Clonidine

Article Author:
Rama Yasaei
Article Editor:
Abdolreza Saadabadi
Updated:
1/21/2018 4:01:15 PM
PubMed Link:
Clonidine

Indications

Clonidine is a 40-year-old medication in the class of antihypertensive medications which act on alpha-adrenergic and imidazoline receptors agonist. Clonidine is an anti-hypertensive 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

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).

Because of the effect of clonidine on the sympathetic nervous system specifically, the reduction the epinephrine in circulation, 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.

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 nucleus tractus solitarii (NTS) excites a pathway that inhibits excitatory cardiovascular neurons. Clonidine has 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 the decrease 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, stimulation of alpha-2-receptors in the dorsal horn reduces the 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.

Administration

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 7 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 to be used interchangeably.

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

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

Renal Impairment Dosing Modification

For renal impairment, it is recommended 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.

Adverse Effects

Clonidine like any other medications 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 uses this medication has, and also because of its slow progress, physicians should monitor patients for signs of depression.

Contraindications

Hypersensitivity to medication, class of alpha-2-agonist. For epidural use: administration above C4 dermatome. Do not discontinue suddenly otherwise there is a risk of rebound hypertension and withdrawal symptoms. Dose adjustment in 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.

Monitoring

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, itself has a potential to be the substance of abuse, and need to be a monitor 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, and as a result, it has much less restriction, and it is less risky to take it for abuse. Unfortunately, many 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 the addictions. Also, the synergistic potential of clonidine when mixed with other benzodiazepines, opioids, or alcohol, can give the individual more potent drowsiness and detachment from reality even further. It is important to notify the patients and try to screen for signs of dependency to clonidine as listed below:

  • Feel of the intense urge for clonidine
  • Feeling the need for the use of clonidine on regular basis
  • 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