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).
Siddall et al. (2000) in a cross-over RCT of 20 subjects with post-SCI neuropathic pain received intrathecal morphine, clonidine or placebo at the lumbar level. Once the subjects received satisfactory pain relief or drug side effects they were given a mixture of clonidine and morphine. Morphine or clonidine showed a trend in pain reduction, which was not statistically significant but when the combination of morphine and clonidine was administered there, was a significant reduction in pain. Siddall et al. (2000) did postulate that by administering half the effective minimum dose of clonidine and morphine together resulted in a synergistic addictive effect above the simple summing up of each drug in isolation. In a study by Uhle et al. (2000) 10 patients were given morphine followed by clonidine via a medical pump. Patients given clonidine experienced a good to excellent reduction in their pain.
There is level 1b evidence (from one RCT: Siddall et al. 2000) that intrathecal clonidine alone does not provide pain relief greater than placebo.
There is level 2 evidence (from one prospective controlled trial: Uhle et al. 2000) that the combination of intrathecal morphine and clonidine provides pain relief greater than placebo.