Clonidine for Pain

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).

Author Year


PEDro Score

Research Design

Total Sample Size

Methods Outcome
Siddall et al. 2000





Population: Age=26-78 yr; Type of pain=neuropathic: 13 had below level neuropathic pain, 4 at level of neuropathic pain, 3 had both neuropathic and nociceptive pain.

Intervention: Placebo, morphine or Clonidine was delivered via catheter into lumbar intrathecal space. The subjects were first given either: 2, 1 mg morphine, 50-100 mcg of Clonidine or placebo. Dosage was increased if the subject had no side effects and no pain relief. Subjects could receive up to 1.5 times the initial drug dosage if necessary. Once the subject received satisfactory pain relief or side effects from the drug they were on they were given a mixture of morphine and Clonidine.

Outcome Measures: Numerical pain rating scale, numerical pain relief score, a verbal pain rating and a nausea scale and sedation scores were recorded.

1.     The administration of morphine or clonidine resulted in a mean reduction in pain levels but this was not statistically significant compared to the effect of placebo.

2.     When the mixture of morphine and clonidine was administered there was a significant reduction in pain when compared to those on placebo (p=0.0084).

Uhle et al. 2000




Population: Age=34-77 yr; Gender males=4, females=6; Time since injury=1-10 yr; Type of pain=neuropathic.

Intervention: Subjects, once implanted with a medical pump, were originally given 3 mL of saline followed by 1 mL of morphine, this was followed by a second dose of morphine (0.02 mg) provided no side effects or benefits were noted. This was followed by Clonidine (30 ug in 1 mL) and then depending on side effects a final dose of Clonidine (50 ug in 1 mL). After each drug administration the catheter was flushed with saline.

Outcomes Measures: Not specified.

1.     Subjects reported a good to excellent pain reduction following the administration of Clonidine administration.

2.     After Clonidine bolus subjects experienced an optimum pain reduction. Average dose of Clonidine was initially 53 ug/day and this decreased (or stabilized) to 44 ug/day.


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.

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