Alpha-2 agonists and analgesia

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Abstract
In addition to their anti-hypertensive effects, alpha-2 agonists also cause analgesia. Since analgesia from these drugs is due primarily to actions in the spinal cord, it is not surprising that analgesia is poor after systemic administration, but profound after injection near the cord (spinal or epidural administration). Advantages of alpha-2 agonists over opioids in the treatment of severe pain include lack of opioid type side effects (addiction, nausea, respiratory depression, pruritus), lack of abuse potential and efficacy in special situations where opioids fail (opioid tolerance, neuropathic pain, reflex sympathetic dystrophy). Clonidine, the lead compound in this category, has been administered epidurally or spinally to over 1,000 patients in published reports, and detailed cerebrospinal fluid pharmacokinetics and pharmacodynamics have been described. Epidural clonidine has been designated as an orphan product in the US for the treatment of intractable cancer pain, and a multi-centre, placebo-controlled, Phase ill trial has demonstrated its safety and efficacy for this indication. As might be expected, epidural clonidine is effective in the setting of opioid tolerance, neuropathic pain and reflex sympathetic dystrophy, but is also effective alone and in combination with other analgesics in the treatment of postoperative and obstetric labour pain. Dexmedetomidine is the only other alpha-2 agonist under clinical development in injectable form. Although dexmedetomidine is a more potent and selective alpha-2 agonist than clonidine, its high lipid solubility leads to rapid systemic absorption after intraspinal use, which will probably lead to sedation and decreased blood pressure. Development of hydrophilic alpha-2 agonists, such as ST-91 and oxymetazoline, could offer unique advantages for this indication.