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Article Author:
Rama Yasaei
Article Editor:
Abdolreza Saadabadi
6/7/2020 9:42:59 PM
For CME on this topic:
Clonidine CME
PubMed Link:


Clonidine is a 40-year-old medication in the class of antihypertensive medications that act on alpha-adrenergic and imidazoline receptors agonist. Clonidine is an antihypertensive drug that lowers blood pressure and heart rate by relaxing the arteries and increasing the blood supply to the heart; it has other FDA-approved indications such as:

  • Treatment of attention deficit hyperactivity disorder (ADHD) in children (FDA approval 2010)
  • Management of tics commonly found with Tourette syndrome
  • Adjunct therapy for severing cancer-related pain[1]

Clonidine has multiple off-label uses such as the management of withdrawal symptoms from opioids, benzodiazepines, and alcohol, and for treatment of anxiety, insomnia, and post-traumatic stress disorder (PTSD).[2][3]

Because of the effect of clonidine on the sympathetic nervous system, specifically, the reduction of circulating epinephrine, it has been used in many other aspects of medicine, for example, control of hot flashes in menopause, restless leg syndrome, and prophylaxis of vascular migraine headaches. Also, there is a test for phaeochromocytoma that is called the clonidine suppression test, in the lab, they measure the catecholamine levels before and after a dose of oral clonidine which, in healthy people, should cause the decrease in the level of catecholamines in circulation.[1][2]

Mechanism of Action

Clonidine hydrochloride is an imidazoline derivative that acting centrally on alpha-2 adrenergic as an agonist. The chemical name for clonidine is 2-((2,6-dichlorophenyl) amino)-2-imidazoline hydrochloride.

Clonidine, as an alpha-adrenergic agonist in the nucleus tractus solitarii (NTS), excites a pathway that inhibits excitatory cardiovascular neurons. Clonidine has an alpha-antagonist effect in the posterior hypothalamus and medulla. The final response is reduced sympathetic outflow from the central nervous system (CNS), which clinically causes a decrease in arterial blood pressure.

One of the theories about the mechanism of action of clonidine in the management of pain in the CNS is that many pain signals occur in the dorsal horn of the spinal cord and are sent to higher centers of the CNS. There is a release of norepinephrine from the descending inhibitory bulbospinal neurons that binds to alpha-2-receptors in the dorsal horn to decrease afferent pain transmission and produces analgesia. Therefore, drugs like clonidine that target alpha-2 receptors can influence the transmission of pain.

Epidural clonidine used as an adjunct to local anesthetics has three different mechanisms of action. First, the stimulation of alpha-2-receptors in the dorsal horn reduces pain transmission. Secondly, clonidine can cause local vasoconstriction that limits vascular removal of local epidural anesthetics. Lastly, clonidine enhances neuraxial opioids, and in combination with fentanyl, interacts in an additive manner, which can reduce the dose of each component by 60% for postoperative analgesia.

The exact mechanism of action of clonidine in the management of attention-deficit hyperactivity disorder (ADHD) is not clear, but it is possible prefrontal cortex brain activity is involved.[4]


Clonidine Forms and Dosages

Transdermal Patch (extended-release)

  • Dosage: 0.1 mg/day, 0.2 mg/day, 0.3 mg/day. Change the patch every seven days
  • Indications: hypertension, smoking cessation, cyclosporine nephrotoxicity, menopausal flushing, and opioid withdrawal

Tablet (immediate-release)

  • Dosage: 0.1 mg, 0.2 mg, 0.3 mg
  • Indications: hypertension, acute hypertension, opioid withdrawal, and pheochromocytoma

Tablet (extended-release)

  • Dosage: 0.1 mg
  • Indications: alcohol withdrawal, smoking cessation, restless-leg syndrome, ADHD, Tourette syndrome, menopausal flushing, dysmenorrhea, postherpetic neuralgia, and psychosis

Injectable Solution

  • Dosage: 100 mcg/ml, 500 mcg/ml
  • Indications: epidural infusion form in cancer pain not controlled by opioid analgesics and as an adjunct in anesthesia
  • The initial dose of 30 mcg/hr and titration is necessary for pain management or potential side effects.

Dosing Considerations

Extended-release and immediate-release types of clonidine are not interchangeable.

In cases of conversion from oral to transdermal clonidine recommendation is:

  • On day one: place transdermal clonidine patch, and administer 100% of the oral dose.
  • On day two: Administer only 50% of the oral dose.
  • On day three: Administer 25% of the oral dose.
  • On day four: Use of the transdermal patch continues without any further oral supplement.

Renal Impairment Dosing Modification

For renal impairment, the recommendation is to start a low dose and titer up with caution. The initial dose should consider the amount of renal impairment. Monitor carefully for hypotension and bradycardia.[5]

Adverse Effects

Clonidine, like any other medication, has a potential for short-term and long-term side effects. Some of the common side effects based on FDA reports include:

Common Reactions (tend to resolve with continued therapy)

  • Abdominal pain
  • Headache
  • Hypotension
  • Fatigue
  • Nausea
  • Emotional instability
  • Constipation
  • Xerostomia
  • Diarrhea
  • Sexual dysfunction
  • Dizziness
  • Sedation

Serious Reactions

  • Angioedema
  • Depression
  • Hypersensitivity
  • Atrioventricular (AV) block
  • Bradycardia
  • Syncope
  • Severe hypotension

Note rebound hypertension and withdrawal symptoms if medication discontinued immediately.

Other Symptoms

  • Fever, headache
  • Fatigue
  • Bradycardia
  • Congestive heart failure
  • Decreased sexual activity
  • Thrombocytopenia
  • Agitation
  • Depression is one of the rarely reported side effects with the chronic use of clonidine; however, because of the variety of applications this medication has, and also because of its slow progress, physicians should monitor patients for signs of depression.


Hypersensitivity to medication, class of alpha-2-agonist. For epidural use: administration above C4 dermatome. Do not suddenly discontinue the drug; otherwise, there is a risk of rebound hypertension and withdrawal symptoms. Dose adjustment is necessary for renal impairment, cardiovascular, bradycardia, hypotension, and severe coronary artery disease (CAD) patients. Also, use with caution in patients with a history of depression, recent myocardial infarction (MI), and syncope.


Clonidine has a black box warning for appropriate use.

  • Dilute 500 mcg/ml strength product before use in a proper solution.

Obstetrical, Postpartum, or Perioperative Use

  • Weigh risk versus benefit
  • Epidural clonidine is not recommended for obstetrical and postpartum perioperative pain control because of increased risk of hemodynamic instabilities like hypotension and bradycardia.

Clonidine Addiction

Even though clonidine is a medication that commonly used for withdrawal symptoms of opioid addiction, it has the potential to be the substance of misuse and needs monitoring in that regard.

Clonidine use, in many cases, does not typically fit the category of addiction stereotype, especially because most of the abusers do not feel like they are doing anything wrong as it is a prescription medication. Clonidine is not in a category of high potential for abuse medication by the United States government. As a result, it has fewer restrictions, and it is less risky to take it for abuse. Unfortunately, much of clonidine abuse starts in rehabilitation centers as it is a common medication for opioid and alcohol withdrawal treatment. Since it helps to reduce the withdrawal symptoms and craving, clinicians should evaluate their concerns about the potential of trading addictions.[6] Also, the synergistic potential of clonidine when mixed with other benzodiazepines, opioids, or alcohol, can give the individual more potent drowsiness and further detachment from reality. It is essential to notify the patients and try to screen for signs of dependency on clonidine as listed below [7]:

  • Feel of the intense urge for clonidine
  • Feeling the need for the use of clonidine regularly
  • Finding that one is taking more clonidine to achieve the same effect.
  • Making sure that there is always a backup supply of clonidine
  • Spending more on clonidine than one can afford
  • Can not picture quitting clonidine
  • Experience withdrawal symptoms such as nausea, vomiting, dizziness, headache, insomnia, restlessness, or anxiety when trying to stop taking clonidine

Enhancing Healthcare Team Outcomes

Clonidine is prescribed by many healthcare professionals, including the nurse practitioner, primary care provider, cardiologist, psychiatrist, and internist. Besides hypertension, clonidine has many off label uses.[3] Clonidine has multiple off-label uses such as the management of withdrawal symptoms from opioids, benzodiazepines, and alcohol, analgesia, and for treatment of anxiety, insomnia, and post-traumatic stress disorder (PTSD). While the drug is relatively safe, it is essential to discuss with the pharmacist about any potential contraindications and adverse effects. The drug is also known to cause physical and psychological dependence.[8]


[1] Khakurel S,Sapkota S,Karki AJ, Analgesic Effect of Caudal Bupivacaine with or without Clonidine in Pediatric Patient. Journal of Nepal Health Research Council. 2019 Jan 28;     [PubMed PMID: 30739935]
[2] Bello M,Oger S,Bedon-Carte S,Vielstadte C,Leo F,Zaouter C,Ouattara A, Effect of opioid-free anaesthesia on postoperative epidural ropivacaine requirement after thoracic surgery: a retrospective unmatched case-control study. Anaesthesia, critical care     [PubMed PMID: 30731138]
[3] Pelayo R,Yuen K, Pediatric sleep pharmacology. Child and adolescent psychiatric clinics of North America. 2012 Oct     [PubMed PMID: 23040905]
[4] Drugs for ADHD. The Medical letter on drugs and therapeutics. 2020 Jan 27     [PubMed PMID: 31999670]
[5] Kuzmin OB,Buchneva NN,Zhezha VV,Serdyuk SV, [Uncontrolled Arterial Hypertension: Kidney, Neurohormonal Imbalance, and Approaches to Antihypertensive Drug Therapy]. Kardiologiia. 2019 Dec 11     [PubMed PMID: 31849313]
[6] Rahimi-Movaghar A,Gholami J,Amato L,Hoseinie L,Yousefi-Nooraie R,Amin-Esmaeili M, Pharmacological therapies for management of opium withdrawal. The Cochrane database of systematic reviews. 2018 Jun 21     [PubMed PMID: 29929212]
[7] Ommi D,Teymourian H,Zali A,Ashrafi F,Jabbary Moghaddam M,Mirkheshti A, Effects of Clonidine Premedication on Intraoperative Blood Loss in Patients With and Without Opium Addiction During Elective Femoral Fracture Surgeries. Anesthesiology and pain medicine. 2015 Aug     [PubMed PMID: 26473101]
[8] Toce MS,Chai PR,Burns MM,Boyer EW, Pharmacologic Treatment of Opioid Use Disorder: a Review of Pharmacotherapy, Adjuncts, and Toxicity. Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2018 Dec;     [PubMed PMID: 30377951]