Autonomic drugs which have proven beneficial in the treatment of neuropathic pain include the alpha–2 agonists (e.g. clonidine) and alpha–1 antagonists (e.g. prazosin, terazosin). The role of the alpha-2 adrenergic system in neuropathic pain has been studied using various pharmacological interventions and animal models.
In animal studies, alpha-2 adrenergic agonists produce analgesia by actions in the periphery, supraspinal central nervous system and in the spinal cord. Clonidine is believed to produce analgesia at the spinal level, in part through stimulation of cholinergic interneurones in the spinal cord. This cholinergic mediation of analgesia, as reflected by cerebrospinal fluid acetylcholine concentration, is activated by intrathecal, but not IV, injection of clonidine. However, clonidine has been shown to produce analgesia to experimental pain stumuli after systemic and epidural injection. However, clinical studies of systemic clonidine for analgesia have yielded conflicting results. Alpha-2 adrenergic agonists produce sedation and reduced blood pressure in addition to analgesia. Small doses (50 mg) of clonidine may reduce blood pressure more after an intrathecal than an IV injection.
Clonidine has also been shown to potentiate the neuropathic pain-relieving action of the NMDA antagonist MK–801 while preventing its neurotoxic and hyperactivity side-effects. Clonidine is available in several different dosage forms and can be administered orally, transdermally or spinally. Conversely, systemic dexmedetomidine, another alpha-2 adrenergic agonist, has been shown neither to prevent nor attenuate neuropathic pain behaviour in rats. Dexmedetomidine has an affinity for all three alpha-2 adrenergic receptor subtypes. The role of the different subtypes of alpha-2 adrenoreceptors remains unclear.