Non-Opioid Pharmacology in Pediatric Pain Management

Alpha-2 Agonists in Pediatric Pain Management

By Vasili Chernishof, MD, Jocelyn Wong, MD, and Eugene Kim, MD
Division of Pain Medicine
Children’s Hospital Los Angeles
Keck School of Medicine
University of Southern California
Los Angeles, California

The α2 adrenergic receptor is a G protein-coupled receptor associated with Gi heterotrimeric G-protein. It responds with a higher affinity to norepinephrine, which is released by sympathetic postganglionic fibers, as well as circulating epinephrine released by the adrenal medulla. The α2 receptor can be found in abundance in the central and peripheral nervous systems, where it is classically located in the pre-junctional terminals. It inhibits the release of vesicles containing norepinephrine through negative feedback. Agonists of the α2 receptor can induce sedation, muscle relaxation, and analgesic effects on the central nervous system (1).  The α2 receptors can also be found on vascular smooth muscle cells, the gastrointestinal tract, and endocrine organs. In addition, α2 receptor activation can lead to transient hypertension, followed by sustained hypotension, inhibition of lipolysis (2), inhibition of insulin release (3), potentiation of glucagon release, contraction of sphincters of the gastrointestinal tract, decrease in salivary gland secretion (1), and platelet aggregation.

Over the years, various drugs with agonist and antagonist properties have been developed to target the α2 receptor. These drugs have been used for various indications such as sedation, anesthesia, treatment of hypertension, as well as psychiatric disorders such as depression, attention deficit hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder. We are going to focus on the two most used α2 agonists in pain practice today: clonidine and dexmedetomidine.

Clonidine
Clonidine is used to treat a variety of conditions as noted above in addition to the treatment of pain. By binding to the α2 adrenoreceptors in the brain stem, clonidine can result in reduction of sympathetic outflow from the central nervous system, which in turn can lead to decrease in peripheral vascular resistance, heart rate, and blood pressure. Clonidine can be used for the treatment of resistant hypertension (5).

Clonidine has also been used for the treatment of ADHD (4), but the exact mechanism remains unknown. It has been postulated that clonidine may regulate subcortical activity in the prefrontal cortex leading to reduced hyperactivity, impulsiveness, and distractibility. In the ICU setting, clonidine has been used to aid in sedation as well as to transition from dexmedetomidine in patients who are hemodynamically stable and able to receive enteral medications (6).

When given epidurally, clonidine can prevent transmission of pain from the spinal cord to the brain by binding spinal presynaptic and postjunctional α2 adrenoreceptors. Epidural clonidine carries a warning with regards to hemodynamic instability, especially hypotension and bradycardia (8). Clonidine can also be used as an adjunct to opioid agonists for relief of opioid withdrawal symptoms in patients with physiologic dependence on opioids undergoing supervised weaning in a medical setting (7).

Administration as an adjunct for peripheral nerve blocks, in a single-center database evaluation, clonidine showed a 20-50% increase in block duration in children (18). It is postulated that clonidine enhances peripheral nerve blockade by interfering with hyperpolarization cation currents (17). Published in 2016, a meta-analysis reviewed the data regarding the efficacy of α2 agonists as adjuncts in pediatric peripheral nerve blocks (19). The results showed beneficial effects of long block duration and a decreased need for supplemental analgesics during the first 24 postoperative hours. Of note, the results did not demonstrate any major adverse effects.

Clonidine is available as a transdermal patch, solution, immediate release oral tablet, and as an extended release tablet. The onset of action of the oral, immediate release formulation is 30 to 60 minutes, with 70-80% bioavailability. Time to peak is one-three hours. Clonidine is extensively metabolized by the liver to inactive metabolites and may undergo enterohepatic recirculation. The elimination half-life in children is about six hours, and in adults may be as high as 12-16 hours. Forty to sixty percent of clonidine is excreted in urine unchanged. Caution must be used in patients with severe renal impairment as the half-life may increase up to 41 hours. The transdermal formulation may take up to three days to reach steady state. Due to skin depot effect, half-life is extended up to 20 hours, and plasma concentration may continue to increase even after patch removal. Concerns regarding clonidine are related to its side-effect profile which include sedation, orthostatic hypotension, dry mouth, and constipation. Extreme caution should be used in patients with cardiovascular disease, cerebrovascular disease, or renal impairment.

The initial dose is dependent on route of administration and indication. Dose for single-injection as an adjunct for peripheral or neuraxial block administration range from 0.5-1 mg/kg (18). Infusions including epidurals can be started at 0.5 mcg/kg/hr and can be adjusted with caution based on clinical effects. Clonidine should not be discontinued abruptly. It is recommended to reduce the dose slowly to decrease risk of withdrawal in the form of rebound hypertension.

Dexmedetomidine
Dexmedetomidine is the pharmacologically active dextroisomer of medetomidine that displays specific and selective α2 adrenoceptor agonism. Compared to clonidine, which has a specificity of 220 : 1 (α2: α1 receptor), dexmedetomidine exhibits a much higher specificity for the α2 receptor, 1620 : 1 (α2: α1 receptor) (9).

Dexmedetomidine was approved by the Food and Drug Administration (FDA) in 1999 for short-term use (<24 hours) in the intensive care unit (ICU) for analgesia and sedation. Dexmedetomidine allows psychomotor function to be preserved while letting the patient rest comfortably. Patients are often sedated but remain arousable. It increases sleep efficiency and quality by reducing sleep fragmentation. Dexmedetomidine can be used to modify the 24-h sleep pattern by shifting sleep mainly to the night, partly restoring normal circadian rhythm (10). 

Dexmedetomidine can also be used for procedural sedation, as well as awake fiberoptic intubation (13). The role of dexmedetomidine in the peri-operative area has continued to expand to include pre-operative anxiolysis, prevention of emergence delirium, inhibition of shivering, management of difficult airway, as well as being used as an adjunct for general and regional anesthesia. The lack of respiratory depression is an enormous advantage over benzodiazepines and opioids. Although dexmedetomidine blunts the CO2 response curve, it does not lead to extreme hypoxia, or hypercapnia. Respiratory rate, CO2 tension, and oxygen saturation are generally maintained (14).

Taking advantage of the modest degree of analgesia, its opioid sparing effects (20), and lack of respiratory depression, dexmedetomidine can be used effectively for post-operative pain control in patients who are at increased risk of upper airway obstruction. Dexmedetomidine has been demonstrated to be safe and effective reducing pain in patients who have undergone craniofacial surgeries such as cleft palate repair (21), craniosynostosis (22), and tonsillectomy (23).

Dexmedetomidine is only available as a solution and should be administered as a single injection or via continuous IV infusion using a controlled infusion device. Depending on concomitant sedation agents and the patient’s current and desired level of sedation, a loading dose of 0.5-1 mcg/kg is often administered over ten minutes (11). Maintenance dose ranges between 0.2 to 1.5 mcg/kg/hour have been reported during randomized, controlled clinical trials (12).

Dexmedetomidine is metabolized extensively in the liver and is 94% protein bound. Both clearance and plasma protein binding are decreased in patients with hepatic impairment. Data from adults indicate limited effects of renal failure on the kinetics of dexmedetomidine (15). Episodes of bradycardia, hypotension, and sinus arrest have been associated with rapid IV administration. Caution should be used in patients with heart block, bradycardia, severe ventricular dysfunction, hypovolemia, or chronic hypertension. Administration of anticholinergics such as glycopyrrolate to increase heart rate during dexmedetomidine-induced bradycardia, have resulted in severe and persistent hypertension (16).

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