Clonidine is an alpha-2 adrenoceptor agonist which has been shown to activate spinal receptors that reduce responses to painful stimuli (Yaksh 1985). Ackerman et al. (2003) note that clonidine inhibits nociceptive impulses by activating alpha-2 adrenoceptors in the dorsal horn of the spinal cord (Rainov et al. 2001). The anti-nociceptive effects of clonidine are thought to be mediated via inhibitory interaction with pre- and post-synaptic primary afferent nociceptive projections in the dorsal horn (Osenbach & Harvey 2001) and possibly by inhibition of substance P release (Ackerman et al. 2003; Hassenbusch et al. 1999). Ackerman et al. (2003) noted selective alpha-2 adrenergic antagonists (e.g. Yohimbine) have been shown to reverse clonidine-induced analgesia (Osenbach & Harvey 2001). Teasell and Arnold (2004) were able to show that venous alpha-adrenoceptor hyper-responsiveness was present in patients with RSD, in diabetic peripheral neuropathy (Arnold et al. 1993) and below the level of lesion in quadriplegics (Arnold et al. 1995). They speculated that this alpha-adrenoceptor hyper-responsiveness was in fact due to alpha-2 adrenoceptor dysfunction leading to overstimulation of the post-synaptic alpha-1 adrenoceptor peripherally. This would fit with the observation that clonidine reduces pain post-SCI below the level of the lesion, presumably through its alpha-2 adrenoceptor agonist function.
Ackerman et al. (2003) noted that clonidine may be useful for patients who are non-responsive to opioids. Clonidine appears to work synergistically with opioids to provide pain relief (Osenbach & Harvey 2001; Plummer et al. 1992; Siddall et al. 2000; Tallarida et al. 1999).