Dexmedetomidine is an intravenous alpha-2 agonist used as a sedative infusion. It has some uniquely useful properties, particularly that it doesn’t suppress respiration (allowing it to be safely used in non-intubated patients). The main drawbacks of dexmedetomidine are logistic: it is expensive and can be administered only as an IV infusion within an ED or ICU. Oral clonidine offers some similar benefits compared to dexmedetomidine, without these logistic constraints.

Clonidine pharmacology

Pharmacodynamics & hemodynamics

Clonidine and dexmedetomidine stimulate several receptors, which may be summarized roughly as follows:

Imidazoline receptors : Causes hypotension

: Causes hypotension Alpha-1 : Causes peripheral vasoconstriction & hypertension

: Causes peripheral vasoconstriction & hypertension Alpha-2 receptors: Alpha-2A : Main therapeutic target, located in the prefrontal cortex and locus ceruleus of the brain. Stimulation reduces sympathetic tone, with sedative/hypnotic effects. Alpha-2B : Located peripherally, causes vasoconstriction. Alpha-2C : Located in striatum and hippocampus, unclear clinical effects.



Clonidine and dexmedetomidine have nearly identical psychiatric effects. The remainder of this section will focus on hemodynamics, which are rather complicated.

Hemodynamic effects depend on the relative selectivity for various receptor subtypes. Imidazoline and alpha-2A receptors tend to cause hypotension, whereas alpha-1 and alpha-2B receptors tend to increase blood pressure.

Clonidine generally causes bradycardia and hypotension. Compared to dexmedetomidine, clonidine exerts a greater effect on imidazoline receptors and therefore tends to cause more hypotension.

However, this is complicated:1

At lower doses, effects on imidazoline and alpha-2A receptors predominate, causing hypotension. At higher doses, clonidine may stimulate peripheral alpha-1 receptors, thereby causing vasoconstriction, which increases blood pressure. 2 This mechanism could serve to protect patients against uncontrolled hypotension if clonidine levels increase. A biphasic effect could explain why patients with clonidine overdose are usually bradycardic, but often maintain adequate blood pressure. 3

This mechanism could serve to protect patients against uncontrolled hypotension if clonidine levels increase. A biphasic effect could explain why patients with clonidine overdose are usually bradycardic, but often maintain adequate blood pressure. Clonidine may function as a catecholamine-sensitizing agent, based on its ability to up-regulate catecholamine receptors. Clonidine infusions seem to reduce the required dose of vasopressor. 4,5

Overall, clonidine often reduces the blood pressure, but it shouldn’t cause profound instability. If a patient experiences marked hemodynamic deterioration following clonidine, other problems should be sought (e.g. occult hypovolemia which was previously being compensated for with an endogenous sympathetic response).

Pharmacokinetics

For an oral agent, clonidine has very favorable pharmacokinetics:6

Bioavailability is excellent (~85%).

Absorption is rapid, with peak plasma levels within 60-90 minutes.

The half-life is 12 hours.

Roughly half is excreted by the kidneys and half is metabolized by the liver. Dual metabolism makes clonidine accumulation less likely if either organ fails.

Clonidine side-effects & contraindications

Like dexmedetomidine, the most concerning side-effects are bradycardia and hypotension. Therefore, clonidine is contraindicated in patients with hypotension, bradycardia, or heart block. Alternatively, if the patient has been able to tolerate dexmedetomidine, then clonidine is likely to be tolerated as well.

This side-effect profile isn’t entirely benign, but it is easily manageable. Critically ill patients are continuously monitored with telemetry. If clonidine causes bradycardia, this will be immediately obvious and can be treated with a peripheral infusion of epinephrine. The ability to manage excess sympatholysis in the ICU provides an added layer of safety, compared to prescribing clonidine on an outpatient basis.

Potential roles of oral clonidine in the ICU

Considerable experience exists regarding the use of clonidine among critically ill patients. For example, in Europe clonidine infusions are routinely used instead of dexmedetomidine infusions.7 Clonidine’s constellation of clinical effects (sedation, analgesia, anti-emetic, anti-shivering) make it potentially useful in a variety of situations.8–10

Compared to IV dexmedetomidine or IV clonidine, oral clonidine has unique strengths and weaknesses:

Strength: Oral clonidine is cheaper and easier to use, with the ability to continue it outside the ICU.

Weakness: Oral clonidine achieves a lower blood level compared to intravenous clonidine. For example, the maximal oral dose of clonidine is generally considered ~2.4 mg/day. This falls within the lower end of the dosing range for intravenous clonidine infusions. 11

Weakness: Oral clonidine requires longer to take effect, making it inadequate for control of acute agitation.

Sedation: Transition from dexmedetomidine infusion to oral clonidine

The main advantage of dexmedetomdine over clonidine is titratability (given the shorter half-life of dexmedetomidine). Once patients have been stably established on dexmedetomidine, they may be gradually transitioned to oral clonidine.12,13

The best description of this process is a prospective study of twenty patients undergoing transition from dexmedetomidine to clonidine.14 Patients on dexmedetomidine were started on 0.2-0.3 mg clonidine PO q6hr. Subsequently, clonidine was titrated within a range of 0.2-0.5 mg q6hr, with weaning of dexmedetomidine. Eventually once patients recovered, clonidine was weaned off. This strategy was generally successful, with 75% of patients able to discontinue dexmedetomidine within 48 hours of starting clonidine.

Insomnia & delirium prevention

Insomnia is a common problem in the ICU. Most drugs which are commonly used to treat insomnia cause delirium (e.g. benzodiazepines, antihistamines, zolpidem). There aren’t many great choices for treatment of insomnia in the ICU (although quetiapine and trazodone seem reasonable). Aside from simply treating insomnia, protecting sleep and preserving circadian rhythm might prevent delirium.

Recently nocturnal dexmedetomine infusions have been shown to prevent delirium.15 Dexmedetomidine theoretically is an ideal treatment for insomnia. However, cost and logistic constraints limit dexmedetomidine use to patients with dangerous nocturnal agitation or refractory delirium.

Clonidine offers a simple and inexpensive solution to this problem, which would mimic the action of dexmedetomidine.16 Clonidine is occasionally used as a sleep aide among outpatients, especially in pediatrics. Nocturnal use of clonidine (e.g. 0.1-0.3 mg an hour before sleep) could facilitate sleep and thereby promote retention of normal circadian rhythms.

Iatrogenic opioid withdrawal

Iatrogenic opioid withdrawal is a problem that we create. When exposed to a continuous opioid infusion, patients will become tolerant and dependent within several days. Subsequently, as patients are weaned off opioids, they may experience symptoms of withdrawal. A multimodal approach to pain in the ICU will greatly reduce this phenomenon, but it is still occasionally encountered.

Clonidine has proven efficacy in the treatment of opioid withdrawal.17 Clonidine has likewise been used to facilitate weaning off opioids in the pediatric and adult ICU.4,18 Using clonidine to taper patients off opioids entirely is probably preferable to transitioning patients to methadone.

Multimodal analgesia

Like dexmedetomidine, clonidine has weak analgesic properties.19–22 Clonidine may synergize with other analgesics, thereby reducing opioid requirements.23,24 More on this below.

Hypertension

One patient’s side-effect is another patient’s therapeutic effect. Clonidine is rarely used solely as an antihypertensive agent, because other more effective antihypertensives are available. However, clonidine could be an excellent choice for a patient with a combination of hypertension, pain, and anxiety.

Nuts & bolts guide to clonidine administration

Dosing for various indications

The doses listed below are based on published reports, but rigorous prospective dose-finding studies haven’t been performed. Therefore, these doses aren’t necessarily optimal. In practice, the dose should be titrated against clinical effects and hemodynamics.

Sedation De novo: Start 0.1-0.2 mg q6hr, may up-titrate to 0.5 mg q6hr if needed. 14,24 Transition from dexmedetomidine: Start 0.2-0.3 mg q6hr, may up-titrate to 0.5 mg q6hr if needed. 14

Insomnia Start 0.1-0.2 mg QHS, may up-titrate to 0.4 mg QHS.

Opioid withdrawal Most studies have used up to ~0.6-1.2 mg/day in divided doses, titrated against symptoms. 17 However, with ICU-level monitoring higher doses may be reasonable (e.g. ~2 mg/day in divided doses). 18

Multimodal analgesia Start 0.1-0.2 mg q12hr, may up-titrate to 0.3-0.4 mg q12hr. 9,25



Accelerated oral titration

Rapid absorption (within <2 hours) combined with an extended half-life (~12 hours) means that an accelerated oral titration may be used.26,27 The first dose is given (e.g. 0.2 mg), with careful observation for therapeutic or toxic effects. If the first dose is well tolerated but the patient doesn’t reach a therapeutic effect, then an additional dose (e.g. 0.1-0.2 mg) can be given after 2 hours. A maintenance dose (e.g. ~0.3-0.4 mg q12hr) may subsequently be continued.

Clonidine weaning

Once the patient is improving, clonidine should be weaned off. Weaning may be initiated in the ICU, but it will often extend beyond the patient’s ICU course. Weaning is important, because one potential pitfall of clonidine use is that it will be continued indefinitely. Clonidine withdrawal is possible, so if the patient is on a high dose then it shouldn’t be stopped abruptly.

Weaning can generally be achieved within several days, following the use of clonidine as a primary sedative agent.14 This involves gradually increasing the dosing interval, as tolerated. For example:

Day 0: Clonidine 0.3 mg q6hr

Day 1: Clonidine 0.3 mg q8hr

Day 2: Clonidine 0.3 mg q12hr

Day 3: Clonidine 0.3 mg daily before sleep

Day 4: Off

Loss of gut access?

What if the patient cannot take oral medication (e.g. prior to a procedure)? Clonidine can also be given sublingually with similar pharmacokinetics compared to enteral clonidine.28,29 This should be adequate to maintain clinical efficacy and prevent rebound symptoms.

Ketamine plus dexmedetomidine/clonidine (e.g., KetaDex)

The use of pain-dose ketamine infusions in critical care has become increasingly common over the last several years (0.1-0.3 mg/kg/hr). Such infusions offer mild to moderate analgesia with an outstanding side-effect profile.

There are several reasons that ketamine may synergize with an alpha-2 agonists to provide superior analgesia, with an improved safety margin:

Synergistic analgesia : Ketamine and alpha-2 agonists both have mild-moderate analgesic effects. The combination of an alpha-2 agonist plus ketamine provides more effective analgesia than either agent alone. 30–32

: Ketamine and alpha-2 agonists both have mild-moderate analgesic effects. The combination of an alpha-2 agonist plus ketamine provides more effective analgesia than either agent alone. Hemodynamic stability : Ketamine tends to increase the blood pressure by stimulating peripheral catecholamine release, whereas alpha-2 agonists tend to decrease blood pressure. The combination might be more hemodynamically stable than an alpha-2 agonist alone.

: Ketamine tends to increase the blood pressure by stimulating peripheral catecholamine release, whereas alpha-2 agonists tend to decrease blood pressure. The combination might be more hemodynamically stable than an alpha-2 agonist alone. Avoid psychomimetic side-effects : The main treatment-limiting side effect of ketamine infusions is psychomimetic side effects which can occur at higher doses (~0.2-0.3 mg/kg/hr). These side-effects are generally minor and easily managed by briefly stopping the infusion and then resuming at a lower dose. Alpha-2 agonists prevent ketamine-induced psychomimetic side-effects, thereby widening the margin of safety when employing ketamine. 33–37 For example, one small study found that clonidine dosed at 0.3 mg BID allowed patients to tolerate ketamine at 0.6 mg/kg/hr – a ketamine dose which should otherwise cause substantial psychomimetic effects. 25

: The main treatment-limiting side effect of ketamine infusions is psychomimetic side effects which can occur at higher doses (~0.2-0.3 mg/kg/hr). These side-effects are generally minor and easily managed by briefly stopping the infusion and then resuming at a lower dose. Alpha-2 agonists prevent ketamine-induced psychomimetic side-effects, thereby widening the margin of safety when employing ketamine. For example, one small study found that clonidine dosed at 0.3 mg BID allowed patients to tolerate ketamine at 0.6 mg/kg/hr – a ketamine dose which should otherwise cause substantial psychomimetic effects. Avoid tolerance? Within a few weeks, patients may develop tolerance to the sedative effects of alpha-2 agonists. 21 Animal models suggest that ketamine may prevent this tolerance, thereby maintaining ongoing efficacy of alpha-2 agonists over time. 38 Thus, it’s possible that ketamine could make dexmedetomidine a more effective and safer agent.

Overall, the combination of ketamine plus an alpha-2 agonist fits nicely into the paradigm of multimodal analgesia: low doses of multiple agents are used for synergistic efficacy, while avoiding the toxicity associated with higher doses of any individual drug. This is in contrast to older approaches to analgesia, which often consisted of snowing patients underneath superhuman doses of opioids.

Ketamine and dexmedetomine both preserve respiration and airway reflexes, allowing them to be used safely used in non-intubated patients. This combination (KetaDex) is excellent option for intubated patients who are approaching extubation. After the patient passes a spontaneous breathing trial, extubation can be performed immediately with continuation of KetaDex throughout the extubation procedure (unlike propofol, which is stopped prior to extubation). The ability of KetaDex to bridge the patient throughout the extubation period makes this smoother, especially for patients with anxiety or agitation.39

Guanfacine: Selective alpha-2A agonist

Guanfacine is a second-generation alpha-2 agonist. Compared to clonidine, guanfacine is a more selective agonist for alpha-2A receptors (compared to alpha-1, alpha-2B, alpha-2C, and imidazoline receptors). Guanfacine retains clonidine’s sedative/hypnotic properties, while causing less hypotension.40–46 However, guanfacine might be a less effective analgesic than clonidine, because some analgesic efficacy may be mediated through the alpha-2B and imidazoline receptors.41,47

From a pharmacokinetic standpoint, guanfacine is absorbed more slowly than clonidine (peak onset over 1-4 hours) with a longer half-life of 16 hours.40 The longer half-life of guanfacine reduces the incidence of rebound symptoms, because the drug auto-tapers itself.46 This longer half-life could allow once-daily dosing before sleep: maximal drug levels at night promote sleep, with some drug remaining during the day to provide a lesser degree of sedation. Outpatient studies have detected a ceiling effect on the antihypertensive effect of guanfacine, wherein doses of 1 mg, 2 mg, or 3 mg all have the same effect on blood pressure.48–50 This implies that up-titrating the guanfacine dose beyond 1 mg daily might increase sedative/hypnotic effects, without increasing hemodynamic instability.51

There is a thinner evidence basis for the use of guanfacine than clonidine, but some evidence does exist. Jose Maldonado at Stanford has utilized guanfacine for delirious/withdrawing patients as a clonidine-alternative with more stable hemodynamics (0.5-3 mg total daily dose).52 Efficacy in opioid withdrawal is well established.42 A recent case report described successful use of guanfacine (1 mg q12hr) to control refractory agitation in an ICU patient with a history of opioid misuse.44

Parting shot: Lofexidine, new fancy-pants alpha-2A agonist

Lofexidine is another selective alpha-2A agonist, similar to guanfacine.53 It’s an old drug, which the FDA didn’t approve for decades. The FDA finally did award it approval for opioid withdrawal this year, amid much fanfare. Lofexidine’s efficacy for withdrawal is equivalent to clonidine, but it causes less hypotension (similar to guanfacine).17 Unfortunately, in the United States lofexidine’s price is ridiculous (~$1,700 for a week’s supply versus guanfacine at under $50). Hopefully the price will come down, because it would be nice to have another alpha-2A agonist in our therapeutic arsenal (lofexidine does have some activity on serotonin receptors, which might give it a slightly different flavor than guanfacine).54

Central alpha-2 agonists (dexmedetomidine, clonidine, guanfacine, and lofexidine) have a variety of useful properties including sedation, analgesia, and treatment of opioid withdrawal.

Dexmedetomidine is the most commonly used agent among critically ill patients in the United States, given its titratability. However, once patients have stabilized on a dexmedetomidine infusion and are recovering from their critical illness, transition to oral clonidine may facilitate liberation from the ICU.

Oral clonidine may have additional roles in the ICU, including adjunctive management of pain, alleviation of opioid withdrawal, management of mild hypertension, and treatment of insomnia.

Ketamine synergizes nicely with alpha-2 agonists for treatment of pain. KetaDex (simultaneously infusions of dexmedetomidine and 0.1-0.3 mg/kg/hr ketamine) may be an excellent option for analgosedation of ICU patients who don’t require deep sedation.

Guanfacine is a more selective alpha-2A agonist with efficacy for opioid withdrawal and anxiety, but less effect on blood pressure than clonidine.

Lofexidine is a selective alpha-2A agonist which recently won FDA approval for opioid withdrawal. It seems very similar to guanfacine, except that it costs about forty times more. 54

Related

Reengineering the analgesic ladder for critically ill patients (PulmCrit)

Opioid-free ED with Sergey Motov (EMCrit) Note that KetaDex makes an appearance in some of the analgesic cocktails listed here.

References

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