Epidural Adjuvants: Clonidine and Dexmedetomidine

Mechanism of Action

• Clonidine and dexmedetomidine are alpha²-adrenergic agonists that produce analgesia via three mechanisms.¹

1. Stimulation of alpha²-adrenergic receptors in the dorsal horn of the spinal cord, thus diminishing pain transmission (mimicking inhibitory descending bulbospinal neurons)
2. Increased acetylcholine levels via the release of norepinephrine via the descending noradrenergic pathways, thus causing cholinergic activation in the dorsal horn
3. Intrinsic blockade of Aδ and C fibers, thus its addition to local anesthetics, will potentiate sensor and motor blockade.

• Alpha²-adrenergic receptors are located on:

1. primary afferent terminals (both at peripheral and spinal endings);
2. neurons in the superficial laminae of the spinal cord; and
3. within several brainstem nuclei implicated in analgesia.

• The presence of adrenoreceptors in these three sites supports the possibility of analgesic action at peripheral, spinal, and brainstem sites. However, clonidine is most potent in the neuraxial space.
• Clonidine is a centrally acting selective partial alpha²-adrenergic agonist, whereas dexmedetomidine is a highly selective alpha²-agonist.

Cardiovascular Effects

• Both clonidine and dexmedetomidine exert hemodynamic changes, mainly hypotension and bradycardia, that may impact a patient’s ability to tolerate the medications when administered via the epidural route.
• Dexmedetomidine administration can lead to varying degrees of heart block and thus should be used with caution in patients with hypovolemia, hypotension, bradycardia, fixed stroke volume, and advanced degrees of heart block.
• Most episodes of hypotension occur within the first 4 days of initiation of the epidural infusion.
• Given the cardiovascular impact of clonidine, the FDA has issued a black box warning for the use of epidural clonidine: “Clonidine hydrochloride injection (epidural clonidine) is not recommended for obstetrical, post-partum, or peri-operative pain management. The risk of hemodynamic instability, especially hypotension and bradycardia, from epidural clonidine may be unacceptable in these patients. However, in a rare obstetrical, post-partum or peri-operative patient, potential benefits may outweigh the possible risks.”³
• Due to concerns about hemodynamic changes in placental blood flow, clonidine is not routinely used in epidural solutions in the obstetrical population.
• Hemodynamic issues are dose-dependent, and studies have shown that in appropriate doses, effective analgesia can be delivered without unwanted cardiovascular effects.⁴

Clinical Use

The advantages of adding alpha2-adrenergic agonists to local anesthetic solution for epidural analgesia:⁵

• Decreased motor block without impacting analgesia as the local anesthetic dose can be reduced.
• When combined with a local anesthetic in an epidural solution, both clonidine and dexmedetomidine will decrease the time of onset of the block and increase the duration of sensory blockade (in comparison to local anesthetic alone).⁶
• They can eliminate the need for opioids in an epidural solution, thus removing the risk of opioid-related side effects such as respiratory depression, nausea, vomiting, and pruritis.
• They have a sedative effect in addition to analgesia, a side effect that may or may not be desired.