Clonidine functions as a sympatholytic by stimulating presynaptic α2-receptors leading to decreased release of norepinephrine at both central and peripheral adrenergic terminals. In addition to its influence on the autonomic nervous system, it is well established that clonidine is an effective analgesic, and this is also attributable to its α2-agonist activity.
Remember that a tremendous amount of modulation of incoming pain signals occurs in the dorsal horn of the spinal cord prior to being sent to higher centers in the CNS. Messages are either strengthened or attenuated by release of various neurotransmitters by primary afferent Aδ or C fibers, interneurons, and descending bulbospinal fibers. Nociceptive stimuli will promote release of excitatory transmitters from primary afferents in the dorsal horn. To compensate, there is simultaneous release of norepinephrine from descending inhibitory bulbospinal neurons, which binds to α2-receptors in the dorsal horn to diminish afferent pain transmission, thereby producing analgesia.
It is logical, therefore, that drugs targeting α2-receptors should influence the transmission and perception of pain. Cocaine, the first spinal anesthetic, produces analgesia largely through its local anesthetic effect, but the noradrenergic stimulation of α2-receptors caused by its blocking of NE reuptake is also contributory. Therefore, it is the mimicking of the actions of descending inhibitory fibers by which clonidine, and all α2-agonists, causes analgesia. It has been shown that administration of the α2-antagonist, yohimbine, will at least partially reverse the sedation and analgesia induced by clonidine.
This is only part of the story, however, as cholinergic activation in the dorsal horn has also been shown to impart analgesia, and clonidine has been shown to increase ACh levels in lumbar CSF. Additionally, epidural clonidine analgesia in volunteers is enhanced by intrathecal injection of the cholinesterase inhibitor, neostigmine, lending further support to the notion that α2-agonists impart analgesia through both cholinergic and noradrenergic transmission.
Clonidine also potentiates sensory and motor blockade of epidural and peripheral nerve block administered local anesthetics. Three mechanisms for this have been given. First, clonidine has intrinsic ability to block conduction in C and Aδ fibers and will intensify conduction block of local anesthetics. Second, clonidine may cause local vasoconstriction and thus impair vascular removal of epidural local anesthetics, although this probably does not occur significantly at clinically-used concentrations. Third, it has been shown that any analgesic, whether neuraxial or systemic, will augment peripheral or spinal blockade. Clonidine also enhances neuraxial opioids, with epidural clonidine and fentanyl interacting in an additive manner. In fact, the dose of each component can be reduced by 60% when combined for postoperative analgesia.
Epidural Clonidine: Summary
- Stimulation of α2-receptors in the dorsal horn diminishes pain transmission (mimics inhibitory descending bulbospinal neurons)
- Increased ACh levels increases analgesia through cholinergic mechanisms (neostigmine improves spinal blocks)
- Intrinsic blockade of Aδ and C fibers
- Local vasoconstriction (probably not effective at clinically used doses)