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14 Articles in Volume 19, Issue #5
Agonism and Antagonism of the Muscles of the Shoulder Joint: An SEMG Approach
Analgesics of the Future: The Potential of IV Formulations for Post-Op Treatment of Pain
Blood Biomarkers Show Promise for Precision Pain Management
Can I Call Myself a “Pain Specialist?”
Cases in Urine Drug Monitoring Interpretation: How to Stay in Control (Part 2)
Fear-Avoidance and Chronic Pain: Helping Patients Stuck in the Mouse Trap
How to Avoid Patient Alienation When Discussing Stress
Managing Phantom Limb Pain with Medication
Nerve Blocks Lead to Improved Quality of Life
Sacroiliac Joint Dysfunction: New Methods in Evaluation and Management
SCS Therapy in a Patient with Advanced Bilateral Kienbocks
Thoracic Epidural Abscess with Cord Compression Following a High-Frequency SCS Trial
What is the evidence to support clonidine as an adjuvant analgesic?
What’s In A Name? In This Case, That Which We Call Addiction Is Not Dependence

What is the evidence to support clonidine as an adjuvant analgesic?

July/August 2019 Ask the Expert - Clonidine may be beneficial for neuropathic pain, but further research on mechanisms of action are lacking.
Pages 16-17

Current Clonidine Indications

Clonidine is a partial agonist with alpha-2a/alpha-1 selectivity. It has been widely investigated in anesthesia and pain therapy in both animals and humans. Clonidine improves the analgesic effects of opioids and local anesthetics. Using clonidine for pain therapy may cause adverse effects, including hypotension and sedation.1 Clonidine is available as the following FDA-approved products: oral tablet, extended-release tablet, transdermal patch, and epidural solution. Clonidine is also often compounded into a topical formulation. For cancer pain, the recommended dosage is 30 mcg/hr as a continuous epidural infusion, titrated based on clinical response.2 For neuropathic pain, transdermal clonidine has been titrated from 0.1 mg/day to 0.3 mg/day or applied as a 0.1% gel three times daily.3

Use for Cancer-Related Pain

Clonidine epidural injection is FDA-approved for the adjunct treatment of cancer-related pain. It is indicated as a combination with opioids for cancer patients experiencing severe pain that is not controlled with opioids alone. In a randomized controlled trial (n = 85), epidural clonidine was successful in reducing pain in 45% of patients, compared to 21% of patients in a placebo group. The only subgroup in this study that reported a significant analgesic effect was the group of patients with neuropathic pain.4 There is also an off-label indication for clonidine transdermal patch for the treatment of chronic pain; the patch is considered to be most effective in managing pain described as sharp and shooting.5

The National Comprehensive Cancer Network (NCCN) 2016 Guidelines for Adult Cancer Pain list clonidine epidural or intrathecal infusions as a commonly used interventional procedure. This treatment may be indicated in patients that have a high possibility of pain relief from a nerve block or failure to achieve adequate analgesia from other medications or presentation of intolerable adverse effects.6

Clonidine is thought to produce analgesia at alpha-2 adrenoreceptors in the spinal cord, limiting analgesia to body regions innervated by spinal segments. (Source: 123RF)

Use for Peripheral Diabetic Neuropathy

A Cochrane review of the use of topical clonidine in patients with peripheral diabetic neuropathy (PDN) assessed two studies. (There were no studies found on topical clonidine for other pain conditions and both trials noted moderate to high risk of bias.) Topical clonidine compared to placebo delivered significantly better results for at least 30% reduction in pain intensity (risk ratio: 1.35, 95% confidence interval: 1.03 to 1.77), but no better for at least 50% reduction in pain intensity. The number needed to treat was 8.33, which is higher than other treatments for PDN. There was no difference in adverse events between groups. Reviewers concluded that topical clonidine should not be used as first-line therapy for PDN, but may be considered when other treatment options have failed or are contraindicated.7

Mechanism of Action

The mechanism of action of clonidine in the treatment of pain is not completely understood. As an epidural infusion, clonidine produces a dose-dependent analgesic effect by preventing pain signal transmission to the brain. Clonidine is thought to produce analgesia at alpha-2 adrenoreceptors in the spinal cord, limiting analgesia to body regions innervated by spinal segments.4 Two proposed mechanisms for the analgesic effects produced by clonidine include the reduction of glutamate and excitatory neuropeptide release from central afferent terminals, as well as the hyperpolarization of dorsal horn neurons.

One study assessed the effects of clonidine on N-methyl-D-aspartic acid (NMDA) receptors in neuropathic pain in rats. The study found an association of clonidine causing suppressed phosphorylation in NMDA receptor NR1 in the spinal dorsal horn. Although the exact mechanism was not discovered, the results may have been due to activation of alpha-2 receptors inhibiting cAMP, which leads to a reduction of protein kinase A (PKA) activity. Due to the dependence of PKA activity on NMDA current, a reduction in PKA may have resulted in the reduced NMDA current. Results from the study showed decreased thermal hyperalgesia and mechanical allodynia in neuropathic rats treated with intrathecal clonidine.8

Several other mechanisms of clonidine have been proposed. Alpha-2 agonists may produce analgesia by inhibiting norepinephrine release from prejunctional alpha-2 receptors, which triggers a sympatholytic effect.9 Alpha-2 agonists may produce an analgesic effect by activating alpha-2 adrenoceptors in the locus coeruleus. Pain relief may be caused by inhibition of Na+ channels. Specifically, clonidine inhibited NaV1.7, a tetrodotoxin-sensitive Na+ channel isoform, in cultured bovine adrenal chromaffin cells. An additive inhibitory effect on NaV1.7 was produced when combined with lidocaine.10


In summary, clonidine is FDA-approved for adjunct treatment in cancer pain, and may be beneficial in neuropathic pain, but evidence of its use outside of epidural injections for cancer pain is lacking. The mechanism of action for the analgesic effects of clonidine is yet to be understood with several possibilities described but not confirmed.

Last updated on: August 2, 2019
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