Background     Alpha-2 adrenergic receptor (α2-AR) agonists are a class of drugs used for a variety of indications including hypertension, pain, sedation, and opioid withdrawal (1-2). The most common α2-AR agonists are clonidine, dexmedetomidine, guanfacine, tizanidine, and lofexidine. This Fast Fact explores the use of α2-AR agonists in seriously ill patients. Other than for opioid withdrawal, their use in the seriously ill population is mostly as 2nd- and 3rd-line drugs.  

Pharmacology   Alpha-2 adrenergic receptors are G-protein coupled receptors found in both the central and peripheral nervous systems. α2-AR agonists have sedative, analgesic, anxiolytic, and sympatholytic effects (1-3).  

Clonidine has many potential uses in seriously ill patients, and is available orally, as a transdermal (TD) patch, and for intrathecal (IT) administration. IT clonidine is an FDA-approved adjunctive treatment for cancer-related pain (4-6) and, in combination with an IT opioid, has been shown to improve analgesia for patients with severe intractable pain (4-6). Limited evidence from a small number of studies suggests that clonidine can also be used to treat neuropathic pain either through TD patches (0.1-0.3 mg/day) or topically using compounded gel formulations (0.1% gel, applied up to three times daily) (4,6). Clonidine causes dry mouth and has been described in case reports as a treatment for sialorrhea via TD patch ranging from 0.1-0.3 mg/24 hr (7). Clonidine has anti-anxiety effects and is recommended in national guidelines for the management of withdrawal from opioids and alcohol, at doses of 0.1-0.3 mg every 6-8 hours, with a maximum daily dose of 1.2 mg (8,9). There is insufficient evidence for clonidine in the treatment of generalized anxiety, however there are anecdotal reports of anxiolytic effect with clonidine when used for attention deficit disorder or pre-operatively in the pediatric population (10,11). Finally, clonidine can be used to transition patients off dexmedetomidine infusions to an oral agent (12). 

Dexmedetomidine is used as an intravenous infusion and is mostly used in intensive care units as a sedative, anxiolytic, and analgesic (see Fast Facts #280 and 397). Based on case reports, a dexmedetomidine infusion in combination with opioids may help with refractory dyspnea at the end-of-life (13-15) at doses of 0.2-0.9 µg/kg/h (14). A key advantage of dexmedetomidine over other sedatives is that it can be adjusted to allow for wakefulness, and it does not depress respiratory drive.   

Guanfacine is an FDA-approved oral therapy for hypertension and pediatric attention deficit disorder. It is used off-label to treat anxiety and agitation mainly in adults. Several case series and a retrospective study have shown favorable outcomes for guanfacine in the reduction of behavioral agitation in hyperactive and mixed delirium, with a lower risk of bradycardia and hypotension than seen with clonidine or dexmedetomidine (16,17). Experts have used doses starting at 0.5-1 mg once or twice per day depending on delirium severity, titrated to effect, with dosing ranging from 0.5 to 4 mg/day (17). Oral guanfacine can be used in individual cases for dexmedetomidine weaning in the ICU and has been shown to be effective and safe at similar doses of 0.5-1 mg two to three times daily (18). A case report found guanfacine effective for severe anxiety and agitation following cardiac surgery (19). 

Tizanidine is used in the treatment of myofascial pain disorders, especially of the head and neck (1). It is FDA-approved for spasticity and muscle cramping for patients with cerebral palsy, amyotrophic lateral sclerosis, multiple sclerosis, or other spastic disorders (20). The recommended starting dose is 2-4 mg, dosed orally every 6-8 hours and titrated up to effect with the maximum daily dose not to exceed 36 mg in divided doses. Based on a few studies with limited evidence, it may also have a role in multimodal analgesia peri-operatively (21). 

Lofexidine is FDA-approved for the management of opioid withdrawal symptoms in adults (3). This selective α2-AR agonist has less risk for hypotension than clonidine. The initial starting dose is 0.54 mg four times daily, which can be titrated up to a maximum dose of 2.88 mg/day based on patient response and tolerability (22). 

Side Effects     All α2-AR agonists share potential side effects of hypotension, orthostatic hypotension, drowsiness, sedation, dizziness, dry mouth, and constipation. Clonidine, dexmedetomidine, and guanfacine also share risk of bradycardia and heart block. In general, oral α2-AR agonists should be gradually tapered (decrease dose by one-third every 3-7 days over a minimum of a 6-to-10-day interval) to avoid rebound hypertension and withdrawal symptoms. Oral clonidine ($0.05-$0.63/tablet), guanfacine ($0.87-$2/tablet) and tizanidine ($1.20-$8/tablet) are available in generic forms and are lower cost than other formulations. Extended release (clonidine $4-$22/tablet; guanfacine $11/tablet) or transdermal (clonidine $33-182/weekly patch) formulations have a higher cost per unit on average. 

Conclusion    α2-AR agonists may be utilized in patients with serious illness to palliate agitation, pain, dyspnea, opioid-withdrawal, and spasticity. Care should be taken to monitor closely for cardiovascular adverse effects. 

References 

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Disclosures: The authors do not have any relevant conflicts of interest to disclose. 
Authors’ Affiliations: MedStar Washington Hospital Center, Washington DC (KB); MedStar Harbor Hospital, Baltimore, MD (JB, PN); Georgetown University School of Medicine (PN)
Conflicts of Interest: None to disclose.