs, and people.²³ Spinal administration of dexmedetomidine provided a powerful antinociceptive effect in dogs,²⁴ and epidural dexmedetomidine was found to decrease the minimum alveolar concentration (MAC) of isoflurane in dogs.²⁵ The addition of dexmedetomidine to the local anesthetic solution in intravenous regional anesthesia in people improved the quality of anesthesia and decreased analgesic requirements but had no effect on the sensory and motor blockade onset or duration.²⁶ Sedation, bradycardia, and decreased cardiac output can occur from systemic absorption, so alpha₂ agonists should not be used in hypovolemic patients or patients with impaired cardiovascular function.^15,17,22,25