Naloxone for Clonidine-induced CNS Depression

Take Home Points

• Clonidine is a central alpha agonist that can cause central nervous system (CNS) depression, apnea, bradycardia, and hypotension in overdose.
• Naloxone is an opioid antagonist and, at high doses, may reverse the CNS effects of clonidine through competitive inhibition of endorphins and enkephalins, avoiding the need for intubation.
• Naloxone dosing: 0.1 mg/kg (maximum 2 mg/dose) repeated every 1-2 minutes with a total maximum dose of 10 mg. If there is no response to standard naloxone dosing, consider trialing naloxone 10 mg IV.
• There is no concern for precipitation of withdrawal in opioid naive patients who have ingested clonidine.
• Call the Utah Poison Control Center at 1-800-222-1222 at any time 24/7 for assistance in managing known or suspected clonidine poisonings.

Clonidine^1-3

Clonidine exerts its action through stimulation of central alpha 2-adrenergic receptors, leading to decreased sympathetic outflow from the central nervous system (CNS) as well as reduced peripheral resistance, heart rate, and blood pressure. Therapeutic uses for clonidine include the treatment of Attention Deficit Hyperactivity Disorder (ADHD), Tourette’s syndrome, conduct and oppositional disorder, hypertension, narcotic withdrawal, cancer-related pain, and delirium tremens. Clonidine is available as transdermal patches (0.1 mg/day, 0.2 mg/day, 0.3 mg/day), immediate-release tablets (0.1, 0.2, 0.3 mg), an extended-release tablet (0.1 mg), compounded oral suspension, intravenous (IV) solution (5 mg/mL), and epidural solution (0.5 mg/mL, 0.1 mg/mL).

Clonidine Toxicity¹

The toxic dose of clonidine varies; 0.1 mg has produced toxic effects in children, and dosing just above the therapeutic range can cause toxicity in adults. The onset of effects is typically about 30 minutes, with peak effect 6-12 hours following ingestion. Clinical presentation of intoxication includes lethargy, somnolence, coma, pupil constriction, apnea, bradycardia, and hypotension. Recovery of the CNS and respiratory effects is typically seen within 24 hours with supportive care; however, bradycardia and hypotension may persist due to clonidine’s long half-life.

Mental status

Children can become unresponsive following clonidine ingestion, but often arouse in response to stimuli.⁴ One theory is that clonidine increases endogenous opioid release, leading to effects similar to an opioid overdose. Following clonidine ingestion of as little as one to two tablets, patients are at risk of severe CNS depression, which can lead to intubation. 

Airway/Breathing

In a review of single-drug ingestions that resulted in endotracheal intubation, clonidine was the drug that most frequently resulted in intubation in children less than 6 years old.⁵ 

Cardiovascular Effects

Clonidine exerts its action on alpha-adrenergic and imidazoline receptors. Alpha-2 adrenergic action decreases norepinephrine release, lowering blood pressure. In very high serum concentrations, peripheral alpha-1 receptors can be stimulated, leading to the release of norepinephrine, causing vasoconstriction and hypertension. Hypertension is usually transient, overcome by the centrally mediated sympathetic inhibition to cause hypotension. Additionally, clonidine is thought to increase the release of beta-endorphin, which causes hypotension and bradycardia. Bradycardia can occur due to increased vagal tone with decreased sympathetic outflow.²  Bradycardia and hypotension are generally responsive to supportive care, which includes atropine for symptomatic bradycardia, IV fluids, and sometimes vasopressors like norepinephrine for hypotension. 

Naloxone

Naloxone is an opioid competitive antagonist that was developed to counter the effects of opioid overdose.⁴ Several case reports have reported observations of reversal of somnolence secondary to naloxone administration in clonidine overdose. Naloxone was administered in some of these cases, as clonidine toxicity was mistaken for opioid toxicity. The proposed mechanism for naloxone in clonidine toxicity is the reversal of the effects of beta-endorphin or the reversal of endogenous opioids.^1,4 Seger and Loden evaluated naloxone administration to children following clonidine ingestion. In this study, sedation resolved in 35 (87.5%) patients after being treated with naloxone following a clonidine ingestion. Naloxone doses ranged from 3.5 mg to 10 mg.⁴ 

Naloxone Indications

In clonidine overdose, administer high-dose naloxone to avoid intubation secondary to CNS depression.

Naloxone Dosing

0.1 mg/kg (maximum 2 mg/dose) repeated every 1-2 minutes with a total maximum dose of 10 mg.⁴ 

Naloxone Safety

Withdrawal

In patients with chronic use of opioids, large doses of naloxone should be avoided due to the risk of precipitating withdrawal. In opioid naive patients who have ingested clonidine, withdrawal is not a concern. 
Call the Utah Poison Control Center at 1-800-222-1222 at any time, 24/7, for assistance in managing known or suspected clonidine poisonings.  

References

1. Smollin C. CLONIDINE AND RELATED DRUGS. In: Olson KR, Smollin CG, Anderson IB, et al., eds. Poisoning & Drug Overdose, 8e. McGraw Hill; 2022. Accessed May 27, 2025. accessmedicine.mhmedical.com/content.aspx?aid=1190445154
2. Yasaei R, Saadabadi A. Clonidine. In: StatPearls. StatPearls Publishing; 2025. Accessed April 14, 2025. http://www.ncbi.nlm.nih.gov/books/NBK459124/
3. Clonidine HCl. Merative Micromedex RED BOOK. Merative Micromedex. Merative 2025. Accessed May 27, 2025. https://www.micromedexsolutions.com/
4. Seger DL, Loden JK. Naloxone reversal of clonidine toxicity: dose, dose, dose. Clin Toxicol (Phila). 2018;56(10):873-879. doi:10.1080/15563650.2018.1450986
5. Beauchamp GA, Giffin SL, Horowitz BZ, Laurie AL, Fu R, Hendrickson RG. Poisonings Associated with Intubation: US National Poison Data System Exposures 2000-2013. J Med Toxicol. 2016;12(2):157-164. doi:10.1007/s13181-015-0528-2